Systemic autoimmune diseases

Jan Novák

Systemic autoimmune diseases

Reaction against universaly expressed antigen

Infliction of several organs or organ systems Laboratory: FW, CRP, proteins of acute

phase

Systemic autoimmune diseases

Often infliction of joints, skin and kidney Sytemic symptoms including fever (Felty‘s syndrome, Still‘s disease) Pacients with systemic autoimmunity are

often examined with the diagnosis Fever of unknown origin Lymphadenopaty of unknown origin

Systemic autoimmune diseases

Often secondary diseases Polyarteritis nodosa – hepatitis B Polymyositis, dermatomyositis - tumors

Systemic lupus erytematosus - etiology Genetic predispozition: HLA A1-A8-DR3,

genes for complement Environmental factors – viruses (herpes, EB,

CMV) Drugs – hydralazin, prokainamid, INH Sex hormones 1:4000 Young women, 20-30 years

Systemic lupus erytematosus - pathogenesis Polyclonal activation of B cells Defect of apoptosis (experimetal model

lpr/lpr, gld/gld = Fas/FasL) Production of antibodies against DNA (ds

DNA), antinuclear antibodies and antibodies against nuclear antigens

Formation of immunocomplexes Defect of complement Immunopatologic rection of 2. a 3. type Vaskulitis

Systemic lupus erytematosus - lyboratory Production of antibodies against DNA (ds

DNA), antinuclear antibodies and antibodies against nuclear antigens (SS-A, SS-B), antibodies against fosfolipides and blood elements

Formation of immunocomplexes Decreased C3, C4 and total complement

(CH50) Hyperglobulinémia FW, CRP and proteins of acute phase

SLE - skin

SLE - symptoms

Perikarditis, myokarditis, endokarditisPleuritis, intersticial alveolitisVaskulitis of CNS – thrombosis, microembolisations, epilepsieLupus anticoagulans – APTT, antikardiolipin antibodies – thrombosis, leukopenie, trombopenie, anemiePolyarteritis, deformations, revmatoid artritislike

Intersticial nefiritis, mezangial glomerulonefritis (GN), fokal progrssing GN, difuse proliferative GN, membranoz GNAmyloidosis

SLE - therapy

Immunosuppression – glukokortikoids, azathioprin, cyklofosfamid, cyklosporin A

Antimalariks Plazmapheresis Symptomatic therapy Anti CD20

Revmatoid arthritis - etiology

Chronic, relapsing systemic inflamatory disease of joints

Destruction of joints, infliction of other organs Genetic risk – HLA DR1, HLA DR4 Environmental factors – viruses, bacteria??? 1-3% population females (2-3x)

Revmatoid arthritis - pathogenesis

Reaction of CD4 T lymfocytes and macrophages against antigens of synovial membrane

Secretion of antibodies IgM against Fc part of IgG (revamtoid factor, Latex), diagnostic importance, not pathogenetic

Vasculitis, synovitis

Revmatoid arthritis – laboratory findings Latex fixation test – detection of RF (IgM anti

IgG) FW, CRP, proteins of acute phase CIK, complement

Revmatoid arthritis – clinical findings MCP, PIP, RC joints Polyarticular symetric

affection Intumescens, synovial

thiskening, exudate, erosion of cartilage and bone by inflammatory tissue

Generation of contractures a deformations

Revmatoid arthritis – extraarthral findings Revmatoid noduses Tendosynovitis Keratokojunktivitis Intersticial lung processes Perikarditis, myokarditis, endokarditis Amyloidosis

Revmatoid arthritis – clonical course In a minority of patients long-lasting or

complete remissin spontaneous or drug-induced

Remisions – relapses Progressive course Kontractures, ankylosis, invalidization

Revmatoid arthritis – therapy Regime – prevention of contractures, rehabilitation NSA DMD – antimalarika, Au, sulfasalazin, metotrexát,

penicilamin, azathioprin, cyklofosfamid, prednison Infliximab Surgical – sinovectomy, joint replacement

Ankylosing spondilytis

HLA B27 Young men, 9x more than

females Sacroileitis Spondylartritis Clinical course – progressive

invalidisation Therapy: rehabilitation!, NSA,

metotrexát Extraarticular complications:

uveitis, entezitis, lung fibrosis, perikarditis

Sclerodermy – systemic sclerosis

Etiology unknown Detection of autoantibodies ANA,

anticentromeric antibodies Stimulation of fibroblasts Clinic – CREST: calcifications, Raynaud‘s

phenomenon, defect of motility of ezophagus, sklerodaktylie, teleangiektazie

Therapy – cyclophosphamid, D-penicilamin = minimal effect, progression

Polymyozitis, dermatomyozitis

Inflammatory diseases of sceletal muscles of unknown origin

Antibodies against nuclear and cytoplazmic components of cells (antisynthetase antibodies (anti Jo-1), ENA, ANA)

CK, LDH, ALT, AST Diagnosis – muscle biopsy

Polymyozitis, dermatomyozitis

In 20% association with cancer

Fatigue of proximal muscle groups

Intersticiál lung fibrosis etc. Therapy: Prednison,

Metotrexát, Cyklofosfamid, Cyklosporin A

Sjogren syndrome

Inflammation and destruction of exocrine glands

Pankreas, mucous, vaginal and bronchial glands

Secondary (RA, SLE, hepatitis) syndrome, primary = disease

9x more often females, HLA DR3 + RF, ENA SS-A, SS-B Therapy – substitution, corticosteroids

Case report

40 years old, healthy man

Case report

Pain of lower limbs the last 2 weeks Erythema of lower limbs Symetric oedema of LL Fever 2 days before admission

Personal history and physical examination PH: ok AA, SA, RA:

ok

Laboratory

FW 84/88, BC: ok, CRP 240. Biochemistry: ok Urine analysis: ok EKG ok Blood cultures and bacteriological survey wo

identification of microbial agent RF, autoantibodies and other immunologic

investigations ok

Case report

Chest X-ray ok Abdominal US ok TT + TE ECHO ok

Clinical course

3 weeks fever Exhaustion, immobility

ATB therapy

Penicilin, Ciprofloxacin Klacid Doxybene Klimicin + Gentamicin

Clinical course

Withdraw of ATB, improvement of clinical course

PET + CT

Clinical course

Muscle biopsy – inflammatory disease similar to polymyositis

Resection and biopsy of suspected lung focus

BALT lymphoma Complete remission

Vasculitis

Descriptive therm for the description of heterogenous inflammatory diseases of vessels (art, cap, ven)

Vasculitis

Vasculitis

Vasculitis - etiology

Primary vasculitis Secondary vasculitis

environmental antigens (infection, allergy, drugs, postiradition)

Self antigens (autoimmune disorders, Tu, GVHD)

Vasculitis - patophysiology

Inflammation of vascullar wall leading to the development of stenosis and aneurysma

Ischemia Immunology

type 3 IPR type 2 IPR Activation of endothel Coagulopathy

Vasculitis

Vasculitis - autoantigens

ANCA (antineutrophil cytoplasmic antibodies) proteinase 3 (PR3) myeloperoxidase (MPO) C (cytoplasmic) P (perinuclear) A (atypical) …….

AECA (antiendothelial cell antibodies) Colagen IV Infection Ag

Vasculitis - autoantigens

Wegener gr. C-ANCA, PR3-ANCA Microscopic polyangiitis MPO Goodpasture sy anti-GBM Ab (colagen IV)

3-15% ANCA Polyarteriitis nodosa P-ANCA

Symptomatology

General symptoms: fever, weight loss, fatigue, myalgia, arthralgia

„Organ specific symptoms“: Lung: hemoptysa, cough, dyspnoe, asthma, infiltration

of lungs (X-ray) ORL: sinusitis, otitis, deafness Skin: purpura, pyodermie, necrosis Eye: uveitis, iridocyclitis,episcleritis CNS a PNS: polyneuropatie, paresis, epileptic

paroxysms, psychotic features Renal: hypertension, proteinuria, erytrocyturia, renal

failure

Therapy of vasculitis

Induction Corticosteroids Cyclophosphamid Plasmapheresis ivig MoAb

Maintenance Corticosteroids Immunosupression

(azathioprin, MTX)

Wegener granulomatosis

Fever, weight loss, fatigue, sinusitis, pneumonia, cough, hemoptysis

Pulmonary infiltrates + glomerulonefritis

Wegenero granulomatosis - diagnosis

+ c-ANCA + anti-PR3

2/4 criteria Nasal/oral

inflammation Abnormal chest X-ray

findings Microhematuria Granulomatous

inflammation of small artheries (biopsy)

88% sensitivity, 92% specifity

Wegenerova granulomatosa – therapy + prognosis w/o therapy 100% deaths median survival 5

months Therapy 87% achieve remission after

corticosteroids + immunosuppression (53% relapses)

Vasculitis - syndoms

Kawasaki disease children Fever, conjunctivitis,

lymph node enlargement, scarlet exantema

15% vasculitis of coronary vessels

AEAb, ANCA, Vbeta 2,8 - superantigens

Goodpasture sy

pulmorenal sy anti-GBM nefritis anti-GBM Ab (colagen

IV) 3-15% ANCA

Vasculitis - syndoms

Churg-Strauss sy (Allergic granulomatous angiitis, AGA)

astma Lung infiltration capilaritis of lung vessels eosinofilia >1500 P-ANCA, MPO cca 50%

Polyarteriitis nodosa

Muscular arteries medium size

kidney, nerves, muscules, skin

(P-ANCA)

Vasculitis - syndoms

Henoch-Schonlein purpura purpura hemorhagic enteritis artritis nefritis Immune complex with IgA (similar to IgA

nephropathy – limited form of H-S) ANCA < 10%

Vasculitis - syndomy

Takayasu arteritis

Younger patients females:males 7:1

Aortal arch, renal arteries

Malignant hypertention ANCA negative

Horton temporal arteritis Older patients 3:2 polymyalgia rheumatica Carotis and its

branches amaurosis ANCA negativ

Vasculitis - syndoms

Behcet disease

Oral and genital ulceration iridocyklitis,uveitis Skin necrosis CNS involvement HLA B5

Buergerova choroba (trombangitis obliterans)

smokers Tromboflebitis migrans Vessels occlusions inflammation It is not a vasculitis, but

primary trombosis