Boala mixta de tesut conjunctiv - 2020

• 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

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

Prevalenta = ??
2,7-10 :100.000 (Japonia)
3.8 per 100,000 Norvegia 2011

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 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
DAYS OF OUR LIFE!!
 Tablou clinic - Debut

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

Fenomen Raynaud (W,B,R)

Sclerodactilia
Artrite
Mai rar: - nevralgie trigeminala
- polimiozita
- artrita acuta
- gangrene digitale
 Tablou clinic

Manifestari generale:
Febra, astenia fizica
Manifestari cutaneo-
mucoase:
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 in special:
Ac IgG anticardiolipin 
Ac antiendoteliali => HTP
Tablou clinic
 Criterii de diagnostic

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

sau >1/1280
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,
- prostaciclina 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 cu compl Cardiace
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
5. 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.
10. 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.
11. Bennett, RM. Clinical manifestations of mixed connective tissue disease. In: Up To Date, Rose,BD (Ed), Up To Date,
Wellesley, MA, DEC, 2004.
12. 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
13. 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.