Boala mixta de tesut conjunctiv - 2012

Descrisa de Sharp in 1972

Asociere de caracteristici comune cu LES, SD, PM

Prezenta in titru crescut a Ac anti-RNP astazi definiti ca

Ac anti U1-RNP

Boala mixta de tesut conjunctiv

Sindromul Overlap ( Overlap Syndromes ) caracterizeaza pacienti

care intrunesc criterii pentru mai multe boli de tesut conjunctiv
( ex: LES+PR, Scl+PM, CREST+CBP ).
Boala nediferentiata de tesut conjunctiv - se refera la pacienti
care nu intrunesc suficiente argumente diagnostice pentru nici
una din bolile de tesut conjunctiv .
Boala mixta de tesut conjunctiv este o entitate clinica distincta
definita pe baza argumentelor genetice, serologice si clinice.

Epidemiologie

Mai frecventa la femei

10/1

=> 15/1

Vrsta de aparitie poate varia; media la 15-30 ani

Prevalenta = ??
2,7-10 :100.000 (Japonia)
Peste DM (1,5/1000.000) , sub LES (20/100.000)

Nu exista date despre o predispozitie etnica sau de rasa

Etiopatogenie
Factori de mediu
- siliciul
- clorura de vinil
- retrovirusuri animale cu similitudini structurale cu U1-RNP
Terenul genetic
- HLA DR2 si DR4
Factori hormonali
Mecanismul leziunilor este imun cu implicarea directa a Ac anti U1 RNP
=>Hiperactiv cel B => Ac anti U1 RNP
=> ipoteza: individ genetic predispus (HLA DRB1*04) dezvolta un raspuns imun
impotriva unui antigen microbian (glicoproteina CMV) ce reactioneaza
incrucisat cu peptidul U1 70 KD

Boala mixta de tesut conjunctivRolul Ac ani U1 RNP

Prezenta Ac anti U1-RNP este definitorie pentru BMTC

Prima constatare poate fi doar un titru crescut de Ac antinucleari (ANA) cu
patern patat in titru crescut
Au patern patat Ac anti Sm , Ac anti U1-RNP, anti Ro, anti La
Uneori la debut pot fi prezenti in titru scazut Ac anti Ro, anti Sm,
anti ADNdc
Spectrul clinic al bolii depinde de persistenta la titru inalt a Ac anti U1-RNP
U1-RNP = ARN bogat in uridina complexat cu trei polipeptide A, C si 70 kD

DAYS OF OUR LIFE!!

Tablou clinic - Debut

De regula insidios: astenie fizic, mialgii, artralgii, febra

Fenomen Raynaud (Maurice Raynaud1862=> W,B,R)
Sclerodactilia
Artrite
Mai rar: - nevralgie trigeminala
- polimiozita
- artrita acuta
- gangrene digitale

Tablou clinic

Manifestari generale:
Febra, astenia fizica

Manifestari cutaneomucoase:
edem al mainilor, rash,
macule eritematoase
la baza degetelor

Fenomenul Raynaud
70-90%
-capilaroscopie

Sd Raynaud
1. Ac antinucleari, Ac anti centr.,Ac anti Scl70
2.Capilaroscopie +++
3.BRGE
4.Puffy fingers
5.Tendon friction rubs
6. Varsta >30, sex M, necroze

Tablou clinic

Manifestari articulare: - artrite nespecifice MCF si IFP

- neerozive, nemutilante
- tenosinovite ale flexorilor
Manifestari musculare: - Mialgia de regula - fara slabiciune
musculara, enzime, modificari EMG
- Miozita de tipul afectarii din PM
Manifestari digestive: - 1/3 inferioara a esofagului => BRGE
- vasculita mezenterica,pseudodiverticuli

Tablou clinic

Manifestari pulmonare (80%)

- fibroza pulmonara interstitiala -sindrom restrictiv cu scaderea
TLCO
- hipertensiunea pulmonara principala cauza de mortalitate
- afectare pleurala revarsate pleurale mici
- pneumonie de aspiratie
- tromboembolii
- infectii

Tablou clinic
Manifestari cardiovasculare - pericardita, cu risc de tamponada
- miocardita
Manifestari renale - GN membranoasa
- amiloidoza si insuficienta renala
- HTA maligna
- Ac anti U1-RNP in titru mare au probabil efect protector
Afectarea nervoasa - lipsa complicatiilor neuropsihice severe
- nevralgia trigeminala
- cefalee, migrene
- infarcte cerebrale
- neuropatii periferice
Sarcina (?) - ischemia vaselor placentare in prezenta Sd R sever;
- Sd AFL

Tablou paraclinic

Teste de inflamatie nespecifica:

VSH, PCR ++ coreland cu gradul

de activitate al bolii
Anemia = normocroma, normocitara, sau (rar) hemolitica
Leucopenia cu limfopenie
~ activitatea bolii
Trombocitopenia rara
Ac anti U1 RNP la titru cresut =>
lipsa afectarii neuropsihice
absenta afectarii renale severe
artrite severe erozive in prezenta FR+
risc pentru HTP

Tablou paraclinic

Gamaglobuline Ig G +++
Hipocomplementemia ( 25% )
FR ( 50%) => artrite erozive
Anticorpi anticardiolipina si anticoagulantul lupic mai putin asociati
manifestarilor de tip trombotic si mai mult HTP
Ac antiendoteliali => HTP

Tablou clinic

Criterii de diagnostic (Alarcon-Segovia)

1.Criteriul serologic: Ac anti U1-RNP la un titru de peste 1:1600

( test de hemaglutinare )
2.Criterii clinice:
- edem al mainilor
- sinovite
- miozita
- fenomen Raynaud
- acroscleroza
Diagnostic pozitiv = Criteriul serologic + 3 criterii clinice

Tratament

Terapii similare cu cele din LES, Scl,

PM, in functie de forma clinica
1/3 semne generale si artrite usoare
=> analgezice si AINS
Fenomen Raynaud=> masuri
generale, nifedipin ret., pentoxifilin,
Artritele neerozive si afectarile
cutanate => hidroxiclorochina
Artrite severe, pleurezii => CS doze
mici
Miozita, vasculitele=> CS doze
mari
BRGE => IPP, dar si prednison 25mg
/zi

Alveolita fibrozanta =>

ciclofosfamida + CS
HTP => -anticoagulante,
-diuretice,
-oxigenoterapie,
- PG in perfuzie continua
(epoprostenol);
- antagonist al receptorului de
endotelina (Bosentan);
- inhibitori de fosfodiesteraza
(sildenafil);
Transplantul pulmonar.

Evolutie, complicatii, prognostic

Strict dependenta de tipul afectarii organice

Complicatii ale terapiei => necroza aseptica, osteoporoza, ATS
accelerata
Artrite deformante - numar mic de pacienti
BRGE => esofag Barret cu risc de carcinom esofagian
Mortalitatea (mai redusa decat in LES) =>
1. HTP progresiva
2. Miocardita
3. HTA renovasculara
4. Hemoragie intracerebrala
5. Infectii

Bibliografie
1.

Sharp, GC, Irvin, WS, Tan, EM, et al. Mixed connective tissue disease: an apparently distinct rheumatic disease syndrome
associated with a specific antibody to an extractable nuclear antigen. Am J Med 1972; 52:148.

2.

Sharp GC, Irwin WS, May CM et al. Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective
tissue disease, systemic lupus erythematosus and other rheumatic diseases. N Engl J Med 1976; 29: 1149-1154.

3.

Nakae, K, Furusawa, F, Kasukawa, R, et al. A nationwide epidemiological survey on diffuse collagen diseases: Estimation
of prevalence rate in Japan. In: Mixed Connective Tissue Disease and Anti-nuclear Antibodies, Kasukawa, R, Sharp, G
(Eds), Excerpta Medica, Amsterdam, 1987. p.9.

4.

Feldman F. Mixed connective tissue disease. Radiol Clin North Am 1988;26:1235-1246

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Robert W Hoffman, Eric L Greidinger, Mixed Connective-Tissue Disease May 2, 2005 eMedicine.com, Inc.

6.

Kahn MK, Borgeois P, Aeschlimann A, De Truchis P. Mixed connective tissue disease after exposure to vinyl chloride. J
Rheumatol 1989; 16: 533-535.

7.

Bennett, RM. Anti-U1 RNP antibodies in mixed connective tissue disease. In: Up To Date, Rose,BD (Ed), Up To Date,
Wellesley, MA, DEC, 2004.

8.

Hoffman, RW, Greidinger, EL, Mixed Connective-Tissue Disease eMedicine.com, Inc. May 2, 2005.

9.

Bennett, RM. Definition and diagnosis of mixed connective tissue disease. In: Up To Date, Rose,BD (Ed), Up To Date,
Wellesley, MA, DEC, 2004.

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Black CM, Maddison PJ, Welsh KI et al. HLA and immunoglobulin allotypes in mixed connective tissue disease. Arthritis
Rheum 1988; 31: 131-135. Query CC, Keene JD. A human autoimmune protein associated with U1 RNA contains a region
of homology that is cross reactive with retroviral p30 gag antigen. Cell 1987; 51: 211-220.
Bennett, RM. Clinical manifestations of mixed connective tissue disease. In: Up To Date, Rose,BD (Ed), Up To Date,
Wellesley, MA, DEC, 2004.
Venables,PJW. Mixed connective tissue disease. In Rheumatology, Third Edition. Hochberg, MC, Silman, JA, Smolen,JS,
Weinblatt, ME,Weisman, MH (Eds), Rheumatology Online. 2005 Elsevier: 1574-1577
Piirainen HI; Kurki PT. Clinical and serological follow-up of patients with polyarthritis, Raynaud's phenomenon, and
circulating RNP antibodies. Scand J Rheumatol 1990;19(1):51-6.

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