Klinikai immunológia Systémás autoimmun kórképek Dr. Műzes Györgyi Semmelweis Egyetem, ÁOK II. Belklinika
Vasculitis: inflammation of the blood vessels blood vessel damage thickening of vessel wall attenuation of vessel wall luminal narrowing or occlusion vessel wall thinning tissue or organ ischemia aneurysm formation or disruption of the vessel wall with hemorrhage into tissues
Nosology of vasculitides (Jennette JC, Falk RJ: CHCC 2012) (AAV) (MPA) (GPA/WG) (EGPA/CSS) Arthritis Rheum 2013, 65: 1-11
Vasculitisek incidenciája /1.000.000 WG 4-13 CSS 1-5 MPA 5-15 HSP 6-11/100.000 PAN 5-10 Takayasu 1-2 GCA 15-35/100.000
Óriássejtes arteritis (GCA) és polymyalgia rheumatica (PMR) PMR * myalgia (vállöv, medenceöv) * felkarizomzat bilat. nyomási fájdalma * acut kezdet (< 2 hét) * We < 40 mm/h * reggeli merevségérzés (> 1 h) * kor > 65 év * depressio és/vagy fogyás * biopsia: granulomatosus vasculitis,óriássejtek poz.: 3 vagy > Th. (GCA, PMR): corticosteroid
GCA Arteritis temporalis vakságot okozhat!
Takayasu s arteritis (TA) chronic large vessel s vasculitis of unknown etiology age of onset is usually between 15-40 yrs. worldwide distribution, with the greatest prevalence in Asians women are affected in 80-90% of cases in Japan, 150 new cases occur each year; in the USA and EU, the incidence rate is 1-3 new cases/ year/million population association with HLA-Bw52 and HLA-B39.2
TA characteristic fundal coronary av anastamoses
TA: HISTOPATHOLOGY Cell-mediated mechanisms: infiltrating cells mainly consist of killer cells and gamma/delta T lymphocytes All layers of large arteries affected: inflammation granuloma formation giant cells
TA: CLINICAL MANIFESTATIONS I. Systemic symptoms: early phase fatigue malaise weight loss night sweats fever -low grade arthralgias ~ 55% myalgias
TA: CLINICAL MANIFESTATIONS II. Vascular compromise: late phase aneurysm formation and rupture vessel stenosis / occlusion -- ischemia catastrophic complications: aortic dissection/rupture aortic valve regurgitation hypertensive crisis MI
ARTERIES subclavian common carotid renal aortic arch/root vertebral pulmonary coronary MANIFESTATIONS arm claudication visual changes, syncope, TIA, headaches HTN, renal failure AI, CHF visual changes, dizziness dyspnea, hemoptysis chest pain, MI
TA: CLASSIFICATION CRITERIA (ACR, 1990) age of onset < 40 claudication of extremities decreased pulsation in 1 or both brachials >10mmHg SBP difference between arms bruit over 1 or both subclavian or abd. aorta angiographic narrowing of aorta or branches patients must meet at least 3 of the 6 criteria (sens.: 91 %, spec.: 98 %)
Polyarteritis nodosa (PAN) * fogyás (> 4 kg) * livedo raticularis * herefájdalom * diffus myalgia, izomgyengeség * mono/polyneuropathia * diastoles hypertonia (> 90 Hgmm) * BUN / Se-kr emelkedés * HBsAg pos. * kóros arteriogram (aneurysma) * biopsia: vasculitis (vegyes infiltr.) pozitív: 3 vagy >
Livedo reticularis
PAN
PAN - aneurysmák
Kawasaki betegség csecsemők vagy (8 év alatti) gyermekek hirtelen kezdődő lázas betegsége bőr, nyálhártya tünetekkel, nyirokcsomóduzzanattal és - ritkán myocardialis infarctussal Japánban aránylag gyakori, másutt igen ritka Patogenezis: vírus, Rickettsia, ill. bakteriális fertőzés eredetűnek tartják, de ennek egyértelmű bizonyítékai nincsenek. Szuperantigén-indukált eredet (?): Staphylococcus aureus vagy Streptococcus infekció, illetve kolonizáció talaján
Kawasaki betegség klasszifikációs kritériumai 1. Perzisztáló láz legalább 5 napig 2. Legalább 4 tünet az alábbiakból: a) nem exsudatív conjunctivalis belövelltség b) oropharynx elváltozásai: nyálkahártya erythema, vagy belövellt vagy száraz, berepedezett ajkak, vagy "málnanyelv c) végtagelváltozások: tenyér és talp erythemája, kéz és láb induratio, periungualis hámlás d) polymorf exanthema e) acut nonpurulens nyaki lymphadenopathia (egy vagy több, legalább 1.5 cm-es nyirokcsomó) Dg.: legalább 4 kritérium megléte esetén
málnanyelv
periungualis lemezes hámlás
MPA A proposed nomenclature for ANCA disease. GPA/WG EGPA/CSS 50-80 % 10-20 % -60 % 75-90 % Falk RJ, Jennette JC, JASN 2010;21:745-752
Perinuclear ANCA (panca)
ANCA in other diseases other autoimmune systemic diseases: SLE, rheumatoid arthritis, myositis inflammatory bowel disease: ulcerative colitis > Crohn s disease other autoimmune hepatobiliary diseases sclerosing cholangitis, autoimmune hepatitis infections: endocarditis, HIV drug-induced ANCA: hydralazine, propylthiouracil, D-penicillamine, minocycline, LTRAs
Epidemiology of AAV Average annual incidence for AVV: 21.8-22.6/1.000.000 Europe Japan GPA/WG: 14.3 2.1 MPA: 6.5 18.2 EGPA/CSS: 0.9 2.4 Geographical distribution Europe and USA Asia GPA/WG: northern areas rare MPA: southern areas frequent Age (yrs) and gender GPA/WG: 64-74 M > F MPA: 60-75 M > F EGPA/CSS: 40-60 M = F
Origin of ANCA Molecular mimicry of the autoag by a bacterial peptide Th1, Treg, Breg Falk RJ, Jennette JC, JASN 2010, 21: 745-752
Granulomatosis with polyangiitis (GPA/WG) classic disease: triad of organ involvement upper airways lower respiratory tract / lungs kidneys histology: granulomas and necrotizing vasculitis limited disease relatively mild and indolent without renal involvement histology: granulomatosis
GPA/WG: upper airway manifestations the most common presenting features (80-90 %) ear manifestations (25-60 %) otitis media nasal/paranasal diseases (30-64-80 %) saddle nose deformity perforated nasal septum mucosal ulcerations, epistaxis purulent nasal discharge nasal polyps sinusitis (30-85 %) laryngotracheal disease asymptomatic --- subglottic stenosis (16-48 %)
GPA/WG: pulmonary manifestations occur in 60-87 % main symptoms: cough, hemoptysis, pleuritis pulmonary infiltrates (67 %) nodules (58 %):multiple, bilateral, and often cavitate CT may reveal infiltrates and nodules undetected by conventional radiographs less common: pleural effusions, diffuse pulmonary hemorrhage (8 %, but with high mortality: 50 %), mediastinal or hilar lymphadenopathy
GPA/WG: renal manifestations presence or absence of renal disease defines the subsets of generalized and limited WG renal disease (GN, T-cell tubulitis, tubular atrophy) 11-18% at presentation 77-85% during the course early renal disease may be clinically silent! patients with the limited form later may develop glomerulonephritis renal disease may progress to fulminant GN within days or weeks may lead to chronic renal insufficiency (42 %) histologpathology: an independent predictor focal / crescentic / mixed / sclerotic
GPA/WG: further manifestations I. ocular: 28-58 % keratitis, conjunctivitis, scleritis, episcleritis, nasolacrimal duct obstruction, uveitis, retinal vessel occlusion, optic neuritis orbital /retroorbital pseudotumor, proptosis cutaneous: 40-50 % ulcers, palpable purpuras, subcutaneous nodules, papules, vesicles active skin lesions mainly indicate disease activity musculoskeletal: 30-60 % several joint patterns: monoarticular, migratory oligoarthritis, symmetric or asymmetric polyarthritis of small and large joints, and myalgy
GPA/WG: further manifestations II. neurologic: 10-50 % peripheral neuropathy: mononeuritis multiplex cranial neuropathy cerebrovascular eventes meningeal and periventricular white matter lesions cardiac: 5-15 % pericarditis myocarditis coronaritis, valvulitis gastrointestinal: < 10 % ulcerations, bleeding, perforations
Wegener granulomatosis (WG) (ACR, 1990) * orr- garat ulcerosus gyulladása * mellkas-rtg. eltérések (multiplex infiltr., cavitatio, nodulus-képződés) * veseérintettség (microscopos haematuria) * biopsia: granulomatosus vasculitis positív: 2 vagy > SENS.: 88.2 %, SPEC.: 92 %
Microscopic polyangiitis (MPA) MPA was first recognized as a distinct entity by Davson and colleagues in 1948 as a subgroup of polyarteritis nodosa (PAN), distinguished by the presence of segmental necrotizing glomerulonephritis The Chapel Hill International Consensus Criteria (1994) defined MPA as a necrotizing vasculitis (pauci-immune: with few or no deposits) affecting small vessels (i.e., capillaries, venules, or arterioles) frequently associated with necrotizing crescentic glomerulonephritis and pulmonary capillaritis
MPA: clinical manifestations constitutional symptoms 76-79 % fever 50-72 % renal 90-100 % musculoskeletal 28-65 % skin 40-70 % pulmonary 20-60 % neurologic 20-30 % ear /nose / throat 20-30 % heart 10-20 % GI-tract 10-30 % eye 10-30 %
MPA: pulmonary disease diffuse alveolar hemorrhage (DAH) is the most serious form of lung involvement (12-30 %) clinical manifestations of DAH range from mild dyspnea and anemia without any hemoptysis to massive hemorrhage and bleeding with profound hypoxia radiographic features of DAH are nonspecific, demonstrating patchy or diffuse alveolar infiltration (CT: more informative!) characteristic histopathology: pulmonary capillaritis
Eosinophilic granulomatosis with polyangiitis (EGPA/CSS) The syndrome defined by Churg and Strauss in 1951 is characterized by three histopathologic features: necrotizing vasculitis infiltration by eosinophils extravascular granulomas The Chapel Hill classification (1994) defined the disease as an eosinophilic granulomatous* inflammation involving the respiratory tract necrotizing vasculitis involving the small-sized vessels strongly associated with allergic rhinitis / asthma* and eosinophilia*
Churg-Strauss syndrome: bowel (photomicrograph)
EGPA/CSS: clinical phases The disease is characterized by three distinct clinical phases prodrome: dominated by allergic/atopic features (allergic rhinitis and asthma often precede the diagnosis of vasculitis by 3 to 7 years limited EGPA/CSS: patchy pulmonary infiltrates with tissue and peripheral eosinophilia systemic necrotizing vasculitis
EGPA/CSS: organ involvement upper airways (50-78 %) paranasal sinus abnormalities* pulmonary disease (35-75 %) migratory infiltrates* pleural effusions (often eosinophilic) pulmonary hemorrhage nervous system manifestation (40-80 %) peripheral neuropathy* renal disease (30-50 %) skin involvement (50-60 %) palpable purpura heart disease (15-48 %) GI-tract involvement (14-45 %) eye (< 10 %)
Churg-Strauss syndr. (CSS) * asthma bronchiale / rhinitis allergica * perifériás / szöveti eosinophilia (> 10 %) * paranasalis sinus eltérések * nem fix tüdőinfiltr.-k * mono/polyneuropathia * biopsia: granulomatosus vasculitis, eosinophil. positív: 4 vagy > SENS.: 85 %, SPEC.: 99.7 %
Shared features of ANCA-associated vasculitides Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg Strauss syndrome (CSS) can be considered together in view of a number of shared pathologic, clinical, and laboratory features preferentially involve small vessels (arterioles, capillaries, venules) similar glomerular lesions (crescents, focal necrosis, pauci-immune) propensity to present as lung-renal syndromes varying prevalence of ANCA positivity
Summary of AVV necrotizing granuloma GPA Wegener s sinusitis subglottic stenosis pulmonary nodules orbital pseudotumor pulmonary capillaritis glomerulonephritis neuropathy MPA ANCA Churg- Strauss EGPA eosinophilia asthma pulmonary infiltrates neuropathy myocarditis
(crescentic, pauci-immun, focal necrotizing)
AAV: principles of treatment general: rapid diagnosis, correct assessment of disease extent and activity if untreated high mortality (at 1 year: 80 %) pharmacotherapy: not curative! main aim: controlling disease activity by induction of remission prevention of relapse management of drug-toxicity
Induction of remission in AAV I. (2013) *localized: co-trimoxazol early systemic: high-dose glucocorticoid (GC) + methotrexate (MTX) or cyclophosphamide (CYC) generalized: hgc + CYC or anti-cd20 rituximab (RTX) or mycofenolate mofetil (MMF) severe: hgc + CYC or RTX + plasma exchange refractory: hgc + RTX / high-dose iv. immunoglobulin (IVIG)/ / MMF / gusperimus / infliximab (IFX) / / anti-cd52 (alemtuzumab) EGPA/CSS: RTX, IFNα
Induction of remission in AAV II. Drugs under investigation: anti-cd20 (ocrelizumab, ofatumumab) anti-blys (belimumab) anti-cd22 (epratuzumab) anti-cd28/b7 (abatacept) anti-il-6r (tocilizumab) proteasome inhibitor (bortezomib) C5aR-inhibitor (CCX168) EGPA/CSS: anti-il-5 (mepolizumab)
Maintenance of remission in AAV (2013) localized: co-trimoxazol systemic: lowgc + azathioprine (AZA) / MTX / MMF/ /leflunomid AAV: prognostic data (2012) 5-year-mortality: 25-28 % (highest in the first year!) main causes of death: < the first year: infections, active vasculitis > the first year: cardiovascular dis., malignancy, infections cumulative survival: at first year: 86-91 % at 2: 82-88 % at 5: 75-82 % *5-year-relapse rate: 38-50 %
Hypersensitív vasculitisek Leukocytoclastikus vasculitisek (korábban hypersensitiv vasculitis) az immunkomplex betegségek jellegzetes képviselői, (pl. sec. módon SLE-hez, rheumatoid arthritishez, Sjögren szindrómához társultan) Néhány formája önálló klinikai entitást képez: szérumbetegség cryoglobulinaemiás vasculitis cutan leukocytoclasticus vasculitisek Henoch-Schönlein purpura (más néven: anaphylactoid vagy allergiás purpura) hypocomplementaemiás urticaria vasculitis
Vasculitis (DIF): immunkomplex (IC) lerakódás
Henoch-Schönlein purpura (HSP) * palpálható purpura * abdominalis angina * kor < 20 év * biopsia: leukocytoclasticus vasculitis pozitív: 2 vagy > Th.: corticosteroid
HSP
Cryoglobulinaemiás vasculitis purpura, arthritis/arthralgia és glomerulonephritis jellemzi Cryoglobulinok: hidegben kicsapódó fehérjék I. típus: monoklonális (IgM, esetleg IgG) (myeloma, Waldenström macroglobulinaemia), II. (kevert) típus: monoklonális (RF aktivitású IgM) és polyklonális Ig(G) - ez a legritkább forma III. (kevert) típus: poliklonális IgG és IgM - ez a forma gyakori infekciókban (HCV!), ritkábban lymphomákban és autoimmun betegségekben. (az összes eset kb. 50 %-a)
Cutan leukocytoclasticus vasculitisek inkább idősebb korban: alsóvégtagi purpurák - kezdetben shubokban jelentkeznek, később állandósulnak részben gyógyszerek szedése után, részben bakteriális vagy más infekciók következtében differenciáldiagnosztika: - ANCA + vasculitisek (ANCA) - cryoglobulinaemiától (cryoglobulin: HCV, autoimmun kórképek) - Schönlein-Henoch purpura (IgA lerakódás)
Hypersensitiv vasculitis klasszifikációs kritériumok: 1. A betegség 16 éves kor felett kezdődött 2. Gyógyszerszedés a betegség kezdetekor 3. Tapintható purpura (thrombocyopeniával nem magyarázható, nyomásra el nem halványodó maculopapulosus purpura) 4. Maculopapulosus bőrkiütés 5. Biopszia (=granulocyták peri- vagy extravascularisan) Dg.: > 3 kritérium jelenléte esetén
Diagnostic approach to small vessel vasculitides Vasculitis suspected ANCA-associated No ANCA-associated Granulomatous IgA deposit Yes No Yes No Asthma/eosinophilia MPA HSP Cryoglobulins Yes No Yes No CSS WG Cryoglobulinemia Other