sindromul antisintetazic - umfiasi.ro de medicina... · cu pneumopatie organizata la o pacienta cu...

M E D I C R E Z I D E N T : G A V R I L E S C U L A U R A

I N D R U M A T O R : D R . Z U G R A V U G E O R G E T A

C O O R D O N A T O R A C T I V I T A T E D I D A C T I C A : C O N F D R E L E N A R E Z U S

SINDROMUL ANTISINTETAZIC

Spitalul Clinic de Recuperare Iasi, 18 mai 2016

DEFINITIE

Grup de boli autoimune cronice rare, aflate in stransa interrelatie, de etiologie necunoscuta, cu implicare organica multipla:

pulmonara(interstitiala),

musculara (miozita),

articulara (artrita inflamatorie non-eroziva),

microvasculara (fenomen Raynaud),

cutanata( „mana de mecanic”).

prezenta in ser a unor anticorpi ce recunosc aminoacil tARN sintetaza, familie de enzime intracitoplasmatice implicate in sinteza proteica

Antisynthetase syndrome: a review of etiopathogenesis, diagnosis and management.Mirrakhimov AE.Curr Med Chem. 2015;

EPIDEMIOLOGIE

Incidenta anuala a PM/DM : 2-10 cazuri/1 mil loc;

Prevalenta : 20-40% din totalul cazurilor de PM/DM

(prevalenta in populatia generala este necunoscuta);

Incidenta Sd anti Jo-1: 1,2-2,5/1 mil, prevalenta

1,5/100.000 loc;

Raport F/B: 2-3/1;

Varsta la debut: medie 50 ani (22-74).

Zampieri S, Ghirardello A, Iaccarino L, Tarricone E, Gambari PF, Doria A. Anti-Jo-1 antibodies.Autoimmunity. 2005 Imbert-Masseau A, Hamidou M, Agard C, Grolleau JY, Chérin P. Antisynthetase syndrome. Joint Bone Spine. 2003 Mileti LM, Strek ME, Niewold TB, Curran JJ, Sweiss NJ. Clinical characteristics of patients with anti-Jo-1 antibodies: a single center experience. J Clin Rheumatol. 2009

PATOGENIE

• Patofiziologia- predispozitia genetica (HLA-DRB1*0301, DQA1*0501 si DQB1*0201-factori de risc pt dezvoltarea Sd AS anti-Jo1), infectiile virale, medicatia.

• Aminoacil– tARN sintetaza catalizeaza legarea covalenta a unui singur aminoacid la ARNt specific in timpul translatiei din cadrul

sintezei proteice.

• ARNt sintetaze- 2 clase:

• I: asociate intr-un complex multienzimatic de 9 sintetaze care functioneaza impreuna;

• II: in forma libera in citoplasma

Antisynthetase syndrome: a review of etiopathogenesis, diagnosis and management.Mirrakhimov AE.Curr Med Chem. 2015; Galina S. Marder , Robert Greenwald, Antisynthetase Syndrome,The inflammatory myopathies, 2009

MECANISM DE ACTIUNE

TABLOU CLINIC

Miozita (> 90%)

Zsanett Csoma et al, Antisynthetase Syndrome: A Different Diagnosis to Dermatomyositis, Acta dermato-venereologica, 2012

http://www.medicaljournals.se/acta/index.php?option=com_content&view=article&id=3&Itemid=47

TABLOU CLINIC-CONTINUARE

Afectarea interstitiala pulmonara (60%)

• cauza majora de morbiditate

• severitatea si tipul afectarii pulmonare influenteaza

prognosticul

• poate aparea in absenta afect musculare (anti

PL12 -60%, Anti Jo1-20%, anti OJ-20%)

• tuse persistenta, durere pleurala, dispnee, scaderea

tolerantei la efort, insuf respiratorie

• degete hipocratice

Chatterjee et al, Antisynthetase syndrome: not just an inflammatory myopathy, 2013


Afectarea articulara(50%) • artralgii sau poliartrita

simetrica a articulatiilor mici de la nivelul mainilor si picioarelor, tipic neeroziva (in special cu subluxatii pe IFD), dar poate fi uneori eroziva si distructiva- deformari articulare

Afectarea cutanata

• Hiperkeratoza- „mana de mecanic”


G. E. Tzelepis et al. Eur Respir J 2008;

©2008 by European Respiratory Society

CT TORACIC, „MANA DE MECANIC”

PA C I E N T C U A C A N T I - J O 1


Alte manifestari

• Fen Raynaud

• Febra (~ 20%)- debut / recaderi

• Rash lupus like, DM-like

• GN mezangiala proliferativa- rara, prognostic bun

• Asociere maligna-

• Ac anti-Ro52/TRIM21 + Ac antisintetazici- fenotip

clinic distinct, caracterizat prin miozita severa si

afectare articulara; asocierea lor -risc crescut de cancer.


PARACLINIC

• Enzime musculare ↑(CK, aldolaza)

• Ac antisintetazici

• VSH,CRP ↑

• Emg: potentiale polifazice mici, amplitudine scazuta, fibrilatii spontane, varfuri pozitive in repaus, iritabilitate, descarcari repetitive de inalta frecventa.

• PFR (↓CV,↓CPT,↓DLCO)

• Rgf toracica, Rgf. articulare

• CT pulmonara de inalta rezolutie

• RMN musculara( hipersemnal), RMN articulara

• Biopsie musculara

• Biopsie pulmonara

• Biopsie cutanata


C. Biopsie cutanata. Atrofie epidermica usoara, degenerarea f.elastice, min. incontinenta pigmentara in straturile superf. dermice, infiltrat

perivascular limfocitic, mucina extracelulara.

D. Biopsie musculara. Variabilitate ↑ f.musculare, fibre degenerate, internalizare nucleara.

Zsanett Csoma et al, Antisynthetase Syndrome: A Different Diagnosis to Dermatomyositis, Acta dermato-venereologica, 2012


Pneumopatie interstitiala non specifica

cu pneumopatie organizata la o

pacienta cu SA.

A. Fibroza interstitiala difuza mutilanta

de tip PINS pred. centro-lobulara.

B , C. Numerosi burjoni fibrosi de

pneumopatie organizata in

compartimentul alveolar

Jouneau et al, Les manifestations pulmonaires du syndrome des antisynthétases

Revue des Maladies Respiratoires, Volume 32, Issue 6, 2015

A F E C T A R E I N T E R S T I T I A L A P U L M O N A R A - I N F I L T R A T I N T E R S T I T I A L C E L U L A R S I P N E U M O N I E O R G A N I Z A T A .

BIOPSIE PULMONARA

Solomon et al, Myositis-related interstitial lung disease and antisynthetase syndrome, 2011

HRCT: (A) OPACITATI CU ASPECT DE STICLĂ MATĂ (B) OPACITATI CU ASPECT DE STICLĂ MATĂ, FĂRĂ ATINGEREA ZONELOR SUBPLEURALE), (C) OPACITATI CU ASPECT DE STICLĂ MATĂ CU INGROSAREA SEPTURILOR INTERLOBULARE, (D) INGROSAREA SEPTURILOR INTERLOBULARE CU BRONSIECTAZIE SI TRACTIUNE, (E) INGROSARE SEPTALA BIBAZALA INTRALOBULARA (F) CONSOLIDARE PERIFERICA ASIMETRICA BIBAZALA

P A C I E N T , 6 6 A , A F . I N T E R S T . + F I B R O Z A . O P . B I L A T , N E R E G U L A T E , A S P E C T D E S T I C L A M A T A ( A L V E O L I T A A C T I V A ) , P R E D B A Z A L A , I N F I L T R A T E R E T I C U L A R E

S U B P L E U R A L E B I L A T E R A L E , I N G R O S A R E A S E P T U R I L O R I N T E R L O B U L A R E .

HRCT TORACIC


Nagarjuna et al, 2016 , Antisynthetase syndrome: An under-recognized cause of interstitial lung disease

SEROLOGIE

• Ac anti-Jo-1 este cel mai frecvent- 15-30% din pacientii cu polimiozita si

60-70% din pacientii cu afectare interstitiala pulmonara.

Jo-1(histidil)

PL-7(treonil)

PL-12(alanil)

OJ(izoleucil)

EJ(glicil)

KS(asparaginil)

Zo(fenilalanil)

HA(tirozil)

Gunawardena et al, Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression, Rheumatology 2009

a. Imunofluorescenta

b. Imunoprecipitare

1: normal serum;

2: anti-Jo-1;

3: anti-PL-12;

4: anti-PL-7;

5: anti-EJ;

6: anti-KS;

7: anti-OJ;

8: anti-Zo;

9: anti-SRP;

10: anti-Mi-2;

11: anti-SAE;

12: anti-155/140;

13: anti-p140.

ANTICORPII ANTI-AMINOACIL-TRNA SINTETAZA SI FENOTIPURILE CLINICE ASOCIATE


• 222 pacienti

• Prevalenta autoanticorpilor specifici miozitei-34.4%,

• Prevalenta autoanticorpilor asociati miozitei-41.4%

• anti-Ro-52 (36.9%)- cel mai frecvent

• anti-Jo-1 (18.9%),

• anti-Mi-2 (8.1%),

• anti-Ku (4.1%),

• anti-SRP (3.2%),

• anti-PL-7 (3.2%),

• anti-PL-12 (2.7%),

• anti-PM/Scl75 (2.7%)

• anti-PM/Scl100 (2.7%)

• Distributia autoAc comparabila intre polimiozita si dermatomiozita

• Prevalenta mai mare anti-Jo-1 in polimiozita, anti Mi-2 in dermatomiozita

CRITERII PROPUSE PENTRU DIAGNOSTICUL SINDROMULUI

ANTISINTETAZIC


DIAGNOSTIC DIFERENTIAL-1

Miozita

• Diselectrolitemii

• Miastenia gravis

• Miopatii

• PNP diabetica

• Distrofie musculara

Afectare int.pulm

• Pneumonie virala

• Fibroza p.idiopatica

• Edem pulm cardiogen

• Sarcoidoza

• Silicoza

• Histiocitoza

• Pneumocistoza

• Pn. int. limfocitica

DIAGNOSTIC DIFERENTIAL-2

Fenomen Raynaud

• Vasculita

• Trombangeita obliteranta

• Boala tromboembolica

• Boala vasculara periferica

• Livedo reticularis

• Acrocianoza

• Sclerodermie

• LES

• Crioglobulinemie

• Macroglobulinemia Waldenstrom

Af.musculara drog-indusa

• Alcool

• Antimalarice

• Clofibrat

• Colchicina

• Ketoconazol

• Statine

• Ciclosporina

• Cocaina

• Derivati Ergot

• Contraceptive Orale

• Bromocriptina

• IFN alfa

• Betablocante

• Antineoplazice

PROGNOSTIC

• Pacientii raspund de obicei la glucocorticoizi si terapie imunosupresoare.

Implicarea doar a musculaturii striate

• Daca pacientii dezvolta boala interstitiala pulmonara; prog -dat de severitatea si tipul leziunilor pulmonare.

• Evolutie progresiva a afectarii pulm. interstitiale

• Varsta inaintata la debut(>60 ani),

• Comorbiditati( neoplasme) ,

• Test pt ANA neg

Rezervat:


TRATAMENT

Glucocorticoizi

• Initiere – doze inalte 4-6 sapt;

• Reducere treptata 9-12 luni;

• Mentinere- cea mai mica doza eficienta pt a mentine remisia

• Pulsterapie (1 g iv. 3-5 zile)

• Miopatia indusa de corticoizi !

• Imbunatatirea fortei musculare- indicator mai fiabil al raspunsului terapeutic decat nivelul CK

• Osteoporoza – profilaxie cu antiresorbtive

• Profilaxie anti Pneumocystis jirovecii


Agenti imunosupresivi- slabiciune musculara profunda, AIP simptomatica

• Azatioprina (+ Prednison)

• Metotrexat (+ AZA)

• Ciclofosfamida- iv lunar- implicare pulmonara severa

• Tacrolimus –AIP, miozita asociata cu SA

• Ciclosporina- AIP

Rituximab- forme refractare, AIP refractara.

Ig iv in doze inalte- polimiozita refractara la GC, Ims

Masuri generale

• Fizioterapie si reabilitare – prevenirea pierderii de masa musculara si a contractiilor musculare

• Dismotilitate orofaringeana, esofagiana- prevenirea aspiratiei, alimentatie parenterala , jejunostoma

Chatterjee et al, Antisynthetase syndrome: not just an inflammatory myopathy, 2013 Bunch et al., Azathioprine with prednisone for polymyositis. A controlled, clinical trial. Ann Intern Med ,1980 Villalba L et al. Treatment of refractory myositis: a randomized crossover study of two new cytotoxic regimens. Arthritis Rheum 1998

CAZ CLINIC 1

• Pacienta, 61 ani

• APP: tiroidita Hashimoto

• CVM: confectii

• Ian. 2001- fen Raynaud, fara slabiciune musculara sau artralgii

• LDH: 628 (RV: 115–225);

• CK: 1041 (RV: 96–140);

• aldolaza: 20.6 (RV: 3–7);

• ALT: 20 (RV: 7–56);

• AST: 36 (RV: 5–40);

• FR: 12 (RV < 20),

• ANA: negativ;

• anti-Jo-1: pozitiv

• Rx toracica: fara modificari patologice

Corticoizi- normalizarea enzimelor musculare dupa 4 luni.

Ian. 2002- pacienta acuza dispnee

Rx . Toracica- infiltrat bazal pulmonar bilateral

Enzime musculare crescute

Mai 2002- CT toracic- aspect difuz de „sticla mata”

PFR: disfunctie ventilatorie restrictiva

De mentionat ca in acel moment, pacienta acuza febra.

2004- ingrosare interstitiala a lobului superior drept si ambele

baze pulmonare benzi dense

2007- agravarea simptomatologiei respiratorii+ modificari de

laborator- s-a initiat pulsterapie cu Ciclofosfamida lunar

sinovita la nivelul policelui bilateral, care a progresat spre o

subluxatie if police

Rx maini: spatiu articular carpometacarpian usor redus

Theilacker et al, Antisynthetase Syndrome: two case reports and literature review,

Revista brasileira de reumatologia, 2015

S U B L U X A T I E I F P O L I C E B I L A T E R A L

PACIENTA,61 A, ANTI JO-1+

Theilacker et al, Antisynthetase Syndrome: two case reports and literature review, Revista brasileira de reumatologia, 2015

CAZ CLINIC 2

• Pacienta, 78 ani, nascuta in Portugalia, fosta brodereasa

• Dermatomiozita-1980- corticoizi 11 ani remisia simptomelor (rash heliotrop, papule Gottron, fen. Raynaud, artralgii)

• In urma cu 5 ani, a prezentat o deformare a art IFD a primelor degete

• Rx maini 2009- semne de artroza IF bilaterala 2-5, IF police, rizartoza unilaterala si osteofite piramidale drepte- subluxatie if police bilateral

• CT toracic: discret pattern reticular, linii subpleurale, opacitati cu aspect de „sticla mata” la periferia pulmonilor

• Ac anti Jo-1 +


O P A C I T A T I C U A S P E C T D E „ S T I C L A M A T A ”

PACIENTA, 78 A, ANTI-JO1 +


CAZ CLINIC 3

• Pacienta, 21 a, rasa africana

• MI: ulcere digitale, fen Raynaud recent, RGE, artralgii, senzatie de ochi uscat

• Ex clinic, rx tx- normale

• In urmatoarele 2 luni a dezvoltat o dispnee progresiva asociata cu slabiciune

musculara(testing muscular 3+/5).

• Ex ap respirator- crepitante fine

• CT(HR)-pneumonie interstitiala difuza, pred. pattern „in fagure de miere”

• PFR- sindrom restrictiv (CV=26%, DLCO=26%)

• CPK=11 700 UI/l (N<160 UI/l)

• EMG- traseu tip miogen

• Biopsia musculara- infiltrat endomisial pred cu Ly B fara vasculita

• Imunohistochimia- supraexpresie difuza de MHC cls I, negativa pentru

complexul de atac membranar C5b9

• Eco cord-normal

• Capilaroscopia-cateva megacapilare

• Biopsia de glanda salivara- sialadenita limfocitica focala (Chisholm and

Mason score Grade III)

• CRP-N

• HB=9,9g/dl (beta-talasemie minora)

• Electroforeza- hipergamaglobulinemie policlonala(22 g/l)

• Imunfluorescenta- ANA+ (1/2560; aspect patat si nucleolar)

Anti-Ro/SSA +

Anti-La/SSB +

• Imuno-DOT- Ac anti –OJ +

• FR, ANCA- negativi

• Trat. imunosupresor- corticosteroizi (1 mg/kg/zi) + CYC pulsuri lunare

0,7g/mp-scadere treptata CS, CYC->AZA ( 2 mg/kg/zi)

• -dupa 41 luni:

• recuperarea fortei musculare,

• normalizarea CK,

• imbunatatirea fct pulmonare( CT toracic stationar, CV=46 %, DLCO=48 %)

• RGE- accentuare- esofag”de sticla”(CT toracic repetat)

• Aparitia sclerodactiliei (scor Rodnan=20), poikilodermie fara telangiectazii

sau maini de mecanic

• Fen Raynaud sever a persistat in ciuda utilizarii Ca-inhibitori, recidiva

ulcerelor digitale in fiecare iarna

Hervier et al, Anti-synthetase syndrome positive for anti-isoleucyl-tRNA synthetase antibodies: an unusual case overlapping with systemic sclerosis and Sjögren's syndrome , Rheumatology 2011

Pulmonar

Muscular

Esofagian Cutanat

Microvascular

CAZ CLINIC 4

• Pacienta, 65 a, se prezinta pt febra (38.5°C), tuse neproductiva, dispnee, senzatie de gat uscat, transpiratii nocturne, pierdere in greutate (3-4 kg).

• AHC: fara patologii cardiovasculare sau reumatice

• APP: HTAE, alergie la agenti de contrast • CVM: nefumatoare, expunere anterioara la fumat pasiv,

produse de curatare chimice

• Trat. de fond: Bisoprolol

• ECG: normala

• PFR: pattern restrictiv( CV=52%, VEMS= 56.3%, IT= 85.1%, DLCO-neefectuat(CV↓))

• RFG=48 ml/min

• CRP=18 mg/l (normal < 5 mg/dl),

• CK= 1402 U/l, CK-MB 45 U/l, • LDH= 335 U/l,

• NT-proBNP=426 pg/ml.

• ANA-negativi

C A R D I O M E G A L I E , A S P E C T R E T I C U L O N O D U L A R P U L M O N A R

RADIOGRAFIE TORACICA

Foris V, Kovacs G, Matucci-Cerinic M, et al., PL-7 positive antisynthetase syndrome and pulmonary hypertension. J Rheumatol 2013;

O P A C I T A T I „ S T I C L A M A T A ” , S E M N E D E F I B R O Z A

CT TORACIC

Foris V,Kovacs G, Matucci-Cerinic M, et al. PL-7 positive antisynthetase syndrome and pulmonary hypertension. J Rheumatol 2013;

• Lavaj bronhoalveolar- celularitate N

• Eco cord-↑presiunii arteriale sistolice pulmonare (42 + 10 mmHg).

Oxigenoterapie pe termen lung(1l/min)

Spironolactona(25 mg),

Furosemid (30 mg),

Prednisolon(25 mg)

Tiotropium inhalator

• dupa 2 luni-ameliorare (tuse seaca, normalizare CK), persistenta dispneei la efort

• cateterizarea cordului dr-↑PAPm si a rezistentei pulmonare, indexului cardiac( 2.61 l/min/min2), fara semne de disf. VS(PAWP 5 mm Hg)

• In urmatorii 4 ani:

Acetilcisteina(600 mg 3 cp/zi),

Spironolactona (50 mg/zi),

Ciclosporina(50 mg/zi),

Prednisolon(20 mg la 2 zile)

Oxigenoterapie

Fizioterapie

• Dupa 4 ani, pacienta se prezinta cu artrita urica, limitata la halucele dr.

• Ex clinic: semn Gaenslen +, fara alte semne de artrita sau fen Raynaud

• AngioCT, scintigrafie vent-perfuzie- au exclus TEP

• CK- N • Rx tx, PFR, scintigrafia pulmonara, polisomnografia- nemodificate

• Hemodinamica pulmonara- sever deteriorata

• Cateterism cord dr- HTAP manifesta asociata cu fibroza pulmonara (mPAP 34 mmHg, PVR 415 dyn s cm-5, PAWP 11 mmHg, IC 2.57 l/min/m2).

• Ac antiPL-7 + - dg Sd antisintetaza asociat cu BIP si HP

• Tratament - + Sildenafil 20 mg 3cp/zi

• Pe parcursul celor 2 ani de followup: • PL-7 +,

• capacitatea de efort↑,

• NT-proBNP -N,

• PFR neschimbate (FVC 52.6%, FEV1 49%, FEV1/FVC 91.2%, pO273.1 mmHg, pCO234.6 mmHg, SO296.7%).

Foris V,Kovacs G, Matucci-Cerinic M, et al. PL-7 positive antisynthetase syndrome and pulmonary hypertension. J Rheumatol 2013;

BIBLIOGRAFIE

1. Mirrakhimov AE, Antisynthetase syndrome: a review of etiopathogenesis, diagnosis and management.Curr Med Chem. 2015;

2. Zampieri S, Ghirardello A, Iaccarino L, Tarricone E, Gambari PF, Doria A. Anti-Jo-1 antibodies.Autoimmunity. 2005

3. Imbert-Masseau A, Hamidou M, Agard C, Grolleau JY, Chérin P. Antisynthetase syndrome. Joint Bone Spine. 2003

4. Mileti LM, Strek ME, Niewold TB, Curran JJ, Sweiss NJ. Clinical characteristics of patients with anti-Jo-1 antibodies: a single center experience. J Clin Rheumatol. 2009

5. Galina S. Marder , Robert Greenwald, Antisynthetase Syndrome,The inflammatory myopathies, 2009

6. Zsanett Csoma et al, Antisynthetase Syndrome: A Different Diagnosis to Dermatomyositis,

7. Acta dermato-venereologica, 2012

8. Chatterjee et al, Antisynthetase syndrome: not just an inflammatory myopathy, 2013

9. Nagarjuna et al, 2016 , Antisynthetase syndrome: An under-recognized cause of interstitial lung disease

10. Gunawardena et al, Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression, Rheumatology 2009

11. Solomon et al, Myositis-related interstitial lung disease and antisynthetase syndrome, 2011

12. Foris V, Kovacs G, Matucci-Cerinic M, et al., PL-7 positive antisynthetase syndrome and pulmonary hypertension. J Rheumatol 2013;

13. Hervier et al, Anti-synthetase syndrome positive for anti-isoleucyl-tRNA synthetase antibodies: an unusual case overlapping with systemic sclerosis and Sjögren's syndrome , Rheumatology 2011

14. M.P.Cruellas et al, Myositis-specific and myositis-associated autoantibody profiles and their clinical associations in a large series of patients with polymyositis and dermatomyositis,Clinics,2013

15. Theilacker et al, Antisynthetase Syndrome: two case reports and literature review, Revista Brasileira de Reumatologia (English Edition),2015


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