Antinuclear autoantibodies in CTD.

Autoantibidy
Anti-ss-DNA

Antigen
Single strand DNA

Disease
SLE, MCTD, RA, SS, Drug induced LE, morphea SLE SLE SLE, lkov LE, RA, SSc, morphea

Anti-ds-DNA* Anti-Sm* Anti Histonov

Double strand DNA complex of proteins rich on RNA Histones

Anti-U1RNP
Anti-rRNP

complex of proteins rich on uridine

ribosomal phosphoproteins

RNA SLE, MCTD, SS SLE

Antinuclear autoantibodies in CTD.

Autoantibody
Anti-Ro/SSA Anti-La/SSB Anti-Jo1* Anti-Mi-2* Anti-RNA pol* Anti-PM-Scl Anti-Scl-70* Anti-Centromere* Anti-Fibrilarin*

Antigen
complex protein/RNA

Disease
SLE, SS, SSc, RA

complex phosphoprotein/ SLE, SS RNA-polymerase III histidyl tRNA syntetase PM/DM nuclear protein complex proteins/ RNA polymerase I-III DM SSc

nucleolar proteins
DNA topoizomerase I kinetochore proteins Part of U3RNP

SSc/PM
SSc SSc SSc

Specific cutaneous lesions of LE

(ie. with typical histopahtological picture of LE)
Acute (systemic) LE: erythema, maculopapular localized - diseminated Subacute LE: annular papulosquamous (psoriasis-like) Chronic LE: discoid: - localized - disseminated hypertrophic (verrucous) LE panniculitis (profundus) mucous LE lupus tumidus lupus pernio

Chronic (discoid, cutaneous, scarring) LE

Chronic (discoid) LE - annular

Chronic (discoid) LE cicatricial alopecia

Chronic (discoid) LE cicatricial alopecia

Chronic LE photosensitivity, inappropriate profession: roofer (tile layer)

Diagnostic criteria of SLE

(American Rheumatology Association = ARA) 1. 2. 3. 4. 5. 6. 7. 8. 9. butterfly erythema Cutaneous manifestations of LE (subacute, chronic) photosensitivity Mucous ulcerations (mouth, nose) polyarthritis, arthralgia, joint swelling serositis (pleuritis, perikariditis) renal (proteinuria > 0,5g/24 h, casts in urine sediment) CNS (spasms, neuropsychiatric symptoms) hematologic (hemolytic anemia, leukopenia, lymfopenia, thrombocytopenia) 10. imunology (anti-ds-DNA, anti-Sm ab., positive BWR) 11. Antinuklear autoantibodies Note. 4 criteria sufficient for diagnosis of SLE

Lupus band test (direct immunofluorescence) Ig (G)+ C3

SLE - urticaria -vasculitis

more burning and painful than itchy pertaine longer than 24 h leaving pigmentations.

splinter hemorrhagia

Subacute LE annular +anti-SSA/Ro and/or anti-SSB/La

bullous

Neonatal lupus erythematosus Mother (may be asymptomatic) positivity of anti-SSA/Ro and/or anti-SSB/La. Congenital heart block in 70% - anti SS-A52 cross react with conduction system - cardiostimulator

Subacute LE papulosquamous-psoriasiform

THERAPY cutaneous LE
Topical: photoprotection, cortikosteroids (external, intralesional), retinoids (tazaroten), pime/tacro-limus, lasers Systemic: if necessary First choice: antimalarics (OH-chlorochin, chlorochin, chlorochin+quinacrine) Second choice: retinoids, dapsone (vasculitis) Third choice: methotrexate, thalidomide, gold, clofazimine, Fourth choice: corticosteroids, azathioprine, cyclosporine, cyclofosfamide, IV imunoglobulins Experimental: alfa-interferon, UVA-1 fototerapy, anti-CD4 ab., topical tacrolimus

Classification dermatomyositis/polymyositis (DM/PM)

1. primary idiopathic PM 2. primary idiopathic adult DM 3. paraneoplastic DM (PM) 4. juvenile DM (PM) 5. DM (PM) accompanying other connective tissue diseases overlap syndrome 6. clinically amyopathic DM

Diagnostic criteria (Bohan a Peter)

dermatomyositis (DM) a polymyositis (PM)

1. muscle weekness - symetric proximal (shoulder and hip girdle muscles-combing hairs, climbing stairs), otherdysfagia, ptosis, hoarse voice 2. In serum signs of muscle damage: raised kreatinkinase (MM-izoenzymu), aldolase, transaminases, myoglobin 3. EMG: elektromyografic signs of myopathy 4. biopsy muscle with inflammatory myopathy (sono, MRI) 5. Cutaneous typical lesions in dermatomyositis Note: sure diagnosis = 1.-4. in PM, at least 3 criteria plus 5. criterium in DM, probable diagnosis = 3 criteria in PM, 2 criteria plus 5. Criterium in DM.

Eyelid edema and Livid erythema

Shawl sign

Papules and erythema over finger joints and knuckles

Nailfold teleangiectasia: On capilaroscopy giant capilaries avascular areas, bushy proliferation

Mechanics hands hyperkeratosis, fissures, ulcers

Muscle atrophy and weakness

Therapy - dermatomyositis
Systemic: cortikosteroids drug of choice combination with immunosupresives (mostly methotrexate), IV imunoglobulins Of cutaneous lesions: similar to lupus erythematosus Course and progonosis: Better with early diagnosis and treatment. In children in 50% complete remission, in 40 % prolonged therapy In adults mostly chronic therapy. Malignancy deteriorate prognosis.

Classification of scleroderma:
Localized scleroderma (morphea) systemic scleroderma

Overlap syndromes
Undifferentiated connective tissue diseases Scleroderma-like diseases (pseudoscleroderma)

MORPHEA SCLERODERMIA CIRCUMSCRIPTA LOCALIZED SCLERODERMA Classification

I. Morphea PLAQUE one(several) plaques disseminated, generalized II. Morphea LINEAR "en coup de sabre" hemiatrophia progressiva faciei III. Morphea PROFUNDA SUBCUTANEOUS morphea profunda fasciitis eosinophilica

I.

MORPHEA plaque
Plaque (to few plaques) Generalized Large plaque Guttate Bullous Nodular (keloid) Morphea pansclerotica Atrophodermia idiopathica progressiva PassiniPierini

Morphea
Inflammatory phase Orange peel appereance Livid erythema

Peripheral red-violet erythema (Lilac ring) Central ivory induration

Generalized morphea

Generalized morphea

Linear morphea

Linear morphea

Linear morphea

Linear morphea - flexion contracture

Linear morphea

Linear morphea

Linear morphea

Facial hemiatrophy

Deep morphea Eosinophilic fasciitis

Deep morphea

Deep morphea

THERAPY - morphea
corticosteroids, vitamin D analogs emolients fysiotherapy Systemic: in extensive involvement, functional defect phototherapy: PUVA therapy,, UVA1 methotrexate Corticosteroids (deep morphea) Others: vitamine E, penicillin, penicillamine, antimalarics Surgical: contractures Course and prognosis: duration 3-5 years. In deep and extensive morphea can be longer. Rarely flare (linear in 13 %). Persistent hyperpigmentation, disability, Topic:

Classification of scleroderma:
localized scleroderma (morphea) systemic scleroderma

overlap syndromes
Undifferentiated connective tissue diseases Scleroderma-like disease

SYSTEMIC SCLERODERMA CLASSIFICATION (acc. skin involvement)

LIMITED (acrosclerosis) Typ I - fingers (acroscleroderma digitalis) Typ II - fingers, forearms, arms (acrosclerodermia proximalis) - intermedial Typ III - trunk diffuse

DIFFUSE

MINIMAL (PRE-) SSc (Raynaud + capilaroscopy and/or ANA+) CREST (calcinosis,oesofagus,Raynaud, sklerodactyly, teleangiectasia) SCLERODERMIA SYSTEMICA SINE SCLERODERMIA

GIT involvement
SYSTEMIC SCLERODERMA
oropharynx (mikrostomie-glossie, shortened frenulum, alveolar resorption etc.) hypomotility/90%/ gastroesofageal reflux esophagitis Barrett.metaplasia stricture gastroparesis malabsorption dysmicrobia diarrhoea bleeding Perforation, volvulus pneumatosis cystoides intestinalis INVESTIGATION rx barium manometry scinti 99m Tc stools - fats, blood

LUNG INVOLVEMENT systemic scleroderma

- alveolitis - interstic. Fibrosis /53% rx, 92% functional/ - pulmonary hypertension - pleura (fluid,fibrosis..) - spontaneous pneumothorax - coincidence with pneumoconiosis - carcinoma - drug pneumonitis (CF, PNCA) -aspiration pneumonia INVESTIGATION
rx spirometry-restriction DLCO blood gas BAL HRCT scinti (67GA,99mTc-DTPA) biopsy

HEART INVOLVEMENT
systemic scleroderma
(in 50% on non-invasive investigation)

- pericarditis (autopsy 71%, symptomatic 7- 20%) - focal fibrosis of heart muscle (autopsy 89%) - fibrosis of conduction system - arythmias /ECG 50%/ - myocarditis - concentric intimal hypertrophy of coronary a.

INVESTIGATION:
ecg, echokardio, Holter, scintigraphy thalium 201, catetrization

KIDNEY INVOLVEMENT
systemic scleroderma
mild : 15 45% pacients
- proteinuria 500mg/24h - hypertension 140/90 - azotemia 9 mmol/1

serious :

3 10%

- chronic renal insufficiency - sklerodermic hypertensive renal crisis (8%)

ANTICENTROMERIC antibodies
(in 12-46% SSc)
(Antigenem jsou centromerov nehistonov proteiny: CENP-A 14-19kD, B 80, C 140, D 47) HLA-DR 1, 4, 5, DRw8, DQB1 Milder, chronic course no renal involvement Less lung, heart and skin May be serious pulmonary hypertension a GIT previous Raynaud phenomena Role in chromosamal breaks ?

SCL-70 antibodies
(in 18-83%)

antigen: DNA topoizomerase I (non-histone protein 70-100kD) HLA-DR 2, 5, DQB1

more serious, shorter course more extensive skin involvement more frequent lung, heart, renal involvement

Systemic scleroderma
classification criteria (ARA)
MAIN: (one is sufficient) proximal scleroderma
OTHER: ( 2 of 3) sklerodactyly Pitting scars on fingers

Bilateral interstitial lung fibrosis

(rx)
Masi AT, et al., Arthritis Rheum, 1980, 23, 581

THERAPY- systemic scleroderma:

no causal drug - symptomatic, organ directed therapy Vasoactive drugs: rheological (pentoxiphyllin), vasodilatation (calcium chanel blocators, prostaglandins), antihypertensives (ACE). Antiinflammatory: NSA, glukokortikosteroids, imunosupresives (cyclophosphamide, azamune, methotrexate). Antifibrotic: penicillamine, interferons, penicilin, extrakorporal phtopheresis. General care of pacient: positive approach to disesase, stop smoking, warm enviroment, massage, exercise, prevention of ed trauma and cold. Course and prognosis: limeted SSc 5 years survival from diagnosis 75-84%, diffuse SSc 34-50%.

Klasifikace sklerodermie:

lokalizovan sklerodermie (morphea) systmov sklerodermie pekryvn syndromy nediferencovan onemocnn pojiva pseudosklerodermie

SYSTMOV SKLERODERMIE
je difuzn onemocnn pojiva a drobnch cv
charakterizovan vznikem fibrzy a vaskulrn

obliterace postihujc pedevm ki,

gastrointestinln trakt, plce, srdce a ledviny. Tuh ke je pitom jeho hlavnm klinickm pznakem, orgnov postien nejdleitjm prognostickm ukazatelem.

Limitovan systmov sklerodermie

(acrosclerosis)
Raynaudv fenomn trvajc roky a desetilet, tu ke aker (ruce, nohy, pedlokt, brce, hlava, krk) me i chybt pozdn vskyt plicn hypertenze (s i bez intersticiln plicn fibrzy), kon kalcifikace, teleangiektazie, GIT postien, kapilaroskopie - ektazie kapilr bez vrazn redukce potu anticentromerov protiltky
tork J: Sklerodermie, Galn, 1996

Difzn systmov sklerodermie

Raynaudv fenomn trv krtce do 1 roku tuh ke - trupu, pa a aker, krepitace lach orgny - asn a vrazn intersticiln plicn fibrza, GIT, ev. ledvin, srdce kapilaroskopie - vrazn ektazie, redukce potu, avaskulrn zny anti Scl-70 protiltky
tork J: Sklerodermie, Galn, 1996

Subacute LE annular +anti-SSA/Ro and/or anti-SSB/La