Il termine di connettivite mista e applicato ad un particolare sottogruppo di pazienti che presentano contemporaneamente aspetti caratteristici del Lupus Eritematoso, della sclerodermia, delle miositi autoimmuni e dell'artrite reumatoide e nel siero il riscontro di una risposta autoimmune contro U1-RNP, una componente dello spliceosoma, la cui funzione e di assistere nello splicing del pre-mRNA a mRNA. Le specifiche componenti dello spliceosoma riconosciute dal siero dei malati di connettivite mista sono dei polipeptidi specifici dell'U1-RNP chiamati 70 kD, A e C (Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. 2000;12(5):386-90).

L'esordio della connettivite mista e molteplice e comprende il fenomeno di Raynaud, l'edema delle dita delle mani che assumono il caratteristico aspetto a 'salsicciotto', poliartriti e rash. Man mano che la malattia evolve compaiono contemporaneamente aspetti tipici del Lupus eritematoso sistemico, della sclerodermia, della polimiosite e dell'artrite reumatoide.
Il fenomeno di Raynaud e il sintomo d'esordio piu comune di tale patologia, talvolta e di grado severo ed associato a necrosi digitale, rappresentando una delle maggiori cause di morbilita.
Un aspetto istopatologico importante comune a bambini e adulti e una vasculopatia proliferativi molto estesa caratterizzata dalla proliferazione di media e intima che determina un restringimento del lume delle arteriose e dei grandi vasi come aorta, coronarie, arterie polmonari e renali. Circa il 50% dei pazienti presenta alterazioni alla capillaroscopia simili a quelle trovate nella sclerodermia, sebbene il riscontro di capillari distrofici, ramificati e simili ad un cespuglio sia caratteristico della connettivite mista. Alcuni pazienti presentano manifestazioni di una vasculopatia generalizzata multiorgano che domina il quadro clinico. In tali casi si e osservata l'associazione con livelli aumentati di attivita dell'ACE (enzima di conversione dell'angiotensina). Inoltre alcuni pazienti presentano autoanticorpi anti-endotelio che in alcuni lavori sembrano legare piu avidamente l'endotelio attivato da citochine come il TNFa (Maddison PJ. Mixed connective tissue disease: overlap syndromes. Best Pract Res Clin Rheumatol. 2000;14(1):111-24).
Oggi si considerano le manifestazioni pleuropolmonari uno degli aspetti piu importanti della connettivite mista con una prevalenza stimata del 20-87%. L'aspetto radiologico piu comune e l'interstiziopatia polmonare (Enomoto K, Takada T, Suzuki E, Ishida T, Moriyama H, Ooi H, Hasegawa T, Tsukada H, Nakano M, Gejyo F. Bronchoalveolar lavage fluid cells in mixed connective tissue disease. Respirology. 2003;8(2):149-56).
L'ipertensione polmonare e una complicanza sempre piu frequente della connettivite mista, con una prevalenza che varia dal 20 all'80%. Talvolta essa e secondaria all'interstiziopatia, ma piu frequentemente e primitiva, dovuta alla proliferazione intimale delle arteriose polmonari. I pazienti con questo quadro clinico hanno una prognosi infausta, con rapida evoluzione verso lo scompenso cardiaco destro. E la maggiore causa di morte.
I test di funzionalita polmonare sono spesso alterati, ma solo una minoranza dei casi e sintomatica.
Circa i 2/3 dei pazienti presentano l'edema delle dita delle mani con aspetto a `salsicciotto'. In questi pazienti la cute e tesa e spessa, presentando all'istologia aumento del collagene dermico e edema considerevole. Questi cambiamenti sono meno importanti nei bambini. Talvolta la sclerodermia e piu estesa. Vi possono inoltre essere molte altre manifestazioni cutanee, da eruzioni eritematose simili al Lupus, come macule papule e porpora o una combinazione di queste, a manifestazioni cutanee della dermatomiosite, come papule di Gottron o il rash eliotropo.
Un altro aspetto importante e la poliartrite che porta all'evoluzione di deformita di Jaccoud a livello di mani e piedi, come risultato di un'involuzione periarticolare causata da lassita ligamentosa e capsulare. Erosioni documentate radiologicamente sono piu frequenti che nel Lupus e possono essere diffuse, interessando le articolazioni interfalangeee e il primo metacarpo, talvolta conducendo ad un'artropatia mutilante. Puo inoltre presentarsi un interessamento vertebrale con sublussazioni che possono condurre il paziente alla morte. E stata osservata un'associazione tra artropatia nella connettivite mista e la presenza di HLA DR4.
Circa il 40% dei pazienti presenta piccoli noduli peritendinei, spesso a livello di gomiti, mani e piedi, che istologicamente non hanno la tipica morfologia dei noduli reumatoidi, ma sono caratterizzati da un'infiammazione non specifica.
Nel 50% dei casi e presente mialgia, ma una miosite franca con debolezza muscolare, aumento del CPK e biopsia patognomonica e rara, sebbene istologicamente siano spesso presenti delle modificazioni infiammatorie focali a livello muscolare asintomatiche.
La disfunzione esofagea e presente in circa il 75% dei casi, caratterizzata da diminuzione della pressione dello sfintere esofageo, ridotta ampiezza della peristalsi dei due terzi distali dell'esofago e talvolta ridotta pressione dello sfintere superiore. Talvolta e asintomatica, ma possono essere presenti disfagia, pirosi, esofagite. Piu rara e l'involuzione intestinale simile a quella della sclerodermia, caratterizzata da malassorbimento e malattia diverticolare.
La piu comune manifestazione cardiaca e la pericardite. All'ecocardiografia in circa un terzo dei pazienti si possono osservare alterazioni a livello pericardio, generalmente emodinamicamente non significanti. Il tamponamento pericardico e raro. E stata riportata un'endocardite verrucosa su valvola mitrale simile al Libman-Sacks.
La nevralgia del trigemino e la manifestazione neurologica piu frequente. Cefalee su base vascolare, talvolta emicrania sono frequenti. Complicanze neurologiche sono rare anche se sono stati riportati casi di meningite asettica e mielite traversa. Anche le glomerulonefriti sono rare, anche se sono stati riportati casi di glomerulonefrite membranosa associata a deposito di IgG e complemento (Maddison PJ. Mixed connective tissue disease: overlap syndromes. Best Pract Res Clin Rheumatol. 2000;14(1):111-24).

La connettivite mista ha distribuzione ubiquitaria. L'esordio e solitamente nella seconda e terza decade, ma puo essere osservata in bambini e anziani. Sono colpite piu le donne. L'esordio e caratterizzato da fenomeno di Raynaud, dita a salsicciotto, artralgia, mialgia e astenia. In alcuni casi vi puo essere un esordio acuto con febbre alta, polimiosite, artrite, manifestazioni neurologiche come nevralgia del trigemino o meningite asettica. I diversi aspetti della malattia si manifestano in mesi o anni. La piu comune causa di morte e l'ipertensione polmonare (Harrison's, Principles of Internal Medicine, 15th Edition, 2001:1945-6).
Il rischio per le donne gravide affette da connettivite mista rimane ancora controverso (Horita Y, Tsunoda S, Inenaga T, Kawano Y, Ishibashi-Ueda H, Chiba Y, Takishita S. Pregnancy outcome in nephrotic syndrome with mixed connective tissue disease. Nephron. 2001;89(3):354-6).

U1-RNP e una componente dello spliceosoma. Il siero dei pazienti affetti da connettivite mista riconosce sia l'U1-RNA sia i polipeptidi che compongono U1. Si e dimostrato che elevati titoli di anti U1-RNA correlano con l'attivita della malattia. Molti altri anticorpi, oltre agli anti-U1-RNP sono stati riconosciuti nella connettivite mista (Kraemer DM, Kraus MR, Kneitz C, Tony HP. Nucleoporin p62 antibodies in a case of mixed connective tissue disease. Clin Diagn Lab Immunol. 2003;10(2):329-31). Gli anticorpi anti-U1-RNP riconoscono tre polipeptidi, chiamati 70 kDa, A e C, che si ritrovano esclusivamente in associazione con l'U1-RNA. In alcuni studi si e concluso che le manifestazioni cliniche della connettivite mista sono associate con la risposta immune verso l'U1-RNP, che e peculiare rispetto a quella osservata nelle altre malattie del tessuto connettivo, sia quantitativamente sia qualitativamente.
Si e recentemente compreso che la predisposizione genetica e probabilmente il maggior determinante sia della suscettibilita alla malattia sia della sua espressione. Molti geni sono stati chiamati in causa, inclusi geni con un importante ruolo nella regolazione della risposta immune e dell'infiammazione come l'HLA di classe II, il recettore delle cellule T, i geni delle immunoglobuline, e anche geni coinvolti nella clearance degli immunocomplessi , nella regolazione delle citochine e nell'apoptosi (Maddison PJ. Mixed connective tissue disease: overlap syndromes Best Pract Res Clin Rheumatol. 2000;14(1):111-24).
Vi e la possibilita che alcuni agenti microbici (Citomegalovirus, virus di Epstein-Barr) inneschino la risposta autoimmune contro l'U1-RNP (Hoffman RW; and Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. 2000;12:386-390).

Alarcon, Segovia e Villareal hanno proposto i seguenti criteri diagnostici: 1) sierologici: positivita ad alto titolo degli anti-U1-RNP nel siero; 2) clinici: edema delle mani, sinoviti, miositi, fenomeno di Raynaud, acrosclerosi. Per porre diagnosi devono essere soddisfatti i criteri sierologici, o essere presenti almeno tre manifestazioni cliniche e l'associazione di edema delle mani, fenomeno di Raynaud e acrosclerosi necessita almeno un'altra manifestazione clinica.
Attualmente gli anticorpi anti-U1-RNP vengono ricercati con l'ELISA, metodo piu sensibile e specifico (Maddison PJ. Mixed connective tissue disease: overlap syndromes. Best Pract Res Clin Rheumatol. 2000;14(1):111-24).

Il trattamento della connettivite mista e essenzialmente lo stesso delle malattie che compongono tale sindrome. Piu della meta dei pazienti hanno decorso favorevole. La sopravvivenza a 10 anni e di circa l'80%, ma varia a seconda del quadro clinico che si presenta (Harrison's, Principles of Internal Medicine, 15th Edition, 2001:1945-6).
L'utilizzo di iloprost che sembra essere efficace e risolutivo per il trattamento dell'ischemia delle dita e del fenomeno di Raynaud recalcitrante, quando utilizzato insieme alla terapia immunosoppressiva convenzionale, puo essere utile nel prevenire complicanze quali la gangrena delle dita e l'eventuale amputazione (Zulian F, Corona F, Gerloni V, Falcini F, Buoncompagni A, Scarazatti M, Martini G, Zacchello F. Safety and efficacy of iloprost for the treatment of ischaemic digits in paediatric connective tissue diseases. Rheumatology (Oxford). 2004;43(2):229-33).
La terapia con le immunoglobuline endovenose, benche molto costosa, puo essere un'opportunita terapeutica in pazienti con MTCD non responsivi alle altre terapie (Ulmer A, Kotter I, Pfaff A, Fierlbeck G. Efficacy of pulsed intravenous immunoglobulin therapy in mixed connective tissue disease. J Am Acad Dermatol. 2002;46(1):123-7).

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