PATH30190_CTD I_MH_2023.pdf

PATH30190 – Oncology/Immunopathology PATH30260 – Oncology & Rheumatology Connective Tissue Diseases I. (Rheumatoid arthritis vs other arthritides) Dr Melinda Halasz, MD, PhD Email: [email protected] 26 Mar & 2 Apr 2024 Learning Objectives At the end of this lecture, you should be able to Classif...

PATH30190 – Oncology/Immunopathology PATH30260 – Oncology & Rheumatology Connective Tissue Diseases I. (Rheumatoid arthritis vs other arthritides) Dr Melinda Halasz, MD, PhD Email: [email protected] 26 Mar & 2 Apr 2024 Learning Objectives At the end of this lecture, you should be able to Classify autoimmune diseases; Be familiar with the general characteristics and clinical course of systemic autoimmune diseases; Discuss the aetiology, clinical features, pathogenesis, diagnosis and treatment of rheumatoid arthritis (RA); Describe the pathology in the joints, and discuss the extra-articular manifestations of RA; Appreciate the importance of early diagnosis and early treatment of RA; Compare the pathogenesis, morphology, major joints affected and clinical course of RA and other arthritides (e.g., osteoarthritis). PATH30190 & PATH30260 CTI 2 Review Autoimmune Diseases Diseases in which the immune system mistakenly recognize self tissues as foreign and attacks them. Autoimmunity = presence of antibodies or T cells that react with self-antigens → NOT necessarily has pathogenic consequences; present in all individuals Mechanisms maintaining selective unresponsiveness to autoantigens: o Sequestration of self-antigens o Generation and maintenance of tolerance - Central deletion of autoreactive lymphocytes - Peripheral anergy of autoreactive lymphocytes - Receptor replacement in autoreactive lymphocytes o Regulatory mechanisms (e.g., regulatory T cells, regulatory cytokines etc.) If any of these mechanisms regulating immune tolerance fails and results in self-reactivity which causes tissue damage → AUTOIMMUNE DISEASE PATH30190 & PATH30260 CTI 3 Review Mechanisms of Tissue Damage in Autoimmune Diseases Autoantibody-mediated AND/OR T-cell-mediated Type II hypersensitivity Type III hypersensitivity Type IV hypersensitivity PATH30190 & PATH30260 CTI 4 Autoimmune Diseases Organ-specific ❑ ❑ ❑ ❑ ❑ ❑ ❑ ❑ ❑ ❑ ❑ ❑ ❑ Systemic = Connective Tissue Disease ❑ ❑ ❑ ❑ Graves’ disease Hashimoto’s thyroiditis Addison’s disease (autoimmune adrenalitis) Pernicious anaemia (autoimmune gastritis) Autoimmune haemolytic anaemia Vitiligo Myasthenia gravis Multiple sclerosis Primary biliary cirrhosis IBD Diabetes mellitus type 1 Goodpasture syndrome Etc. PATH30190 & PATH30260 Rheumatoid arthritis (RA) Systemic lupus erythematosus (SLE) Sjӧgren’s syndrome Dermatomyositis, polymyositis, inclusion-body myositis ❑ Systemic sclerosis/Scleroderma (SS) ❑ Mixed connective tissue diseases(MCTD)/Overlap syndromes/Sclerodermatomyositis ❑ Systemic vasculitis ▪ Polyarteritis nodosa ▪ Microscopic polyangiitis ▪ Wegener granulomatosis ▪ Churg-Strauss syndrome ▪ Takayasu arteritis ▪ Temporal arteritis ▪ Etc. CTI 5 Connective Tissue Diseases – General Characteristics o o o o o o o o o o Female predominance, middle-aged Genetic predisposition & environmental factors (e.g., infections) Multi-organ involvement, inflammatory signs Immunological abnormalities, e.g., autoantibodies Well-defined clinical picture and disease course Chronic Often fluctuate between periods of flares and remission Early diagnosis is crucial!!! Diagnostic criteria Severity = disease activity + damage (Scoring systems, e.g., DAS28 for RA) Environmental factors Genetic susceptibility PATH30190 & PATH30260 Immunological abnormalities [ Undifferentiated connective tissue disease (UCTD) ] CTI “Classic” autoimmune disease with clinical symptoms 6 Connective Tissue Diseases – Spectrum of Symptoms “UNUSUAL” ASSOCIATION OF SYMPTOMS o Fever of unknown origin RA o Elevated ESR and/or CRP o Polyarthritis o Skin symptoms (e.g., dermatitis, vasculitis, sclerodactyly, livedo reticularis etc.) o o o o o o o o o SLE Raynaud’s phenomenon Recurrent serositis (pleuritis, pericarditis) Scleroderma Proteinuria, haematuria Leukopaenia Sicca symptoms (dry eyes, dry mouth) Symmetrical proximal muscle pain / weakness of extremities Myositis “Unexplained” polyneuritis, neuropathy Symptoms of antiphospholipid syndrome (recurrent arterial venous thrombosis, spontaneous abortions etc.) Lung fibrosis or pulmonary arterial hypertension PATH30190 & PATH30260 CTI 7 Classification of Arthritides CTD IMMUNE MEDIATED INJURY NON-IMMUNE MEDIATED INJURY RA RA variants ❑ Juvenile idiopathic arthritis (JIA) ❑ Still’s disease (sJIA and adult-onset Still’s) ❑ Felty’s syndrome Secondary OA DEGENERATION ❑ Osteoarthritis (OA) SERONEGATIVE SPONDYLOARTHROPATHIES ❑ Ankylosing spondylitis ❑ Reactive arthritis/Reiter’s syndrome ❑ Enteropathic arthritis ❑ Psoriatic arthritis PATH30190 & PATH30260 CTI METABOLIC DERANGEMENTS (Crystal deposition) ❑ Gout ❑ Pseudogout (Chondrocalcinosis) INFECTION ❑ Septic Arthritis 8 Rheumatoid Arthritis (RA) Chronic systemic autoimmune inflammatory disorder that primarily attacks the synovial joints, producing a proliferative synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints. Prevalence: 1% Female : male = 3:1 Onset: 20 - 50 years (but JIA < 16y, EORA > 60y) VIDEO: https://www.youtube.com/watch?v=GZk6hqDII7k https://www.youtube.com/watch?v=g1oshTI1jsM PATH30190 & PATH30260 CTI 9 RA – Clinical Features Early RA Begins slowly and insidiously (60-80%) General symptoms: o Malaise o Weakness o Fatigue o Musculoskeletal pain ( 50% of patients) o Low-grade fever o Weight loss Inflammation of the joints, tendons and bursae o Swelling, “boggy” o Warmth o Pain o Tenderness (sore to touch) Early morning joint stiffness lasting more than 30 min that eases with physical activity Reduced joint function Deformities in advanced RA PATH30190 & PATH30260 CTI 10 RA – Joint Involvement Symmetrical polyarthritis DIP Hand involvement early in disease: → MCP and PIP joints are affected Small joints are affected before the larger ones (wrists, ankles, knees, elbows, shoulders) PIP MCP Hips and spine is usually spared Rarely upper cervical and temporomandibular joint Wrist PATH30190 & PATH30260 CTI 11 Joint Deformities in Advanced RA DIP - hyperextension PIP - flexion Radial deviation of wrist & Ulnar deviation of fingers Z-shaped thumb DIP - flexion PIP - hyperextension Volar subluxation 'Dinner fork' deformity PATH30190 & PATH30260 CTI 12 RA - Aetiology Unknown Environment–gene interactions promote loss of tolerance to self-proteins that contain a citrulline residue, which is generated by post-translational modification. Genetic predisposition o o o HLA-DR4 (DRB1 allele) PTPN22 PADI4 (Peptidyl Arginine Deiminase 4) Environmental factors o Smoking o Infections ? - Periodontitis (Porphyromonas gingivalis; Aggregatibacter actinomycetemcomitans) - Epstein-Barr virus o Gut microbiome o Dietary factors https://www.nejm.org/doi/full/10.1056/nejmra1004965 PATH30190 & PATH30260 CTI 13 RA - Pathogenesis Periodontitis ACPAs bind to citrullinated proteins and form immune complexes that can mediate local synovial inflammation by activating complement or Fc receptors for IgG (FcγRs) Production of anti-citrullinated protein antibodies Nature Reviews Immunology 15, 30–44 (2015) doi:10.1038/nri3785 PATH30190 & PATH30260 CTI 14 RA - Pathogenesis ❑ Cytokine-mediated inflammation, with helper T cells being the principal source of the cytokines ❑ Autoantibodies: - Anti-CCP = ACPA (anti-cyclic citrullinated peptides or anti-citrullinated protein antibodies) - Rheumatoid Factor (RF) (autoantibody against the Fc portion of IgG) PATH30190 & PATH30260 CTI 15 RA - Pathogenesis In synovium: Inflammatory synovium invades & destroys bone; this is mediated by osteoclasts. o Macrophages: → Inflammatory cytokines: TNFα, IL-1, IL-6 → Fibroblast-like synoviocytes (FLS) activation, proliferation: → RANKL → osteoclast activity → bone erosion → Proteases → cartilage degradation → FLS migrate from joint to joint → symmetrical arthritis o TH17 cells → IL-17 → Macrophages, FLS, RANKL → Inflammation o TH1 cells → IFNγ o Plasma cells → cytokines, Abs Cytokines: vascular permeability, adhesion molecules → angiogenesis In synovial fluid: o Immune complexes o Neutrophils → proteases, ROS → bone and cartilage degradation, inflammation PATH30190 & PATH30260 CTI Nature Reviews Immunology 7, 292-304 (2007) doi:10.1038/nri2062 16 RA - Pathogenesis In synovial fluid: o Immune complexes o Neutrophils → proteases, ROS → bone and cartilage degradation, inflammation Nature Reviews Rheumatology 10, 593–601 (2014) doi:10.1038/nrrheum.2014.80 PATH30190 & PATH30260 RA – Morphologic Alterations in the Joints o Destructive proliferative synovitis o Gross: oedematous, thickened, hyperplastic synovium covered by delicate and bulbous fronds o Micro: Synovial cell hyperplasia with finger-like projections; dense inflammatory infiltrates; increased vascularity; fibrinopurulent exudate on the synovial and joint surfaces; inflammation extends to subchondral bone (→ periarticular erosions, subchondral cysts) o Pannus formation (= oedematous synovium, inflammatory cells, granulation tissue and fibroblasts that grows over the articular cartilage) → Progressive degradation of cartilage → Fibrous ankylosis → Bony ankylosis o Joint deformities, subluxation and dislocation o Synovial cysts (Baker cyst - in the popliteal fossa) PATH30190 & PATH30260 CTI 18 RA – Joint Deformities Late-stage RA Note the symmetry of joint involvement! Volar subluxation of MCPJs → Prominence of metacarpal heads Ulnar deviation of fingers Rheumatoid nodules PATH30190 & PATH30260 CTI 19 RA - Extraarticular manifestations Skin: Firm, non-tender subcutaneous nodules (RHEUMATOID NODULES – 25% of patients: composed of central fibrinoid necrosis surrounded by epithelioid macrophages, lymphocytes, and granulation tissue) on extensor surfaces of forearms and elbows, but can also be found in heart valves, lung, pleura, pericardium, peritoneum and spleen Necrotising vasculitis due to circulating antigen-antibody complexes; e.g., digital arteries Infections Musculoskeletal: Osteoporosis, muscle atrophy, tunnel syndromes (nerve entrapment) Lungs: Pleuritis, bronchiolitis, interstitial fibrosis, nodules Heart: Pericardial effusions, myocardial infarction Cardiovascular disease Eye: Episcleritis, scleritis; keratoconjunctivitis sicca - Sjӧgren’s syndrome may be present in 15% Lymphadenopathy Vasculitis related peripheral neuropathy Liver: CRP, ESR, hepcidin → Anaemia Lymphoma Felty’s syndrome: RA + splenomegaly + neutropenia Caplan’s syndrome: RA + pneumoconiosis Secondary amyloidosis PATH30190 & PATH30260 CTI 20 RA - Extraarticular manifestations PATH30190 & PATH30260 CTI 21 RA - Diagnosis Based on 1) signs and symptoms of chronic inflammatory arthritis, together with 2) laboratory and 2020 ACR/EULAR (American College of Rheumatology / 3) radiographic results European League Against Rheumatism) classification criteria ACR/EULAR criteria (2020): Points for ❑ Joint Involvement ≥6/10 = definite RA ❑ Serology ❑ Acute phase reactants (CRP, ESR) ❑ Duration of symptoms Laboratory findings: ✓ Elevated CRP or ESR SEROLOGY: ✓ RheuMatoid factor (80%) ▪ Non-specific ▪ Autoantibodies (usually IgM) against IgG Fc portion ▪ Marker for activity ✓ ACPA / anti-CCP ▪ Specific PATH30190 & PATH30260 CTI 22 Figure 26-45 RA – Joint Deformities Intra-articular erosions Subluxations Diffuse osteopenia Joint space narrowing Periarticular bony erosions Ulnar drift of the fingers PATH30190 & PATH30260 CTI 23 Rheumatoid arthritis – Treatment Early recognition and treatment is important for achieving control of disease and prevention of joint injury and disability!!! COMBINATION THERAPY: short-term glucocorticoids + combination of DMARDs JOINT DESTRUCTION ❑ NSAIDs → to alleviate pain & inflammation ❑ Glucocorticoids → short-term, to control flares; E.g., Prednisone Untreated RA: Poor outcome ❑ DMARDs (Disease-Modifying AntiRheumatic Drugs) → to slow disease progress Window of E.g., Methotrexate, hydroxychloroquine, sulfasalazine, leflunomide opportunity ❑ Biologic DMARDs ❑ TNF-α inhibitors: mAb: Infliximab, adalimumab, golimumab, Treated RA: certolizumab pegol; decoy receptor: Etanercept Good outcome ❑ B-cell targeted therapy: anti-CD20 mAb - Rituximab ❑ Interleukin targeted therapy: IL-1R antagonist - Anakinra TIME anti-IL-6R mAb – Tocilizumab; IL17 inhibition - Secukinumab ❑ T-cell targeted therapy: Abatacept, belatacept – prevent APCs from delivering the co-stimulatory signal to T cell ❑ RANKL inhibitor – Denosumab; GM-CSF inhibitor - Mavrilimumab ❑ Small molecule kinase inhibitor against JAKs (Tofacitinib, baricitinib, filgotinib) PATH30190 & PATH30260 24 USMLE → Recommended to have a PPD skin test for tuberculosis prior starting therapy PATH30190 & PATH30260 CTI 25 USMLE RA Variants ❑ Felty’s syndrome = Seropositive RA + Splenomegaly + Neutropaenia ❑ Caplan’s syndrome = RA with pneumoconiosis In dust exposed persons ❑ w/ Sjӧgren’s syndrome (15%) ❑ Juvenile idiopathic arthritis (JIA) / JRA Age at onset: < 16 years VIDEO: https://www.youtube.com/watch?v=6Iq8EBAoDAw https://www.youtube.com/watch?v=E67Z6UER_Dc ❑ Still’s disease = Systemic onset JIA (sJIA) Age at onset: 0-5 years ❑ Adult-onset Still’s disease Age at onset: > 16 years PATH30190 & PATH30260 CTI 26 USMLE Juvenile Idiopathic Arthritis (JIA) ❑ Juvenile idiopathic arthritis (JIA) / JRA o Age at onset: < 16 years o Minimum duration: ≥ 6 weeks o 3 major types: - Oligoarticular: ≤ 4 joints in first 6 months after presentation; RF- , 60% ANA+; knee, ankle, wrist and/or elbow; 20% uveitis - Polyarticular: > 4 joints; small joints; 20% RF+ - Systemic JIA ❑ Still’s disease = Systemic JIA (sJIA) o 10-15% of all JIA o Onset: 0 -5 years of age; F : M = 1:1 o Arthritis in one or more joints (wrist, knee, ankle) o High spiking fevers o Transient salmon coloured macular rash o Lymphadenopathy o Hepatomegaly and/or splenomegaly o Serositis (pleuritis or pericarditis) PATH30190 & PATH30260 CTI 27 Classification of Arthritides IMMUNE MEDIATED INJURY NON-IMMUNE MEDIATED INJURY RA RA variants ❑ Juvenile idiopathic arthritis (JIA) ❑ Still’s disease (sJIA and adult-onset Still’s) ❑ Felty’s syndrome Secondary OA DEGENERATION ❑ Osteoarthritis (OA) SERONEGATIVE SPONDYLOARTHROPATHIES ❑ Ankylosing spondylitis ❑ Reactive arthritis/Reiter’s syndrome ❑ Enteropathic arthritis ❑ Psoriatic arthritis PATH30190 & PATH30260 CTI METABOLIC DERANGEMENTS (Crystal deposition) ❑ Gout ❑ Pseudogout (Chondrocalcinosis) INFECTION ❑ Septic Arthritis 28 Seronegative Spondyloarthropathies Group of diseases characterized by Absence of rheumatoid factor (→ seronegative); Involvement of sacroiliac joints (with or without arthritis in other peripheral joints) Association with HLA-B27 Pathologic changes begin in the enthesis rather than in the synovium Include: o Ankylosing spondylitis o Reactive arthritis o Psoriatic arthritis o Arthritis associated with inflammatory bowel disease (ulcerative colitis, Crohn’s disease) PATH30190 & PATH30260 CTI 29 Ankylosing Spondylitis (Rheumatoid spondylitis / Marie-Strümpell arthritis / Bechterew’s disease ) Seronegative chronic synovitis associated with destruction of articular cartilage and bony ankylosis usually involving the sacro-iliac and apophyseal (facet) joints Can cause fusion of vertebrae Male > female Onset: 20-30 years 90% HLA-B27+ PATH30190 & PATH30260 → ‘Bamboo spine’ CTI 30 Ankylosing Spondylitis Chronic dull pain in the lower back or gluteal region Morning lower back stiffness (at least 30 min) which improves with physical activity May occur in any part of the spine or the entire spine, in the sacroiliac joint, hips, shoulders and knees. Asymmetric As the disease progresses → loss of spinal mobility and chest expansion, with a limitation of anterior flexion, lateral flexion, and extension of the lumbar spine → Schober test Systemic disease: Uveitis, aortitis (→ aortic regurgitation), lung fibrosis May be associated with IBD (1-10%) Early diagnosis is important to prevent the development of irreversible deformity. PATH30190 & PATH30260 CTI 31 Reactive Arthritis (Reiter’s Syndrome) Defined by the triad of o Arthritis (Dactylitis – ‘sausage finger’, bony spurs) o Non-gonococcal urethritis or cervicitis o Conjunctivitis Mostly men, 20-40 years old 80% HLA-B27+ Onset often within weeks following infection of the gastrointestinal tract (Shigella, Salmonella, Yersinia, Campylobacter) or the genitourinary system (Chlamydia) +/- oral ulceration, heart block, aortic regurgitation 50% chronic resembling AS May be self-limiting, frequently recurring, chronic or progressive The episodes of arthritis usually wax and wane over a period of several weeks to 6 months. 15-50 % of affected individuals have recurrent arthritis, tendinitis, fasciitis, and lumbosacral pain that can cause significant functional disability. PATH30190 & PATH30260 CTI 32 Enteropathic Arthritis Occurs in ~20% of patients with IBD More commonly in CD than UC Axial arthritis – sacroiliitis and spondylitis: - Insidious onset of low back pain, - Morning stiffness, exacerbated by prolonged sitting or standing, improved by moderate activity, - Independent of GI symptoms Peripheral arthritis (non-deforming, non-erosive) in 10–50% of IBD patients. o Acute, self-limiting attacks, lasting less than 10 weeks; Asymmetrical and affecting large joints (knees, hips and shoulders); Strong correlation to IBD activity o Chronic, lasting months to years; More likely symmetrical, affecting small joints of the hands; Independent of bowel activity Enthesitis (heel, knee) Other extraintestinal manifestations seen in IBD in addition to arthropathy: uveitis, pyoderma gangrenosum, erythema nodosum, finger clubbing. PATH30190 & PATH30260 CTI 33 Psoriatic Arthritis Affects ~10% of patients with psoriasis at 20-40 years 90% seronegative (10% RF+) HLA-B27, HLA-Cw6 associated Joint involvement variable o Often starts with DIP joints o Dactylitis (sausage finger/toe) 33% o Also, ankles, knees, hips, SI and facet joints o Asymmetric o Histologically like RA but usually not as destructive o 5% get arthritis mutilans: osteolysis→ collapse of soft tissue causing “telescopic fingers” o Erosive - “pencil in cup” osteolysis Iritis and conjunctivitis PATH30190 & PATH30260 CTI 34 Psoriatic Arthritis PATH30190 & PATH30260 CTI 35 Seronegative Spondyloarthropathies PATH30190 & PATH30260 CTI 36 Classification of Arthritides IMMUNE MEDIATED INJURY NON-IMMUNE MEDIATED INJURY RA RA variants ❑ Juvenile idiopathic arthritis (JIA) ❑ Still’s disease (sJIA and adult-onset Still’s) ❑ Felty’s syndrome Secondary OA DEGENERATION ❑ Osteoarthritis (OA) SERONEGATIVE SPONDYLOARTHROPATHIES ❑ Ankylosing spondylitis ❑ Reactive arthritis/Reiter’s syndrome ❑ Enteropathic arthritis ❑ Psoriatic arthritis PATH30190 & PATH30260 CTI METABOLIC DERANGEMENTS (Crystal deposition) ❑ Gout ❑ Pseudogout (Chondrocalcinosis) INFECTION ❑ Septic Arthritis 37 Osteoarthritis (OA) Degenerative joint disease characterised by progressive erosion of articular cartilage Most common type of chronic joint disease. Risk increases with age – an ageing phenomenon (PRIMARY OA) Principally affects middle aged individuals and older adults Risk factors: Age > 50 years Obesity Previous joint injuries Lower leg deformity PATH30190 & PATH30260 CTI 38 OA – Signs and Symptoms Pain that worsens with movement and eases with rest, or if severe OA: pain at rest and at night Short-lived morning joint stiffness Crepitus (grating or popping sensation in the joint) Decreased range of movement Wasting of surrounding muscle groups Joint effusion Tenderness Compression of nerve roots (cervical spine) → Neurological deficits PATH30190 & PATH30260 CTI 39 OA – Joint Involvement Usually oligoarticular (few joints), but may be generalised Often asymmetrical Commonly involved joints: o Weight bearing joints Hips, knees, cervical & lumbar spine o Small joints of hands PIP joints (Bouchard’s nodes) DIP joints (Heberden’s nodes) 1st MCP joints o Small joints of the foot 1st MTP joint PATH30190 & PATH30260 CTI 40 OA - Pathogenesis Joint space narrowing “Bone on bone” Loss of articular cartilage Bone spurs osteophytes This series of images is from MedcoHealth PATH30190 & PATH30260 CTI 41 OA - Pathogenesis Arthroscopy Loose bodies: → Small pieces of cartilage or bone may break loose into the synovial fluid PATH30190 & PATH30260 CTI 42 OA - Pathogenesis o Granular soft articular surface (chondromalacia) S E V E R I T Y o Eburnation of underlying exposed bone (polished ivory surface) o Loose bodies (“joint mice”) o Cystic spaces of subchondral bone o Bone remodelling (mushroom-shaped osteophytes, bone spurs) o Joint deformity PATH30190 & PATH30260 CTI 43 OA - Pathogenesis Degenerative disorder of articular cartilage: (1) Chondrocyte injury, (due to ageing, genetic and biochemical factors); (2) Chondrocyte proliferation → inflammatory mediators, proteases, proteoglycans, collagen → remodelling, inflammatory changes; (3) Repetitive injury and chronic inflammation → chondrocyte drop out, progressive abrasive loss of articular cartilage, and extensive subchondral bone changes PATH30190 & PATH30260 CTI 44 OA - Pathogenesis Tissue damage → synovial macrophages, chondrocytes, T cells and synoviocytes → TNF, IL-1β and IL-6 Synoviocytes and macrophages → proteases (MMPs) → further cartilage degradation T cells and B cells are recruited by the cytokine milieu in the synovial fluid and contribute to local synovitis. Synovial macrophage → TGF-β, BMP → Osteoblasts →Subchondral sclerosis, osteophytes Osteophytes → IL-6 and RANKL → Osteoclast DOI: 10.1038/nrrheum.2013.44 PATH30190 & PATH30260 CTI 45 X-ray is diagnostic PATH30190 & PATH30260 OA – X-ray CTI Loss of joint space Osteophytes Subchondral sclerosis Subchondral cysts 46 Gout Inflammatory arthritis associated with hyperuricaemia and intraarticular sodium urate crystals Recurrent bouts of painful acute arthritis Most commonly affects metatarsophalangeal joint of first toe (PODAGRA) M > F, 40-60 years PATH30190 & PATH30260 CTI 47 Gout PRIMARY: 90% (Urate overproduction) o Diet o Enzyme defects (known and unknown) o Decreased excretion SECONDARY: 10% o Overproduction ▪ Increased cell turnover (Chemotherapy) ▪ Inborn errors of metabolism (Lesch-Nyhan syndrome) o Reduced excretion ▪ Chronic renal failure PATH30190 & PATH30260 CTI 48 Gout Raised plasma uric acid ( > 0.5 mmol/L) Deposition of monosodium urate crystals in joints Acute inflammatory monoarthritis - Repeated attacks (10%: more than one joint involved) Chronic tophaceous arthritis → Gouty tophi: deposits of crystals in the inflamed synovial membranes and periarticular tissue → Severe damage to the cartilage, joint destruction and deformity, skin ulceration Chronic complications: o Uric acid renal calculi o Renal failure - Gouty nephropathy (20% of mortality in gout) PATH30190 & PATH30260 CTI 49 Tophi Gout Joint aspiration shows needle shaped urate crystals which are negatively birefringent under polarized light PATH30190 & PATH30260 CTI 50 Pseudogout (Chondrocalcinosis/Calcium pyrophosphate dihydrate deposition disease) M : F = 1:1, > 50 years old Generally asymptomatic Acute pain and swelling in knee, wrist or shoulder (rare in small joints) Chondrocalcinosis - calcification of fibrous and hyaline cartilage → as deposits enlarge, they may rupture Intra-articular crystals ingested by macrophages → neutrophils recruited → precipitate acute synovitis May mimic RA or OA Associated with many metabolic diseases (e.g., diabetes, hypothyroidism, ochronosis) Associated with chronic electrolyte disturbances: o Hypophosphataemia o Hypomagnesaemia o Hyperparathyroidism o Haemochromatosis o Wilson’s o Alkaptonuria PATH30190 & PATH30260 CTI 51 Pseudogout Joint aspirate: o Weakly positively birefringent rhomboid crystals on polarisation o Intra or extracellular o May be cloudy and associated with fever and ↑ peripheral WCC o Exclude septic arthritis Treatment is supportive Responds well to intra-articular corticosteroid therapy Recurrent attacks uncommon PATH30190 & PATH30260 CTI 52 Septic Arthritis Infection in the joint → “Hot red monoarthritis” (primarily knee, hip or shoulder) o Direct inoculation through injury o Direct spread from adjacent infection o Haematogenous spread Staphylococcus aureus: older children and adults (prosthetic joint infections) → 50% mortality Neisseria gonorrhoeae: young adulthood, mainly in sexually active Haemophilus influenzae: in children < 2 years Gram negative bacilli: elderly Potentially joint destructive Medical emergency o Aspirate o Stain o Culture PATH30190 & PATH30260 CTI 53 Summary RA PATH30190 CTI PsA AS OA 54