1. Boala mixta de tesut conjunctiv - 2015
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

2. 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.

3. Epidemiologie Mai frecventa la femei 10/1 => 15/1
Vrsta de aparitie poate varia; media la ani
Prevalenta = ??
2,7-10 : (Japonia)
Peste DM (1,5/ ) , sub LES (20/ )
Nu exista date despre o predispozitie etnica sau de rasa

4. 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

5. Boala mixta de tesut conjunctiv-
Rolul 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

6. DAYS OF OUR LIFE!!

7. Tablou clinic - Debut
De regula insidios: astenie fizică, mialgii, artralgii, febra
Fenomen Raynaud (Maurice Raynaud1862=> W,B,R)
Sclerodactilia
Artrite
Mai rar: - nevralgie trigeminala
- polimiozita
- artrita acuta
- gangrene digitale

8. Tablou clinic Manifestari generale: Manifestari cutaneo- mucoase:
Febra, astenia fizica
Manifestari cutaneo-
mucoase:
edem al mainilor, rash,
macule eritematoase
la baza degetelor
Fenomenul Raynaud
70-90%
-capilaroscopie

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. Tablou clinic

17. 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

18. Tratament 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.
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

19. 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

21. Bibliografie
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.
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:
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, p.9.
Feldman F. Mixed connective tissue disease. Radiol Clin North Am 1988;26:
Robert W Hoffman, Eric L Greidinger, Mixed Connective-Tissue Disease May 2, 2005 eMedicine.com, Inc.
Kahn MK, Borgeois P, Aeschlimann A, De Truchis P. Mixed connective tissue disease after exposure to vinyl chloride. J Rheumatol 1989; 16:
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.
Hoffman, RW, Greidinger, EL, Mixed Connective-Tissue Disease eMedicine.com, Inc. May 2, 2005.
Bennett, RM. Definition and diagnosis of mixed connective tissue disease. In: Up To Date, Rose,BD (Ed), Up To Date, Wellesley, MA, DEC, 2004.
Black CM, Maddison PJ, Welsh KI et al. HLA and immunoglobulin allotypes in mixed connective tissue disease. Arthritis Rheum 1988; 31: 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:
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 Elsevier:
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.