Rheumatology E-learning. University of Szeged Department of Rheumatology and Immunology

Transcription

1 Rheumatology E-learning University of Szeged Department of Rheumatology and Immunology

2 Overview Prototype autoimmune disease The most common and variable systemic autoimmune connective disease Female:male: 10:1 Prevalence: 1:2000 Typical age at onset: years More prevalent among people with African and Hispanic origin

3 Disease course, prognosis Course: fluctuating. Provoking factors (e.g. sunshine, infection, drug): exacerbation or flare or relapse After treatment: remission Active disease causes acuta organ failure (nephritis, cerebritis, arthritis, severe skin laesions, respiratory failure etc.) and may even cause death. Furthermore, it leads to irreversible damage (e.g. renal failure, deforming arthritis, lung fibrosis, finger necrosis, etc.) The aim of patient care: 1. prevent relapses 2. detect disease activity as early as possible (e.g. proteinuria, synovitis, pericardial rub, subtle cognitive decline), and treat effectively Prognosis: 10 year survival now is higher than 90% But: nephritis occurs in 40-50%, and end-stage renal failure develops still in about 10-15% of affected patients Irreversible damage (related to both disease and drug /corticosteroid!/ accumulates, and quality of life is still poor

4 Joint involvement in SLE Articular (polyarthritis / polyarthralgia) Most common manifestation (70-80% of patients) Symmetric, involving mostly the small joints Fingers, wrists > shoulders > feet, knees, elbows Joint pain, tenderness, swelling and reduced mobility Usually there is less swelling and shorter morning stiffness than in rheumatoid arthritis Pain is often severe In contrast with rheumatoid arthritis, there is no pannus, no cartilage and bone destruction (= nonerosive on radiograph) But may be deforming in many cases

5 SLE arthritis Deformities look like those in RA (ulnar deviation, swan neck, etc.) But: they are not fixed, but reducible, even hypermobile due to ligamentous laxity: Jaccoud s arthropathy:

6 Skin involvements Very common (> 50%) Acute: photosensitive rash, butterfly erythema, small vessel vasculitis (purpura or urticarial) Subacute: SCLE (subacute cutaneous LE) Chronic: discoid LE, livedo reticularis, panniculitis Photosensitive rash, butterfly erythema and SCLE are provoked by ultraviolet light (sunshine)

7 SLE butterfly erythema Erythematous plaque over the nose and the cheeks, but the nasolabial folds are spared

8 SLE photosensitive dermatitis

9 SLE photosensitive rash

10 Subacute cutaneous lupus Predilection sites: arms, upper torso

11 Note also the Jaccoud s arthropathy Severe subacute cutaneous LE provoked by sun-exposure

12 SLE discoid laesion

13 Discoid lupus erythematosus

14 SLE digital vasculitis

15 Haematological involvement Anaemia autoimmune, Coombs-positive haemolytic autoimmune myelopathy (decreased haematopoesis) non-haemolytic (anaemia of the chronic disease) Leukopenia, lymphopenia Thrombocytopenia

16 Haemolytic anaemia in SLE Normocytic, Coombs-positive, reticulocyte count high, Fe norm/high, LDH high, bilirubin high, haptoglobin low Chronic or acute haemolytic crisis Warm antibodies IgG phagocytosis extravascular sequestration in the spleen Cold antibodies IgM bind between 4-15 C complement activation intravascular haemolysis

17 Leukopenia in SLE WBC: < 4000/ul Lymphocyte: <1500 Activity sign! if WBC decreases, lupus flare may be suspected Anti-lymphocyte antibodies, accelerated apoptosis If a lupus patient presents with fever, other inflammatory symptoms: leukopenia helps in the differentiation from infection vs lupus flare Must be differentiated from myelosuppressive adverse effects of immunosuppressive drug (e.g. azathioprin, methotrexate, mycophenolate mofetil)

18 Thrombocytopenia in SLE May be chronic and mild-to-moderate (platelet count > 50 G/L) treatment may not be necessary In other cases, it may be acute and critical (platelet as low as < 5 G/L) immediate agressive immunosuppression is necessary Anti-platelet (GP IIb/IIIa complex) antibodies Fc-receptor-mediated phagocytosis in the spleen Diff. dg.: Antiphospholipid syndrome Drug adverse effect Infection Thrombotic thrombocytopenic purpura

19 Bone marrow histology from an SLE patient with fatal pancytopenia CD8-positive cytotoxic lymphocytic infiltration Megakariocyte hyperplasia

20 Serositis Pleuritis, pericarditis, ascites Pleuritis (prevalence in SLE: 30-40%) Sharp chest pain exacerbated by inspiration, cough Dyspnea Coughing Physical exam: Pleuritic rub Dullness on percussion, diminished respiratory sounds on auscultation

21 Pericarditis Prevalence in SLE: 30-40% Symptoms Dull or sharp retrosternal pain Increasing dyspnea Physical finding Pericardial rub (synchronous with heart sounds) Increased heart dullness with percussion Diminished heart sounds with auscultation If severe: dilated jugular veins, cyanosis, dyspnea, signs of heart failure Diagnosis: ECG, echocardiography If severe: emergency. Achieve quick dg and diff dg with physical exam, ECG and echocardiography, and administer corticosteroid. If not, pericardium drainage with puncture or surgical fenestration is performed, but with appropriate dg it can usually be prevented

22 Lupus nephritis Acute or chronic glomerulonephritis Prevalence in SLE: 40-50%! Key determinant of prognosis, organ damage and quality of life in SLE Progresses to end-stage renal disease in about 10% of affected patients Frequently diagnosed late urinalysis on every patient visit!

23 Lupus nephritis - symptoms Nephritis syndrome Proteinuria (>0,2 g/die) Microscopic haematuria (dysmorphous red blood cells) Leukocyturia ( sterile pyuria ) Cellular (red blood cell or white blood cell) casts Hypertension Renal function impairment Nephrotic syndrome Proteinuria > 3,5 g/die Hypalbuminaemia Hyperlipidaemia Oedema Nephroso-nephritis syndrome Asymptomatic proteinuria or microscopic haematuria

24 Lupus nephritis clinicopathological classification

25 Dysmorphous red blood cell Mickey mouse red blood cell Red blood cells with small ear or bud indicating that they have passed through the glomerulus. They always indicate glomerular disease! Simple but vital differentiation from lower urinary tract origin.

26 Red blood cell cast

27 Diffuse proliferative lupus GN Courtesy of Prof. Éva Kemény Éva (Dept of Pathology

28 Membranous lupus nephritis (ISN/RPN class V ) Courtesy of Prof. Kemény Éva (Dept of Pathology)

29 Vascular involvement is SLE Raynaud s phenomenon Livedo reticularis Arterial and venous thrombosis, pulmonary embolism (see: Antiphospholipid syndrome - APS), Vasculitis Accelerated atherosclerosis (APS)

30 Raynaud s phenomenon Transient white (one-phase), white and blue (twophase the most common) or white, blue and red (three-phase) discolouration of the fingers Often associated with pain, numbness this may be the presenting complaint, rather than the discolouration In severe cases: ulceration, gangrene may develop (especially in the most severe forms of Raynaud s, i.e. in systemic sclerosis, systemic vasculitis or antiphospholipid syndrome

31 Differential diagnosis of Raynaud s phenomenon Primary Raynaud s: no underlying disease. Vasomotor lability, vegetative dystonia, requires no specific treatment Secondary Raynaud s: there is an underlying disease involving the circulatory system Systemic connective tissue autoimmune disease (systemic sclerosis, SLE, systemic vasculitis, antiphospholipid syndrome, Sjögren s syndrome but: in rheumatoid arthritis: almost never) Thoracic outlet syndrome (compression) Hypothyreoidism, hyperthyreoidism Smoking, atherosclerosis, diabetes mellitus Hyperviscosity (paraproteinaemia, polycythaemia vera)

32 Raynaud s phenomenon

33 Digital ischaemia

34 Livedo reticularis If transient, provoked by cold: probably normal If fixed: severe microcirculatory abnormality e.g. antiphospholipid syndrome in this case, it may herald a subsequent vascular catastrophy, e.g stroke

35 Leukocytoclastic vasculitis Leukocytic infiltration, vessel wall necrosis, degradation of granulocytes Clinically presents as purpura or urticarial vasculitis Frequent in SLE, Sjögren s and small-vessel vasculitides (ANCA-associated or Henoch- Schönlein)

36 Purpura

37 Anti-phospholipid syndrome Arterial or venous thrombosis, repeated spontaneous abortion or intrauterine death caused by autoantibodies that promote thrombosis (antiphospholipid antibodies) Primary or secondary (associated with SLE, RA, infection or malignancy) Acute symptoms: Stroke, myocardium infarction, bowel infarction, hypadrenia, obliterative atherosclerosis, gangraene, deep venous thrombosis, pulmonary embolism. Chronic symptoms: Dementia, focal neurological signs, epilepsy, valvular heart disease, infertility, premature birth. Catastrophic anti-phospholipid syndrome simultaneous thrombosis in more than two organs Antibodies: anti-cardiolipin, anti-beta2-gpi, lupus anticoagulant (prolonged activated partial thromboplastin time) Must be suspected in every case with early vascular events, even if autoimmune symptoms are not present!

38 Pulmonary involvement Acute: lupus pneumonitis (e.g. lymphocytic interstitial pneumonitis - LIP, organizing pneumonia - OP) diffuse alveolitis diffuse pulmonary haemorrhage Chronic fibrosing alveolitis (non-specific interstitial pneumonitis NSIP) pulmonary hypertension shrinking lung syndrome

39 Acute lupus pneumonitis Progressive dyspnea Coughing Fever Often accompanied by pleuritis pleuritic chest pain Bilateral infiltrates on radiography and lung CT

40 Lymphocytic interstitial pneumonitis

41 Diffuse pulmonary haemorrhage Haemorrhagic alveolitis, alveolar capillaritis Acute, severe alveolar capillary wall damage Immune complex-deposition Acute dyspnea, coughing, rapid anaemia, haemoptoe Mortality: 40-80% Iv. methylprednisolone, iv. cyclophosphamide, plasmapheresis

42 Bilateral alveolar patchy infiltrates (alveolar filling) On histology: immune-complex deposition in the perialveolar interstitium

43

44 Central nervous system in SLE Anti-phospholipid-mediated Focal, ischaemic laesions Stroke, transverse myelitis, chronic cognitive decline Non-anti-phospholipid-mediated Diffuse cerebral dysfunction ( lupus-cerebritis ) Psychosis, altered mental status, epilepsy, headache

45 SLE further organ involvements Endocarditis, myocarditis Fever, low-grade fever Weight loss, chronic fatigue syndrome Myositis Oral ulceration Secondary Sjögren s syndrome Retinal vasculitis, episcleritis Autoimmune hepatitis Amenorrhaea, infertility, repeated spontaneous abortion, intrauterine death, premature birth

46 SLE laboratory changes Elevated ESR, but CRP is typically normal Cytopenia (anaemia, leukopenia, thrombopenia) Proteinuria, haematuria Antinuclear antibody (ANA) Anti-double-stranded DNA antibody (anti-dsdna) Extractable nuclear antibody (ENA) anti-ssa/ro, anti-ssb/la, anti-u1rnp, anti-sm Anti-phospholipid antibodies (anti-cardiolipin, anti-beta2- glycoprotein 1), lupus anticoagulant Anti-nucleosome, anti-c1q (nephritis!) Decreased complement-3 (C3), C4

47 ANA homogenous pattern Direct immunofluorescence: autoantibodies that bind to cell nucleus are visualized by radiolabelled antibodies screening method, and the exact autoantigen-specificity is determied by ELISA

48 ANA speckled pattern

49 ANA nucleolar pattern

50 ANA anti-centromere positivity

51 SLE pathogenesis I. Increased apoptosis (UV light, infection, drugs) INCREASED SUPPLY OF ANTIGEN (CHROMATIN) Impaired apoptosisregulation Complement-receptor 1 polymorphism Immune-complex clearance

52 SLE pathogenesis II. Viral and self nucleic acids activate the type- I interferon system through Toll-like receptors

53 Self-perpetuating circle of immunecomplex-mediated IFN-α activation and autoantibody production Key players: plasmocytoid dendritic cells, interferonalpha, autoantibodyproducing B-cells and plasma cells, Th2, Th17, and to lesser extent, Th1 cells Rönnblom L, Arthritis Rheum 2006;54:408

54 Effector pathways in analogy with Coombs-Gell classification of allergic pathways Activated Th0 (naive)- lymphocytes Activated Th2 lymphocytes B-lymphocytes plasma cells III. Immune-complex deposition: II. Direct autoantibodymediated cell Nephritis damage Vasculitis Dermatitis Cytopenia Anti-phospholipid-symptoms Myositis Th17 and Th1 effector T- cells IV. Predominantly cellmediated organ manifestations Arthritis Serositis Central nervous system symptoms Dermatitis Sec. Sjögren s syndrome

55

56 Management of SLE Lifestyle patient education: Avoid sunshine always use suncream when leaving home Oral anticoncipient: to be avoided in anti-phospholipid positive patients and during active disease Aim: control of flares, and preservation of remission During flares: corticosteroids and other immunosuppressants intensity is determined by the severity of flare (low-medium-high dose corticosteroid + methotrexate, cyclophosphamide, rituximab, intravenous immunoglobulin, plasmapheresis, etc.) After disease has become quiescent: tapering of corticosteroids, use of maintenance immunosuppression (hydroxychloroquine + less potent immunosuppressants e.g. azathioprin, methotrexate)

57 Treatment Mild cases (mild skin or joint involvement): NSAID, topical skin treatment, hydroxychloroquine Chloroquine, hydroxi-chloroquine Originally: antimicrobial agent against malaria Proven to reduce the frequency and severity of flares (current guidelines: lifelong antimalarial to every lupus patient!) Vitamin D Effective immunomodulatory agent: reduces autoimmunity, promotes antimicrobial defense Prevents osteoporosis mandatory if corticosteroids are administerd

58 Treatment II. Cases of intermediate severity E.g. serositis, cytopenia, marked skin or joint involvement, etc., but no involvement of vital organs (renal, pulmonary, central nervous system, cardiac) During active disease: corticosteroid (12-64 mg methylprednisolon) + azathioprin, methotrexate, cyclosporine, mycophenolate mofetil In remission: taper off corticosteroids, maintain other immunosuppressants for 3-5 years (+ antimalarial, Vitamin D3 lifelong)

59 Treatment III Severe, life-threatening organ involvements (carditis, nephritis, systemic vasculitis, cerebral manifestations): high-dose intravenous corticosteroid (500 mg methylprednisolone) + iv. cyclophosphamide Or: + rituximab (anti-cd20 monoclonal antibody) In critical situations: plasmapheresis or iv. immunoglobulin Maintenance: mycophenolate mofetil, tacrolimus cyclosporine (especially membranous nephritis, thrombocytopenia, myositis) belimumab (monoclonal antibody to the cytokine B-lymphocyte stimulator (BLyS)

60 Rituximab (anti-cd20) long-lasting B-cell depletion

61 B-lymphocyta stimulator (BLyS) or B- cell activating factor (BAFF) Cancro et al J Clin Invest 2009

62 Belimumab (anti-blys), the first approved biologic in lupus