Simposio Nazionale in Riabilitazione in Reumatologia Grado 8-9 maggio 1987

2. Simposio Nazionale in Riabilitazione in Reumatologia Grado 8-9 maggio 1987

3. Terapia farmacologica 2007 Maria Teresa Mascia

4. E’ normale ad una certa età Non c’è molto da fare E poi….. Se le deve tenere così

5. Terapia farmacologica paracetamolo oppioidi FANS (COX-2, etc.) steroidi intrarticolari Sintomatici ad azione rapida Topici FANS e capsaicina glucosamina solfato condroitin solfato diacereina orale Sintomatici ad azione lenta (Sysadoa) i.a. acido jaluronico glucosamina solfato diacereina • Farmaci “condrometabolici”

6. Terapia farmacologica FANS (tollerabilità) • Intolleranza gastroenterica (soggettiva od oggettivabile all’EGDS sotto forma di erosioni, ulcere, emorragie o perforazioni) • Nefropatia • Azione sull’aggregazione piastrinica • Diminuzione: FANS tradizionali • Ritenzione idro-elettrolitica, ipertensione • Altri effetti collaterali: • SNC • Ipersensibilità • Epatotossicità • Interazioni farmacologiche

7. L’armamentario terapeutico Il trattamento del dolore prevede secondo le Linee Guida Trattamento sistemico per via orale Paracetamolo (acetaminofene) Coxib FANS Analgesici oppioidi

8. Norme da seguire per l’utilizzo del FANS • Nel periodo iniziale meglio utilizzare un antiinfiammatorio per bloccare la flogosi • 1 solo FANS alla volta ( il recettore è spesso 1 solo e quindi i farmaci si spiazzano ; non vi è vantaggio ma si aumentano i rischi) • Tempo adeguato ( es. inutile x 3 giorni, alcuni farmaci non hanno ancora raggiunto lo steady state) • Dosaggio minimo efficace ma considerando l’emivita ( inutile ad esempio ridurre il dosaggio utilizzando 1 sola volta al giorno un farmaco che ha 4-8 ore di emivita) • La somministrazione i.m evita solo la lesione da contatto della mucosa gastrica

9. Posizione delle Agenzie Regolatorie (AIFA,EMEA, FDA, Canada): • i coxib in commercio (celecoxib, etoricoxib), con le limitazioni previste, presentano un favorevole rapporto rischio / beneficio • I dati disponibili di tollerabilità CV (endpoint secondario) mostrano una sostanziale sovrapponibilità tra coxib e FANS tradizionali. I coxib hanno mostrato superiore tollerabilità GIrispetto ai FANS tradizionali

10. Terapia farmacologica FANS (tollerabilità) • Intolleranza gastroenterica (soggettiva od oggettivabile all’EGDS sotto forma di erosioni, ulcere, emorragie o perforazioni) • Nefropatia • Azione sull’aggregazione piastrinica • Diminuzione: FANS tradizionali • Ritenzione idro-elettrolitica, ipertensione • Altri effetti collaterali: • SNC • Ipersensibilità • Epatotossicità • Interazioni farmacologiche

11. Eventi avversi dei FANS COXIB • Dispepsia • Anemia - Sanguinamento GI • Erosioni • Ulcere - Sanguinamenti/perforazioni APP.DIGERENTE • Disfunzioni renali • Insufficienza renale - acuta/cronica • Ipertensione • Insufficienza cardiaca RENE PIASTRINE • Favoriscono l’emorragia

13. The efficacy of duloxetine, non-steroidal anti-inflammatory drugs, and opioids in osteoarthritis: a systematic literature review and meta-analysis his analysis suggests no difference between duloxetine and other post-first line oral treatments for osteoarthritis (OA) in total WOMAC score after approximately 12 weeks of treatment. BMC Musculoskelet Disord. 2014

14. Osteoartrosi • PRIMARIA? • SECONDARIA? • SEDE INTERESSATA? • MANO • GINOCCHIO • ANCA • Diffusa • Artrosi • nell’uomo • Modelli sperimentali • Farmaci? • Combinazioni? • Supplementazioni? • Dosaggi? • Durata del trattamento • Cicli? • Long term?

15. ACR 2012

16. ACR

17. 2013

18. Artrosi mano-linee guida italiane 2013

20. There are currently no licensed structure modifying osteoarthritis therapies. • Thehope remains that maintaining or improving structural pathology will prevent subsequent progression of symptoms

21. NICE 2014

22. CONDROPROTETTORI Non sono raccomandati in nessuna linea guida

23. ACR Washington- novembre 2006 The Great Debate : Perspectives on Glucosamine and ChondroitinSulphate

24. David T. Felson – ACR Washington- novembre 2006

25. 2001 2010

26. U.S. glucosamine market volume, by application, 2012-2022 (Tons) Nutritional supplements is expected to be the fastest growing application segment over 4.0% from 2015 to 2022

27. Kwoh, C. K. et al. The Joints on Glucosamine (JOG) Study: the effect of oral glucosamine on joint structure, a randomized trial. Arthritis Rheum. 2014 • To determine the short-term efficacy of oral glucosamine supplementation (1500/day) by evaluating structural lesions in the knee joints, as assessed using 3T magnetic resonance imaging (MRI). • The results of this short-term study provide no evidence of structural benefits(i.e., improvements in MRI morphologic features or urinary CTX-II excretion) from glucosamine supplementation in individuals with chronic knee pain.

28. Hochberg, M. C. et al. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann. Rheum. Dis. 2014 • 400 mg CS + 500 mg glucosamine hydrochloride 3/day or 200 mg celecoxib • Although the celecoxib group had a faster and more substantial response in the first 4 months of the study, by the 6-month endpoint, responses were similar across both groups. WOMAC pain score WOMAC stiffness score or WOMAC function score Joint swelling and effusion were similarly decreased in both groups.

29. Revisione 2015

30. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the kneeChao Zeng, Jie Wei, Hui Li, Yi-lun Wang, Dong-xing Xie, Tuo Yang, Shu-guang Gao, Yu-sheng Li, Wei Luo & Guang-hua Lei • This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. • All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. • In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects Scientific Reports 5, Articlenumber: 16827 (2015)

31. Combined glucosamine and chondroitin sulfate provides functional and structural benefit in the anterior cruciate ligament transection model. • 2008 • Benefici clinici ( analgesia) e strutturali • Aumento dei valori del CS nelle cartilagini • Ridotte alterazioni cartilaginee • 2016 • Ridotti livelli di IL1beta e TNF alfa • Ridotti MMP-3, C-telopeptide del collagene II • Migliorati parametri microstrutturali

32. Long-term effects of glucosamine/chondroitin sulfate on the progression of structural changes in knee osteoarthritis: 6-year follow-up data from the osteoarthritis initiative.Arthritis Care Res.2016 • The researchers compared MRI-assessed cartilage volume at baseline and at 6 years of follow-up. • The treatment was associated with a significant reduction in loss of cartilage volume. • Furthermore, the protective effects of treatment were significantly greater in patients who received the therapy for 2 years or longer.

33. Cochrane Condroitin for osteoarthritis.2015 • Chondroitin (alone or in combination with glucosamine) was better than placebo in improving pain in participants with osteoarthritis in short-term studies. The benefit was small to moderate with an 8 point greater improvement in pain (range 0 to 100) and a 2 point greater improvement in Lequesne's index (range 0 to 24), both seeming clinically meaningful.

34. CochraneDiacerein for osteoarthritis 2014 • Symptomatic benefit provided by diacerein in terms of pain reduction is minimal. • The small benefit derived in terms of joint space narrowing is of questionable clinical relevance and was observed only for OA of the hip.

35. Figure 1 Schematic of the knee joint depicting the synovial joint tissues affected in OA Hunter, D. J. (2010) Pharmacologic therapy for osteoarthritis—the era of disease modification Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2010.178

36. Table 1 Human clinical trials of DMOADs Hunter, D. J. (2010) Pharmacologic therapy for osteoarthritis—the era of disease modification Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2010.178

37. Figure 2 DMOADs that are currently in phase II and phase III trials in OA Hunter, D. J. (2010) Pharmacologic therapy for osteoarthritis—the era of disease modification Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2010.178

38. Table 1 Completed trials of potential DMOADs Mastbergen, S. C. et al.(2013) Functional articular cartilage repair: here, near, or is the best approach not yet clear? Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.29

39. Table 2 Potential DMOADs currently in clinical development for OA Mastbergen, S. C. et al.(2013) Functional articular cartilage repair: here, near, or is the best approach not yet clear? Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.29

40. Table 1 Major trials using anti‑β-NGF (tanezumab) in patients with OA Pfizer Inc, Eli Lilly To Recommence Phase 3 Trials For Pain Drug Tanezumab Chevalier, X. et al.(2013) Biologic agents in osteoarthritis: hopes and disappointments Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.44

41. Figure 4 Effect of adalimumab on new erosions in patients with hand OA Although a rationale exists, the available evidence does not support the current use of biologic therapy in OA. Results of clinical studies indicate that pain in OA is driven by complex mechanisms and not only by proinflammatory cytokines Permission obtained from BMJ Publishing Group. Verbruggen, G., Wittoek, R., Cruyssen, B. V. & Elewaut, D. Ann. Rheum. Dis.71, 891–898 (2012) Chevalier, X. et al.(2013) Biologic agents in osteoarthritis: hopes and disappointments Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.44

42. β-NGF, β-nerve growth factor; BMP-7, bone morphogenetic protein-7; OP-1, osteogenic protein-1; Dkk-1, dickkopf-related protein-1; FGF, fibroblast growth factor; HSA, human serum albumin; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein; rhBMP-7, recombinant human BMP-7; rhFGF; recombinant human FGF; rhPTHrP; recombinant human PTHrP; MMP13, matrix metalloproteinase 13; OA, osteoarthritis; PRP, platelet-rich plasma; TGF-β, transforming growth factor-β.

43. BUON LAVORO