Tratamentul Biologic al

manifestarilor extra-articulare in
bolile reumatice
 Obiectiv
Evaluarea impactului terapie biologice asupra
manifestarilor non-articulare in bolile
autoimune si inflamatorii ce afecteaza in
principal sistemul musculoscheletal
Dintre terapiile biologice existente in prezent :

 Inhibitorii de TNFa - primii agenti aprobati pentru tratamentul PR, SA, Pso.

 Mai tarziu
– Rituximab (ac anti CD20)
– Abatacept (inhibitor al caii de costimulare a Limfocitelor T CD28-CD80)
– Tocilizumab (inhibitor receptor IL-6)
• pentru Poliartrita Reumatoida .

• Schimbarea modului de evaluare si a strategiei terapeutice

T2T
• Elaborarea unor Ghiduri de evaluare si tratament

• Alegerea tratamentului- influentata

– Comorbiditati – contraindicatii
– Manifestarile extraarticulare

https://www.ncbi.nlm.nih.gov/pubmed/23815014
• Manifestari extraarticulare – afectarea unor alte organe si
sisteme ce nu fac parte din sistemul musculosckeletal

 Marker de severitate – influeteaza prognosticul

 Influenteaza alegerea unei strategii terapeutice

• Factori de risc pentru aparitia manifestarilor extraarticulare

– Boala cu evolutie indelungata
– Fumatul
– Factori genetici :HLA B27, HLA DRB1
– Imunologici : FR, ac anti CCP, ANA

• Tratamentul afectiunii de fond – previne /amelioreaza

 • Poliartrita reumatoida
• Spondilita anchilozanta
• Artopatia psoriazica
• Artrita idiopatica juvenila
Terapiile disponibile
• Inhibitori de TNF • Inhibitor de IL-17
– - Secukinumab
– Etanercept – - Ixekizumab
– Infliximab • Blocant de IL-12/23
Afectiunile care – - Ustekinumab
– Adalimumab
primesc terapie • Blocanti ai
biologica – Certolizumab costimularii
– Golimumab – Abatacept
• Ac anti CD 20
• Inhibitor de IL-1
– Rituximab
– - Anakinra • Inhibitorii de JAK
• Afectarea oculara – - Canakinumab kinase
– Uveita – - Rilonacept – Tofacitinib
– Sclerita,
episclerita • Psoriazis cutanata • Inhibitor de IL-6
– Keratoconjunctivit• Boala inflamatorie – - Tocilizumab
a sicca intestinala
• Sd Sjogren (B.Chron, RCUH)
secundar • Sd Felty
• Vasculita
reumatoida Ce manifestari
extraarticulare beneficiaza
 Afectarea oculara
• Afectarea oculara in bolile reumatologice –
rezultatul unui proces inflamator imun mediat
care poate determina sechele grave sau chiar
pierderea vederii.
A Meta-Analysis of the Prevalence of the Ocular
Manifestations in All Inflammatory Rheumatic
Diseases Jacqueline Hayworth and Janet E. Pope , Medicine, University of Western Ontario and U of
1 2 1

Toronto, Toronto, ON, Canada, 2University of Western Ontario, London, ON, Canada Meeting: 2015 ACR/ARHP
Annual Meeting

• 7124 studii, 263 recenzii complete

– 13 studii -SA
– 31 studii -AIJ
– 12studii - Pso
– 11 studii - PR
– 165 alte afectari sistemice
 Manifestarile oculare cel mai frecvent
intalnite :
• Uveita
– SA - 22% (95% CI: 16-24%)
– JIA
• forma oligoarticulara 36% (20-51%),
• forma poliarticulara 13% (8-19%)
– Pso 15% (5-24%) uveita anterioara ; 0.2% uveita
posterioara

• Keratoconjunctivita sicca - 16% (8-25%),

• Simptome Sicca - 31% (21-42%),
• Keratita ulcerativa marginala - 1-3%, PR
• Episclerita - 1-2%
• Vasculita retiniana - 0.2%.
 Tratament
• Uveita = inflamatie a uveei (membrana
intermediara vascularizata, care hraneste ochiul,
constituita din iris, corpul ciliar si coroida)
Terapie biologica
 Cand nu mai sunt eficiente DMARD
sintetice

 Antagonitii TNF a
 Etanercept
 Adalimumab scad riscul aparitie al uveitei la
 Certolizumab
 Infliximab
pacientii cu Spondilita ankilozanta
 Golimumab
• David T Yu Assessment and treatment of ankylosing spondylitis in adult Apr 21, 2016. https://www.uptodate.com/contents/assessment-and-treatment-of-ankylosing-
spondylitis-in-adults?source=search_result&search=golimumab%20uveitis&selectedTitle=6~150
• Yazgan SEfficacy of golimumab on recurrent uveitis in HLA-B27-positive ankylosing spondylitis Int Ophthalmol. 2017 Feb
 Published first 2 March 2017.

• Au fost inclusi 1365 pacienti cu SA (406 ADA, 354 ETN, 605 IFX).
• Datele au fost colectate din Registrul Suedez de Reumatologie (2003-2010)
• Istoric de uveita anterior inceperii terapiei biologice

S-a observat o incidenta mai mare a uveitei in randul pacientilor tratati cu

Etanercept – comparativ cu Adalimumab si Infliximab .
Rezultate sustinute si de un alt studiu asemanator efectuat pe o cohorta de
pacienti din SUA.

Ac monoclonali (IFX,ADA)confera o protectie mai buna comparativ cu

proteina de fuziune (ETN)
 Adalimumab (80 mg sc doza de incarcare si ulterior 40 mg sc /sapt )

– 2 studii randomizate – eficacitate in tratamentul

• uveitei posterioare
• pan uveitei

AIJ - Studiul SYCAMORE (20 mg/0.8 ml pentru pacientii<30 kg sau 40 mg/0.8 ml

pentru pacientii > 30 kg inj sc la 2 sapt )

 Eficacitatea asocierii Adalimumab + metotrexat pentru pacientii cu uveita

activa
 Perioada 18 luni – pacientii care au asociata ADA au avut recaderi mai
putine dar s-au observat mai multe reactii adverse

In 2016 – EMA si FDA au aprobabat utilizarea ADALIMUMAB

pentru tratamentul uveitei non-infectioase la adulti

• http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000481/human_med_000822.jsp&mid=WC0b0
1ac058001d124
 Afectare corneei, sclerita, episclerita -
• Utilizare terapiei biologice
PR
in formele severe, cu Extrapolare
evolutie rapida, refractare la - Eficacitate in ceea ce priveste afectare oculara
tratamentul sistemic cu la pacientii cu Granulomatoza cu poliangiita
DMARDs sintetice - daca nu exista raspuns la 4 sapt de
tratament se indica schimbare
imunosupresiei
rituximab
2 doze -1 g la15 zile ).
Sau
4 doze (375 mg/m2 administrare saptmanala )

https://www.uptodate.com/contents/treatment-of-scleritis?source=related_link#H5960341
• Agentii anti TNFa- utili in tratamentul PR

Nu exista un consens intre oftalmologi vis a vis de

beneficiile aduse afectarii oftalmologice

Raportari de cazuri

– Infliximab – partial eficient in tratamentul scleritei

rezistente
• Doza 3-5 mg/kg administrate la un interval de 4-8 sapt
• Sunt necesare studii mai amanuntite

– Etanercept – nu pare sa aiba eficacitate

• Extrapolare dintr-un Studiu – pac cu Granulomatoza cu poliangiita
– nu si-a dovedit eficacitatea pentru mentinerea remisiunii

https://www.uptodate.com/contents/treatment-of-scleritis?source=related_link#H5960341
 Sd Sjogren secundar

• Tratamentul afectiunii de baza

• Tratament igieno dietetic – lacrimi artificiale, saliva
artificiala , igiena dentara adecvata
Isi propune sa observe prevalenta simptomelor Sicca si sd Sjogren secundar la
pacientii cu Poliartrita Reumatoida .
• 337 pacienti , Test Schirmer, evaluare debit salivar nestimulat .

Pacientii care prezentau Sd sjogren secumdar

- Aveau un numar mai mare de articulatii dureroase

Nici unul dintre pacientii care erau in tratament cu antagonisti de TNF a nu

au prezentat simptome de sjogren secundar

- Comparativ cu 22% din restul Populatiei de pacienti studiati

• The Sjögren’s Syndrome Foundation (SSF) + American College of
Rheumatology(ACR) au elaborat cateva linii de ghid pentru practica clinica
– April 2017

Agenti biologici pentru tratamentul Sicca & manifestarilor sistemice

 Inhibitori de TNF a
– ghidurile nu recomanda utilizarea de agenti anti TNF pentru tratamentul
simptomelor Sicca la pacientii cu Sjogren primar
- !!! nu trebuie sa descurajeze utilizarea inhibitorilor de TNF la pacientii cu
prezinta o alta afectare reumatologica (PR) in care exista indicatie pentru
tratamentul afectarii articulare

 Rituximab: mai multe studii randomizate recomanda

– tratamentul keratoconjunctivitei sicca si a xerostomie la pacientii cu sd
Sjogren primar ce nu au raspuns la terapia conventionala
– O optiune - Sd. Sjogren primar complicat cu vasculita +/- crioglobulinemie,
inflamatie severa a parotidelor , afectare pulmonara, si neuropatie periferica
.

!!!! Calitatea dovezilor pentru utilizare Rituximabului este scazuta – dar

consesnul se bazeaza pe parerea expertilor si experienta utilizarii rituximab in
alte afectiuni .
Carsons SE, Vivino FB, Parke A, et al. Treatment guidelines for rheumatologic manifestations of Sjögren’s syndrome: Use of biologic agents,
management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res (Hoboken). 2017 Apr;69(4):517–527.
 Boala inflamatorie intestinala
Inflamatia peretelui intestinal
• RCUH
• B. Crohn
• In 10% din cazuri nu pot fi diferentiate

Frecvent impune utilizarea terapiei biologice vs afectarea articulara

• !!! Utilizarea inhibitorilor de TNF a

– colaborare Reumatolog/gastroenterolog –
in functie de severitate
• Richard J Farrell, Overview of the medical management of severe or refractory Crohn disease in adults https://www.uptodate.com/
• Yousif I A-Rahim Anti-tumor necrosis factor therapy in ulcerative colitis https://www.uptodate.com/
 • Inhibitori TNFa
– Ac monoclonali :
• Infliximab 5mg/kg iv la 0,2,6 sapt apoi 5mg/kg la 8 sapt
• Adalimumab – 40 mg sc/sapt
• Golimumab – 50 mg sc/ luna (doza de incarcare – pt afectarea intestinala activa)
• Certolizumab pegol – Initial: 400 mg sc, cu repetare la 2 si 4 saptmani;
– Intretinere : 200 mg la 2 sapt sau 400 mg la 4 sapt
– Etanercept – nu are beneficiu pe afectare intestinala

• Raspuns inadecvat
– dupa 3 luni de tratament – swich cu un al doilea anti TNF
– Inhibitor IL 12/23 – Ustekinumab – B. Crohn

• Se incearca obtinerea unei vindecari complete a mucoasei intestinale –

chiar si la pac asimptomatici
• Imbunatatirea inflamatiei intestinale se asociaza cu scaderea inflamatie
articulare .

https://www.uptodate.com/contents/treatment-of-arthritis-associated-with-inflammatory-bowel-
disease?source=search_result&search=inflamatory%20bowel%20disease%20therapy&selectedTitle=6~150#H832953704
 Afectarea cutanata – Psoriazis
• Afectare cutanata cronica ce poate aveam impact
devastator asupra calitatii vietii

• Terapia biologica utilizata atunci cand

• esueaza tratamentul topic si cu DMARDsintetice
– Agenti anti TNF
• Adalimumab
• Etanercept
– doze mai mari decat cele indicate pentru afectarea articulara
50mgx2/sapt -12 saptamani, apoi saptmanal
• Infliximab
• Golimumab
• Certolizumab pegol
– Ac anti IL-12/23 – ustekinumab
– Ac anti IL-17 - secukinumab
• Steven R Feldman, Treatment of psoriasis in adults https://www.uptodate.com/
• https://www.psoriasis-association.org.uk
• Graeme M. Lipper, Which Psoriasis Biologics Have the Best Response Rates? https://www.medscape.com/viewarticle/866789
• Psoriazis eritrodermic – Infiliximab- singurul
cu date suficiente.
– Etanercept – studiu open-label,10 cazuri – si-a
dovedit eficacitatea

– Raportari de cazuri – eficienta

• Adalimumab
• Ustekinumab

• https://www.psoriasis-association.org.uk
• Graeme M. Lipper, Which Psoriasis Biologics Have the Best Response Rates? https://www.medscape.com/viewarticle/866789
 Vasculita reumatoida
• Tipic la pacientii cu PR • Predispozitie catre vasele medii-
– boala eroziva, cele mai frecvente sisteme
– de lunga durata implicate
– Pielea
• Afecteaza mai multe tipuri de vase – Sistemul nervos periferic
• artere medii • Vasa nervorum
• arteriole • Polineuropatia simetrica
• venule post capilare
– Ochiul (sclerita,
episclerita)
• Severitatea variabila - oculize
vasculara, necroza, ischemie tisulara – Sistemul cardiovascular
– asemanatoare altor vasculite – Sistemul muscular
sistemice

• Larry W Moreland, General principles of management of rheumatoid arthritis in adultshttps://www.uptodate.com/contents/treatment-of-

rheumatoid-vasculitis?source=search_result&search=biologic%20therapy%20in%20AR%20vasculitis&selectedTitle=4~150
• Strategie terapeutica

– tipul,
– distributia afectarii sistemice
– severitatea

Rituximab = alternativa a imunosupresiei cu ciclofosfamida

Rituximab + doze mari corticosteroizi vs CYC + corticosteroizi

– La pacientii tineri
– Incercare de prezervare a fertilitatii
– Risc crescut de malignitate
– Insuficienta renala
– Citopenie

• Ciclofosfamida – experienta mai indelungata la pacientii cu afectare severa

• Patrick Whelan, Treatment of rheumatoid vasculitis https://www.uptodate.com/contents/treatment-of-rheumatoid-

vasculitis?source=search_result&search=rheumatoid%20vasculitis&selectedTitle=2~66
• Rituximab – indicatii
– tratamentul ulcerelor cutanate induse prin vasculita

– Afectarea sistemica + asociere doze mari de corticosteroizi

(pericardica,aortita, afectare pulmonara sau renala)

– Aparitia RV sub tratament cu MTX- se pastresaza DMARDs si se adauga

RTX

Doze
– 375 mg/m2 I iv saptamanl – 4 saptmani
– 1000mg adm iv la interval de 2 saptmani , cu posibilitatea repetarii la 6
luni (protocolul aprobat in PR)

– Nu exista studii care sa compare eficacitatea celor 2 regimuri de

administrare

• Patrick Whelan, Treatment of rheumatoid vasculitis https://www.uptodate.com/contents/treatment-of-rheumatoid-

vasculitis?source=search_result&search=rheumatoid%20vasculitis&selectedTitle=2~66
• Peter A Merkel Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis https://www.uptodate.com/
 Sd Felty
PR + Splenomegalie + Neutropenie
• 8 cazuri raportate – adm RTX
Strategia terapeutica – sinovita
• raportari de cazuri – neutropenia evolutie favorabila

• serii de cazuri
• experienta clinica. • Alte cazuri
– ameliorarea articulara
Metotrexat – persistenta neutropeniei
Rituximab de prima intentie
• RTX preferat agentilor anti TNFa
– In 6 cazuri in care au fost folosite ADA,
ETN, IFX
• Nu au corectata neutropenia
• Ameliorarea afectarii articulare si scadere
sd inflamator
https://www.uptodate.com/contents/drug-therapy-in-feltys-
syndrome?source=search_result&search=felty&selectedTitle=1~30
 • Alti agenti Biologici —
– raspuns inadecvat la MTX si RTX
– Doze mari de prednison pentru controlul artritei si neutropeniei

– ABATACEPT 10 mg/kg la 0,2,4 sapt , ulterior la 4 saptamani

– Preferat inhibitori TNF a si Tocilizumab, Tofacitinib (lipsa studii)

Jonathan Kay Drug therapy in Felty's syndrome https://www.uptodate.com/

 Amiloidoza (AA)
• Asociata cu afectiunile inflamatorii cronice
• Incidenta AA evaluata pe 2 serii de pacienti(cea mai mare 374
pacienti) in UK a aratat urmatoarea incidenta:
• AIJ : 7 -48 %
• PR : 23 - 51 %
• SA: 0- 12 %
• Pso: 4 %
• BII: 2- 5 %

Tratamentul principal – controlul afectiunii inflamatorii

Utilizarea terapiei Biologice – a influentat Prezenta factorilor de risc

- regresia manifestarilor clinice
 Cea mai mare experienta Experienta sumara
• Pacienti cu PR tratati cu Inhibitori
TNFa • Inhibitori TNFa mai noi
 ETANERCEPT  certolizumab pegol
 infliximab
 Adalimumab  golimumab

• Inhibitor IL1
(anakinra)

capacitatea de a scadea nivelul amiloidului seric A

Eficacitate dovedita doar pt ETANERCEPT – preventia

progresie si inducerea regresiei amiloidozei

Nelson Leung Renal amyloidosis https://www.uptodate.com/

Peter D Gorevic, MD Causes and diagnosis of secondary (AA) amyloidosis and relation to rheumatic diseases https://www.uptodate.com/
Peter D Gorevic Treatment of secondary (AA) amyloidosishttps://www.uptodate.com/
 • 2006- Eficacitate TOCILIZUMAB(inhibitor IL6) pentru Tratamentul AA la un
pacient cu AIJ

– multiple studii de evaluare a eficientei la Pacientii cu PR

– Raportari izolate de cazuri – Pacienti cu BII(B Crohn), boli autoinflamatorii
sau vasculite (poliarterita nodoasa , Behcet)

 Pacientii cu PR si amiloidoza renala

 Scadere dramatica a sd inflamator si amiloid seric A
 O incidenta mai mica a progresiei catre hemodializa

Studiu retrospectiv 42 de pacienti – PR+ Amiloidoza renala

 Tocilizumab / inhibitor TNFa

– Tocilizumab – mai eficient pt normalizarea valorilor Amiloidului

seric
– Inhibitorii TNFa – reduc rapid valorile Amiloidului seric
• Foarte rar determina normalizare in practica clinica
Nelson Leung Renal amyloidosis https://www.uptodate.com/
Peter D Gorevic, MD Causes and diagnosis of secondary (AA) amyloidosis and relation to rheumatic diseases https://www.uptodate.com/
Peter D Gorevic Treatment of secondary (AA) amyloidosishttps://www.uptodate.com/
 In incheiere
• Controlul adecvat al bolii - remisiunea / activitatea minima
PREVINE aparitia manifestarilor extraarticulare

• Aparitia Manifestarilor extraarticulare

– orieteaza strategia terapeutica
– Poate reprezenta o necesitate a introducerii terapiei biologice

• Trebuie ales agentul biologic adecvat prin colaborare intre

Reumatolog, pacient si ceilalti medici specialisti implicati
 In incheiere
Cateva exemple ...

Pacient cu SA + uveita
Pacient cu PR 1. IFX 1. IFX/ADA
• Af oculara 2. ETN 2. ETN/CERT/GOLI + B inflam intest
(sclerita/keratoconjun 1. IFX/ADA/CERTO/GOLI
3. RTX
ctivita sicca)
2. USTK
• Vasculita reumatoida
1. RTX
• AA 1. Tocilizumab
2. ETN
3. IFX/ADA
Va multumesc!

NU chiar 7 dintr-o lovitura !

 Bibliografie
• Jacqueline Hayworth1 and Janet E. Pope2,A Meta-Analysis of the Prevalence of the Ocular Manifestations in All Inflammatory Rheumatic
Diseases Meeting: 2015 ACR/ARHP Annual Meeting
• https://www.ncbi.nlm.nih.gov/pubmed/23815014
• David T Yu Assessment and treatment of ankylosing spondylitis in adult Apr 21, 2016. https://www.uptodate.com/contents/assessment-and-
treatment-of-ankylosing-spondylitis-in-adults?source=search_result&search=golimumab%20uveitis&selectedTitle=6~150
• Yazgan SEfficacy of golimumab on recurrent uveitis in HLA-B27-positive ankylosing spondylitis Int Ophthalmol. 2017 Feb
• http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000481/human_med_000822.jsp&mid=WC0b01ac058001d12
4
• https://www.uptodate.com/contents/treatment-of-scleritis?source=related_link#H5960341
• Hans-Jacob Hag A study of the prevalence of sicca symptoms and secondary Sjögren's syndrome in patients with rheumatoid arthritis, and its
association to disease activity and treatment profile
• Carsons SE, Vivino FB, Parke A, et al. Treatment guidelines for rheumatologic manifestations of Sjögren’s syndrome: Use of biologic agents,
management of fatigue, and inflammatory musculoskeletal pain. Arthritis Care Res (Hoboken). 2017 Apr;69(4):517–527.
• Richard J Farrell, Overview of the medical management of severe or refractory Crohn disease in adults https://www.uptodate.com/
• Yousif I A-Rahim Anti-tumor necrosis factor therapy in ulcerative colitis https://www.uptodate.com/
• https://www.uptodate.com/contents/treatment-of-arthritis-associated-with-inflammatory-bowel-
disease?source=search_result&search=inflamatory%20bowel%20disease%20therapy&selectedTitle=6~150#H832953704
• Steven R Feldman, Treatment of psoriasis in adults https://www.uptodate.com/
• https://www.psoriasis-association.org.uk
• Graeme M. Lipper, Which Psoriasis Biologics Have the Best Response Rates? https://www.medscape.com/viewarticle/866789
• Larry W Moreland, General principles of management of rheumatoid arthritis in adultshttps://www.uptodate.com/contents/treatment-of-
rheumatoid-vasculitis?source=search_result&search=biologic%20therapy%20in%20AR%20vasculitis&selectedTitle=4~150
• Patrick Whelan, Treatment of rheumatoid vasculitis https://www.uptodate.com/contents/treatment-of-rheumatoid-
vasculitis?source=search_result&search=rheumatoid%20vasculitis&selectedTitle=2~66
• Peter A Merkel Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis https://www.uptodate.com/
• https://www.uptodate.com/contents/drug-therapy-in-feltys-syndrome?source=search_result&search=felty&selectedTitle=1~30
• Jonathan Kay Drug therapy in Felty's syndrome https://www.uptodate.com/
• Nelson Leung Renal amyloidosis https://www.uptodate.com/
• Peter D Gorevic, MD Causes and diagnosis of secondary (AA) amyloidosis and relation to rheumatic diseases https://www.uptodate.com/
• Peter D Gorevic Treatment of secondary (AA) amyloidosishttps://www.uptodate.com/