Boala mixta de tesut conjunctiv 2015 Descrisa de

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 U 1 -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 U 1 -RNP Terenul genetic - HLA DR 2 si DR 4 Factori hormonali Mecanismul leziunilor este imun cu implicarea directa a Ac anti U 1 RNP =>Hiperactiv cel B => Ac anti U 1 RNP => ipoteza: individ genetic predispus (HLA DRB 1*04) dezvolta un raspuns imun impotriva unui antigen microbian (glicoproteina CMV) ce reactioneaza incrucisat cu peptidul U 1 70 KD

Boala mixta de tesut conjunctiv. Rolul Ac ani U 1 RNP Prezenta Ac anti U 1 -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 U 1 -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 U 1 -RNP = ARN bogat in uridina complexat cu trei polipeptide A’, C’ si 70 k. D

DAYS OF OUR LIFE!!

Tablou clinic - Debut De regula insidios: astenie fizică, mialgii, artralgii, febra Fenomen Raynaud (Maurice Raynaud 1862=> 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 Scl 70 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 U 1 -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 U 1 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 U 1 -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 25 mg /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 5. Robert W Hoffman, Eric L Greidinger, Mixed Connective-Tissue Disease May 2, 2005 e. Medicine. 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-U 1 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 e. Medicine. 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 U 1 RNA contains a region of homology that is cross reactive with retroviral p 30 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. 11. 12. 13.