Ankylosing spondylitis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Vamsikrishna Gunnam M.B.B.S [2]

## Overview

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Pharmacologic medical therapies for ankylosing spondylitis(AS) include Nonsteroidal anti-inflammatory drugs (NSAIDs), tumor necrosis factor (TNF) blocker, and interleukin 17 (IL-17) inhibitors.Ankylosing spondylitis (AS) is a chronic inflammatory disease which is manifested by back pain and gradually to spinal stiffness.While treating the AS patients the primary goal is to maximize long-term health-related quality of life.

## Medical Therapy

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* Medical therapy for AS is according to the guidelines proposed by [1][2][3]
* Assessment of SpondyloArthritis international Society (ASAS)
* European League Against Rheumatism (EULAR)
* American College of Rheumatology (ACR)/Spondylitis Association of America (SAA)/Spondyloarthritis Research and Treatment Network (SPARTAN) collaboration
* Pharmacologic medical therapies for ankylosing spondylitis(AS) include Nonsteroidal anti-inflammatory drugs (NSAIDs), tumor necrosis factor (TNF) blocker, analgesics, sulfasalazine,intraarticular injections and interleukin 17 (IL-17) inhibitors.

##### Nonsteroidal antiinflammatory drugs(NSAIDs)[4][5][6][7][8][9]

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* The first line treatment for all the patients who are having symptomatic ankylosing spondylitis (AS) are with Nonsteroidal antiinflammatory drugs(NSAIDs).
* 70 to 80 percent patients who are taking NSAIDs report substantial relief of back pain and stiffness.
* Play a crucial role in delaying the progression of ankylosing spondylitis.
* Regardless of which NSAID used, the maximum dose is usually required to manage AS.
* Treating with NSAIDs in AS especially in patients with increased erythrocyte sedimentation rate (ESR) shows especially effective in decreasing the ESR.[10]

Adult

* Preferred regimen (1): Indomethacin: Initial: 75 mg once daily, may increase to 75 mg twice daily (maximum dose: 150 mg/day) for at least 4 weeks.[11]
* Preferred regimen (2): Celecoxib or Etoricoxib: Oral: 200 mg once daily or 100 mg twice daily.[12][13][14][15][16][17]

#### Tumor necrosis factor alpha antagonists(TNF-alpha)[18][19][20][21][22]

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* Infliximab, etanercept, adalimumab, certolizumab, and golimumab are the available tumor necrosis factor alpha inhibitors(TNF-alpha) to treat AS.
* In AS there is no much of a use in adding immunomodulatory drug, such as methotrexate (MTX) as the evidence shows no additional benefit but may increase the cost and the risk of adverse effects.[23][24]
* Treating patients in AS with tumor necrosis factor alpha inhibitors(TNF-alpha) shows significant improvements in disease progress and function such as at least 40 percent improvement from baseline were seen.[25]
* Adalimumab, etanercept, and infliximab have the same efficacy and potency in treating the AS patients.[26]
* Patients who are getting treated with tumor necrosis factor alpha inhibitors shows approximately 80% good response and at least 50% improvement from the baseline of the disease.[27]
* Response to TNF antagonists: The following parameters are sighs of a good response to TNF antagonists[28][29]
* Age, especially young patients.
* Elevated C-reactive protein (CRP).
* The best predictor is, Shorter disease duration.
* Treating with TNF alpha inhibitors in patients with AS shows beneficial effect in improving bone density.[30][31][32]

##### Side Effects[33]

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* Using TNF-alpha inhibitors increases the risk of reactivation of latent tuberculosis and
* Using TNF-alpha inhibitors increases the risk of exacerbation or development of demyelinating disease.

Adult Dosage

* Preferred regimen (1): Infliximab 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 6 weeks thereafter.
* Preferred regimen (2): Etanercept once-weekly dosing: 50 mg once weekly; maximum dose (rheumatoid arthritis): 50 mg/week.
* Preferred regimen (3): Adalimumab IV: 2 mg/kg at weeks 0, 4, and then every 8 weeks thereafter.
* Preferred regimen (4): Certolizumab Initial: 400 mg, repeat dose 2 and 4 weeks after initial dose; Maintenance: 200 mg every 2 weeks or 400 mg every 4 weeks.

##### Disease-modifying antirheumatic drugs(DMARDs)

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* The use of DMARDs regarded as useful but is limited in AS patients with sulfasalazine.
* Preferred regimen (1): Oral: Initial: 500 mg once daily; may increase up to 2 to 3 g/day in divided doses.

Other DMARDs

* Methotrexate

* Leflunomide

##### Glucocorticoids

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* Pharmacologic medical therapies for Ankylosing spondylitis (AS) include Glucocorticoids but using them for long term basis for patients is not suggested, although high doses of prednisolone may have shown some benefit for very short-term therapy.[34]

* Prednisolone has dose-dependent therapeutic properties in AS.[35][36]
* Preferred regimen (1): Prednisolone: oral: 0.1 to 2 mg/kg/day in 3 or 4 divided dose.

##### Monoclonal antibody[37][38]

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* In the United States Secukinumab has been approved for use in patients with AS.[39]
* Secukinumab, is an anti-interleukin (IL)-17A monoclonal antibody.[40]
* IL-17A a proinflammatory cytokine which plays important role in the pathogenesis of AS.[41]
* Preferred regimen (1): Secukinumab:150 mg administered subcutaneously weekly for four weeks, then every four weeks thereafter.
* Preferred regimen (2): Ustekinumab: IV: Infuse over at least 1 hour; use of IV set with an in-line, low-protein binding filter (0.2 micrometer) required.
* Preferred regimen (3): Pamidronate:30 mg/10 mL (10 mL); 90 mg/10 mL (10 mL).[42]
* Preferred regimen (4): Rituximab IV: 1,000 mg on days 1 and 15.[43]

##### Turmeric[44][45]

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* Curcuma longa (turmeric) has a very long history of extensive use in Ayurvedic medicine as a treatment for inflammatory conditions in India.[46]
* Turmeric contains 3 active components called curcuminoids[47]
* Curcumin(diferuloylmethane)
* Demethoxycurcumin
* Bisdemethoxycurcumin

* Turmeric when administered orally in the diet improves both the wasting and histopathological signs of inflammation.
* Curcumin also suppress the expression of inflammatory cytokines such as TNF-α.
* Curcumin when combined with IL-10, curcumin inhibited NF-κB quite effectively.[48]
* Preferred regimen(1): Turmeric :150 mg of curcumin twice daily, decreases the levels of expression of inflammatory cytokines such as TNF-α and IL-6 in serum.[49]
* Preferred regimen(2):Turmeric: 2 gms/day of curcumin can suppress NF-κB activation.[50]

## References

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1. ↑ Braun J, van den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, Collantes-Estevez E, Dagfinrud H, Dijkmans B, Dougados M, Emery P, Geher P, Hammoudeh M, Inman RD, Jongkees M, Khan MA, Kiltz U, Kvien T, Leirisalo-Repo M, Maksymowych WP, Olivieri I, Pavelka K, Sieper J, Stanislawska-Biernat E, Wendling D, Ozgocmen S, van Drogen C, van Royen B, van der Heijde D (June 2011). "2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis". Ann. Rheum. Dis. 70 (6): 896–904. doi:10.1136/ard.2011.151027. PMC 3086052. PMID 21540199.
2. ↑ Zochling J, van der Heijde D, Burgos-Vargas R, Collantes E, Davis JC, Dijkmans B, Dougados M, Géher P, Inman RD, Khan MA, Kvien TK, Leirisalo-Repo M, Olivieri I, Pavelka K, Sieper J, Stucki G, Sturrock RD, van der Linden S, Wendling D, Böhm H, van Royen BJ, Braun J (April 2006). "ASAS/EULAR recommendations for the management of ankylosing spondylitis". Ann. Rheum. Dis. 65 (4): 442–52. doi:10.1136/ard.2005.041137. PMC 1798102. PMID 16126791.
3. ↑ Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, Smith JA, Borenstein D, Hiratzka J, Weiss PF, Inman RD, Majithia V, Haroon N, Maksymowych WP, Joyce J, Clark BM, Colbert RA, Figgie MP, Hallegua DS, Prete PE, Rosenbaum JT, Stebulis JA, van den Bosch F, Yu DT, Miller AS, Reveille JD, Caplan L (February 2016). "American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis". Arthritis Rheumatol. 68 (2): 282–98. doi:10.1002/art.39298. PMC 5123840. PMID 26401991.
4. ↑ Ardoin SP, Sundy JS (May 2006). "Update on nonsteriodal anti-inflammatory drugs". Curr Opin Rheumatol. 18 (3): 221–6. doi:10.1097/01.bor.0000218940.04613.cc. PMID 16582683.
5. ↑ Zochling J, van der Heijde D, Dougados M, Braun J (April 2006). "Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis". Ann. Rheum. Dis. 65 (4): 423–32. doi:10.1136/ard.2005.041129. PMC 1798100. PMID 16126792.
6. ↑ van den Berg R, Baraliakos X, Braun J, van der Heijde D (August 2012). "First update of the current evidence for the management of ankylosing spondylitis with non-pharmacological treatment and non-biologic drugs: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis". Rheumatology (Oxford). 51 (8): 1388–96. doi:10.1093/rheumatology/kes066. PMID 22513148.
7. ↑ Lequesne M (February 1990). "Methodology issues in the evaluation of NSAID in inflammatory rheumatic diseases". J Rheumatol Suppl. 20: 25–8. PMID 2182853.
8. ↑ Kroon FP, van der Burg LR, Ramiro S, Landewé RB, Buchbinder R, Falzon L, van der Heijde D (July 2015). "Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis)". Cochrane Database Syst Rev (7): CD010952. doi:10.1002/14651858.CD010952.pub2. PMID 26186173.
9. ↑ Wanders A, Heijde D, Landewé R, Béhier JM, Calin A, Olivieri I, Zeidler H, Dougados M (June 2005). "Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial". Arthritis Rheum. 52 (6): 1756–65. doi:10.1002/art.21054. PMID 15934081. Vancouver style error: initials (help)
10. ↑ Kroon F, Landewé R, Dougados M, van der Heijde D (October 2012). "Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis". Ann. Rheum. Dis. 71 (10): 1623–9. doi:10.1136/annrheumdis-2012-201370. PMID 22532639.
11. ↑ Calin A, Elswood J (June 1990). "A prospective nationwide cross-sectional study of NSAID usage in 1331 patients with ankylosing spondylitis". J. Rheumatol. 17 (6): 801–3. PMID 1974927.
12. ↑ van der Heijde D, Baraf HS, Ramos-Remus C, Calin A, Weaver AL, Schiff M, James M, Markind JE, Reicin AS, Melian A, Dougados M (April 2005). "Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study". Arthritis Rheum. 52 (4): 1205–15. doi:10.1002/art.20985. PMID 15818702.
13. ↑ Barkhuizen A, Steinfeld S, Robbins J, West C, Coombs J, Zwillich S (September 2006). "Celecoxib is efficacious and well tolerated in treating signs and symptoms of ankylosing spondylitis". J. Rheumatol. 33 (9): 1805–12. PMID 16960941.
14. ↑ Dougados M, Béhier JM, Jolchine I, Calin A, van der Heijde D, Olivieri I, Zeidler H, Herman H (January 2001). "Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug". Arthritis Rheum. 44 (1): 180–5. doi:10.1002/1529-0131(200101)44:1<180::AID-ANR24>3.0.CO;2-K. PMID 11212158.
15. ↑ Matsumoto AK, Melian A, Mandel DR, McIlwain HH, Borenstein D, Zhao PL, Lines CR, Gertz BJ, Curtis S (August 2002). "A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis". J. Rheumatol. 29 (8): 1623–30. PMID 12180720.
16. ↑ Lories RJ (December 2012). "Etoricoxib and the treatment of ankylosing spondylitis". Expert Opin Drug Metab Toxicol. 8 (12): 1599–608. doi:10.1517/17425255.2012.741120. PMID 23126318.
17. ↑ Sieper J, Klopsch T, Richter M, Kapelle A, Rudwaleit M, Schwank S, Regourd E, May M (March 2008). "Comparison of two different dosages of celecoxib with diclofenac for the treatment of active ankylosing spondylitis: results of a 12-week randomised, double-blind, controlled study". Ann. Rheum. Dis. 67 (3): 323–9. doi:10.1136/ard.2007.075309. PMID 17616556.
18. ↑ Sieper J (2009). "Developments in the scientific and clinical understanding of the spondyloarthritides". Arthritis Res. Ther. 11 (1): 208. doi:10.1186/ar2562. PMC 2688219. PMID 19232062.
19. ↑ Breban M, Ravaud P, Claudepierre P, Baron G, Henry YD, Hudry C, Euller-Ziegler L, Pham T, Solau-Gervais E, Chary-Valckenaere I, Marcelli C, Perdriger A, Le Loët X, Wendling D, Fautrel B, Fournié B, Combe B, Gaudin P, Jousse S, Mariette X, Baleydier A, Trape G, Dougados M (January 2008). "Maintenance of infliximab treatment in ankylosing spondylitis: results of a one-year randomized controlled trial comparing systematic versus on-demand treatment". Arthritis Rheum. 58 (1): 88–97. doi:10.1002/art.23167. PMID 18163509.
20. ↑ Baji P, Péntek M, Szántó S, Géher P, Gulácsi L, Balogh O, Brodszky V (May 2014). "Comparative efficacy and safety of biosimilar infliximab and other biological treatments in ankylosing spondylitis: systematic literature review and meta-analysis". Eur J Health Econ. 15 Suppl 1: S45–52. doi:10.1007/s10198-014-0593-5. PMC 4046080. PMID 24832835.
21. ↑ Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, Benkhalti Jandu M, Tugwell P, Wells GA (April 2015). "TNF-alpha inhibitors for ankylosing spondylitis". Cochrane Database Syst Rev (4): CD005468. doi:10.1002/14651858.CD005468.pub2. PMID 25887212.
22. ↑ Corbett M, Soares M, Jhuti G, Rice S, Spackman E, Sideris E, Moe-Byrne T, Fox D, Marzo-Ortega H, Kay L, Woolacott N, Palmer S (February 2016). "Tumour necrosis factor-α inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation". Health Technol Assess. 20 (9): 1–334, v–vi. doi:10.3310/hta20090. PMC 4781282. PMID 26847392.
23. ↑ Li EK, Griffith JF, Lee VW, Wang YX, Li TK, Lee KK, Tam LS (September 2008). "Short-term efficacy of combination methotrexate and infliximab in patients with ankylosing spondylitis: a clinical and magnetic resonance imaging correlation". Rheumatology (Oxford). 47 (9): 1358–63. doi:10.1093/rheumatology/ken207. PMID 18573802.
24. ↑ Marzo-Ortega H, McGonagle D, Jarrett S, Haugeberg G, Hensor E, O'connor P, Tan AL, Conaghan PG, Greenstein A, Emery P (November 2005). "Infliximab in combination with methotrexate in active ankylosing spondylitis: a clinical and imaging study". Ann. Rheum. Dis. 64 (11): 1568–75. doi:10.1136/ard.2004.022582. PMC 1755262. PMID 15829577.
25. ↑ Callhoff J, Sieper J, Weiß A, Zink A, Listing J (June 2015). "Efficacy of TNFα blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis". Ann. Rheum. Dis. 74 (6): 1241–8. doi:10.1136/annrheumdis-2014-205322. PMID 24718959.
26. ↑ McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, Hill RA, Jones A, Mujica Mota R, Walley T (August 2007). "Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation". Health Technol Assess. 11 (28): 1–158, iii–iv. PMID 17651658.
27. ↑ Anderson JJ, Baron G, van der Heijde D, Felson DT, Dougados M (August 2001). "Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis". Arthritis Rheum. 44 (8): 1876–86. doi:10.1002/1529-0131(200108)44:8<1876::AID-ART326>3.0.CO;2-F. PMID 11508441.
28. ↑ Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J (June 2004). "Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis". Ann. Rheum. Dis. 63 (6): 665–70. doi:10.1136/ard.2003.016386. PMC 1755042. PMID 15037444.
29. ↑ Rudwaleit M, Claudepierre P, Wordsworth P, Cortina EL, Sieper J, Kron M, Carcereri-De-Prati R, Kupper H, Kary S (April 2009). "Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis". J. Rheumatol. 36 (4): 801–8. doi:10.3899/jrheum.081048. PMID 19273449.
30. ↑ Barnabe C, Hanley DA (October 2009). "Effect of tumor necrosis factor alpha inhibition on bone density and turnover markers in patients with rheumatoid arthritis and spondyloarthropathy". Semin. Arthritis Rheum. 39 (2): 116–22. doi:10.1016/j.semarthrit.2008.04.004. PMID 18585759.
31. ↑ Durnez A, Paternotte S, Fechtenbaum J, Landewé RB, Dougados M, Roux C, Briot K (October 2013). "Increase in bone density in patients with spondyloarthritis during anti-tumor necrosis factor therapy: 6-year followup study". J. Rheumatol. 40 (10): 1712–8. doi:10.3899/jrheum.121417. PMID 23950191.
32. ↑ Chopin F, Garnero P, le Henanff A, Debiais F, Daragon A, Roux C, Sany J, Wendling D, Zarnitsky C, Ravaud P, Thomas T (March 2008). "Long-term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis". Ann. Rheum. Dis. 67 (3): 353–7. doi:10.1136/ard.2007.076604. PMID 17644538.
33. ↑ Baeten D, Kruithof E, Van den Bosch F, Van den Bossche N, Herssens A, Mielants H, De Keyser F, Veys EM (September 2003). "Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease?". Ann. Rheum. Dis. 62 (9): 829–34. PMC 1754658. PMID 12922954.
34. ↑ Haibel H, Fendler C, Listing J, Callhoff J, Braun J, Sieper J (January 2014). "Efficacy of oral prednisolone in active ankylosing spondylitis: results of a double-blind, randomised, placebo-controlled short-term trial". Ann. Rheum. Dis. 73 (1): 243–6. doi:10.1136/annrheumdis-2012-203055. PMID 23625982.
35. ↑ Maksymowych WP, Jhangri GS, Fitzgerald AA, LeClercq S, Chiu P, Yan A, Skeith KJ, Aaron SL, Homik J, Davis P, Sholter D, Russell AS (March 2002). "A six-month randomized, controlled, double-blind, dose-response comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal antiinflammatory drug-refractory ankylosing spondylitis". Arthritis Rheum. 46 (3): 766–73. doi:10.1002/art.10139. PMID 11920413.
36. ↑ Bandinelli F, Scazzariello F, Pimenta da Fonseca E, Barreto Santiago M, Marcassa C, Nacci F, Matucci Cerinic M (2016). "Low-dose modified-release prednisone in axial spondyloarthritis: 3-month efficacy and tolerability". Drug Des Devel Ther. 10: 3717–3724. doi:10.2147/DDDT.S115099. PMC 5115695. PMID 27881910.
37. ↑ Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, van der Heijde D, McInnes I, van Laar JM, Landewé R, Wordsworth P, Wollenhaupt J, Kellner H, Paramarta J, Wei J, Brachat A, Bek S, Laurent D, Li Y, Wang YA, Bertolino AP, Gsteiger S, Wright AM, Hueber W (November 2013). "Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial". Lancet. 382 (9906): 1705–13. doi:10.1016/S0140-6736(13)61134-4. PMID 24035250.
38. ↑ Baeten D, Sieper J, Braun J, Baraliakos X, Dougados M, Emery P, Deodhar A, Porter B, Martin R, Andersson M, Mpofu S, Richards HB (December 2015). "Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis". N. Engl. J. Med. 373 (26): 2534–48. doi:10.1056/NEJMoa1505066. PMID 26699169.
39. ↑ Blair HA, Dhillon S (July 2016). "Secukinumab: A Review in Ankylosing Spondylitis". Drugs. 76 (10): 1023–30. doi:10.1007/s40265-016-0598-8. PMID 27255593.
40. ↑ Braun J, Baraliakos X, Kiltz U (2016). "Secukinumab (AIN457) in the treatment of ankylosing spondylitis". Expert Opin Biol Ther. 16 (5): 711–22. doi:10.1517/14712598.2016.1167183. PMID 26982813.
41. ↑ Dubash S, McGonagle D, Marzo-Ortega H (March 2018). "New advances in the understanding and treatment of axial spondyloarthritis: from chance to choice". Ther Adv Chronic Dis. 9 (3): 77–87. doi:10.1177/2040622317743486. PMC 5833172. PMID 29511503.
42. ↑ Maksymowych WP, Lambert R, Jhangri GS, Leclercq S, Chiu P, Wong B, Aaron S, Russell AS (January 2001). "Clinical and radiological amelioration of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy". J. Rheumatol. 28 (1): 144–55. PMID 11196517.
43. ↑ Song IH, Heldmann F, Rudwaleit M, Listing J, Appel H, Braun J, Sieper J (May 2010). "Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial". Arthritis Rheum. 62 (5): 1290–7. doi:10.1002/art.27383. PMID 20461780.
44. ↑ Haibel H, Fendler C, Listing J, Callhoff J, Braun J, Sieper J (January 2014). "Efficacy of oral prednisolone in active ankylosing spondylitis: results of a double-blind, randomised, placebo-controlled short-term trial". Ann. Rheum. Dis. 73 (1): 243–6. doi:10.1136/annrheumdis-2012-203055. PMID 23625982.
45. ↑ Aggarwal BB, Gupta SC, Sung B (August 2013). "Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers". Br. J. Pharmacol. 169 (8): 1672–92. doi:10.1111/bph.12131. PMC 3753829. PMID 23425071.
46. ↑ Jurenka JS (June 2009). "Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research". Altern Med Rev. 14 (2): 141–53. PMID 19594223.
47. ↑ Jurenka JS (June 2009). "Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research". Altern Med Rev. 14 (2): 141–53. PMID 19594223.
48. ↑ Sugimoto K, Hanai H, Tozawa K, Aoshi T, Uchijima M, Nagata T, Koide Y (December 2002). "Curcumin prevents and ameliorates trinitrobenzene sulfonic acid-induced colitis in mice". Gastroenterology. 123 (6): 1912–22. doi:10.1053/gast.2002.37050. PMID 12454848.
49. ↑ Tham CL, Liew CY, Lam KW, Mohamad AS, Kim MK, Cheah YK, Zakaria ZA, Sulaiman MR, Lajis NH, Israf DA (February 2010). "A synthetic curcuminoid derivative inhibits nitric oxide and proinflammatory cytokine synthesis". Eur. J. Pharmacol. 628 (1–3): 247–54. doi:10.1016/j.ejphar.2009.11.053. PMID 19958764.
50. ↑ Sung B, Kunnumakkara AB, Sethi G, Anand P, Guha S, Aggarwal BB (April 2009). "Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model". Mol. Cancer Ther. 8 (4): 959–70. doi:10.1158/1535-7163.MCT-08-0905. PMC 2694943. PMID 19372569.

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