Molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritisScientific Research
Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study
Abstract
Background
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of bone and cartilage. Although its etiology is unclear, hydroxyl radicals have been proposed to be involved in the pathogenesis of RA. Molecular hydrogen (H2) has recently been shown to be a selective scavenger for hydroxyl radicals. A method has also been developed to treat water containing extremely high concentrations of H2. We hypothesized that H2 in water could complement conventional treatments by reducing oxidative stress in RA.
Methods
Twenty rheumatoid arthritis (RA) patients drank 530 ml of water containing 4 to 5 ppm molecular hydrogen (water high in H2) daily for 4 weeks. After a 4-week washout period, patients continued to drink high-H2 water for 4 weeks. Urinary 8-hydroxydeoxyguanine (8-OHdG) and disease activity (DAS28, using C-reactive protein [CRP] levels) were estimated at the end of every 4 weeks.
Results
Drinking water high in H2 appears to increase H2 concentrations in the body more than water saturated with H2 (1.6 ppm). On average, urinary 8-OHdG was significantly reduced by 14.3% (p < 0.01). DAS28 also decreased from 3.83 to 3.02 over the same period (p < 0.01). After the washout period, both urinary 8-OHdG and mean DAS28 decreased compared with the end of the drinking period. During the second drinking period, the mean DAS28 decreased from 2.83 to 2.26 (p < 0.01). Urinary 8-OHdG did not decrease further but remained below baseline. All 5 patients with early RA (duration < 12 months) who did not show antibodies to cyclic citrullinated peptide (ACPA) achieved remission, and 4 of them were asymptomatic at the end of the study.
Conclusion
The results show that the hydroxyl radical scavenger H2 is effective in reducing oxidative stress in patients with this disease. High H2 water can significantly improve symptoms of RA.
References
Smith HS, Smith AR, Seidner P: Painful rheumatoid arthritis. Pain Physician. 2011, 14: E427-E458.
McInnes IB, Schett G: The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011, 365: 2205-2219. 10.1056/NEJMra1004965.
Chinopoulos C, Adam-Vizi V: Calcium, mitochondria and oxidative stress in neuronal pathology. Novel aspects of an enduring theme. FEBS J. 2006, 273: 433-450. 10.1111/j.1742-4658.2005.05103.x.
Papa S: Mitochondrial oxidative phosphorylation changes in the life span. Molecular aspects and physiopathological implications. Biochim Biophys Acta. 1996, 1276: 87-105. 10.1016/0005-2728(96)00077-1.
Quinn MT, Gauss KA: Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J Leukoc Biol. 2004, 76: 760-781. 10.1189/jlb.0404216.
Cross AR, Segal AW: The NADPH oxidase of professional phagocytes–prototype of the NOX electron transport chain systems. Biochim Biophys Acta. 2004, 1657: 1-22. 10.1016/j.bbabio.2004.03.008.
Filippin LI, Vercelino R, Marroni NP, Xavier RM: Redox signalling and the inflammatory response in rheumatoid arthritis. Clin Exp Immunol. 2008, 152: 415-422. 10.1111/j.1365-2249.2008.03634.x.
Winyard PG, et al: Measurement and meaning of markers of reactive species of oxygen, nitrogen and sulfur in healthy human subjects and patients with inflammatory joint disease. Biochem Soc Trans. 2011, 39: 1226-1232. 10.1042/BST0391226.
Hadjigogos K: The role of free radicals in the pathogenesis of rheumatoid arthritis. Panminerva Med. 2003, 45: 7-13.
Kasai H, et al: Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis. 1986, 7: 1849-1851. 10.1093/carcin/7.11.1849.
Maki H, Sekiguchi M: MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis. Nature. 1992, 355: 273-275. 10.1038/355273a0.
Ishibashi T, Hayakawa H, Sekiguchi M: A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides. EMBO Rep. 2003, 4: 479-483. 10.1038/sj.embor.embor838.
Negishi H, et al: The relation of oxidative DNA damage to hypertension and other cardiovascular risk factors in Tanzania. J Hypertens. 2001, 19: 529-533. 10.1097/00004872-200103001-00002.
Nishikawa T, et al: Evaluation of urinary 8-hydroxydeoxy-guanosine as a novel biomarker of macrovascular complications in type 2 diabetes. Diabetes Care. 2003, 26: 1507-1512. 10.2337/diacare.26.5.1507.
Shen J, et al: Telomere length, oxidative damage, antioxidants and breast cancer risk. International journal of cancer. Journal international du cancer. 2009, 124: 1637-1643. 10.1002/ijc.24105.
Bashir S, Harris G, Denman MA, Blake DR, Winyard PG: Oxidative DNA damage and cellular sensitivity to oxidative stress in human autoimmune diseases. Ann Rheum Dis. 1993, 52: 659-666. 10.1136/ard.52.9.659.
Miyamoto M, Kotani K, Ishibashi S, Taniguchi N: The relationship between urinary 8-hydroxydeoxyguanosine and metabolic risk factors in asymptomatic subjects. Medical principles and practice: international journal of the Kuwait University, Health Science Centre. 2011, 20: 187-190. 10.1159/000319774.
Masugata H, et al: Association between Urinary 8-Hydroxydeoxyguanosine, an Indicator of Oxidative Stress, and the Cardio-Ankle Vascular Index in Hypertensive Patients. J Atheroscler Thromb. 2012, 19: 747-755. 10.5551/jat.12716.
Ohsawa I, et al: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007, 13: 688-694. 10.1038/nm1577.
Gharib B, et al: Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. Comptes rendus de l’Academie des sciences. Serie III. Sciences de la vie. 2001, 324: 719-724.
Abraini JH, Gardette-Chauffour MC, Martinez E, Rostain JC, Lemaire C: Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture. J Appl Physiol. 1994, 76: 1113-1118.
Fontanari P, et al: Changes in maximal performance of inspiratory and skeletal muscles during and after the 7.1-MPa Hydra 10 record human dive. Eur J Appl Physiol. 2000, 81: 325-328. 10.1007/s004210050050.
Ohta S: Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des. 2011, 17: 2241-2252. 10.2174/138161211797052664.
Kajiyama S, et al: Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 2008, 28: 137-143. 10.1016/j.nutres.2008.01.008.
Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N: Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr. 2010, 46: 140-149. 10.3164/jcbn.09-100.
Schellekens GA, et al: The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000, 43: 155-163. 10.1002/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2–3.
Van Gaalen FA, et al: Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum. 2004, 50: 2113-2121. 10.1002/art.20316.
Seo T, Kurokawa R, Sato B: A convenient method for determining the concentration of hydrogen in water: use of methylene blue with colloidal platinum. Medical gas research. 2012, 2: 1-10.1186/2045-9912-2-1.
Ito M, et al: Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Medical gas research. 2012, 2: 15-10.1186/2045-9912-2-15.
Saito S, et al: Quantitative determination of urinary 8-hydroxydeoxyguanosine (8-OH-dg) by using ELISA. Res Commun Mol Pathol Pharmacol. 2000, 107: 39-44.
Ghoshal UC: How to interpret hydrogen breath tests. Journal of neurogastroenterology and motility. 2011, 17: 312-317. 10.5056/jnm.2011.17.3.312.
Goebel KM, Storck U, Neurath F: Intrasynovial orgotein therapy in rheumatoid arthritis. Lancet. 1981, 1: 1015-1017.
Salvemini D, Cuzzocrea S: Therapeutic potential of superoxide dismutase mimetics as therapeutic agents in critical care medicine. rit Care Med. 2003, 31: S29-38. 10.1097/01.CCM.0000042468.64712.21.
Afonso V, Champy R, Mitrovic D, Collin P, Lomri A: Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine. 2007, 74: 324-329. 10.1016/j.jbspin.2007.02.002.
Edaravone Acute Infarction Study Group: Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis. 2003, 15: 222-229.
Arii K, Kumon Y, Ikeda Y, Suehiro T, Hashimoto K: Edaravone inhibits the disease activity in rheumatoid arthritis. J Clin Pharm Ther. 2006, 31: 197-199. 10.1111/j.1365-2710.2006.00722.x.
Buchholz BM, et al: Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2008, 8: 2015-2024. 10.1111/j.1600-6143.2008.02359.x.
Suzuki YJ, Forman HJ, Sevanian A: Oxidants as stimulators of signal transduction. Free Radic Biol Med. 1997, 22: 269-285. 10.1016/S0891-5849(96)00275-4.
Finkel T: Oxygen radicals and signaling. Curr Opin Cell Biol. 1998, 10: 248-253. 10.1016/S0955-0674(98)80147-6.
Qin ZX, et al: Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. Atherosclerosis. 2012, 220: 343-350. 10.1016/j.atherosclerosis.2011.11.002.
Ishibashi T, et al: Mammalian enzymes for preventing transcriptional 598 errors caused by oxidative damage. Nucleic Acids Res. 2005, 33: 3779-3784. 10.1093/nar/gki682.
Bang H, et al: Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum. 2007, 56: 2503-2511. 10.1002/art.22817.
Remans PH, et al: Clinical, Intracellular free radical production in synovial T lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum. 2005, 52: 2003-2009. 10.1002/art.21111.
Breedveld FC, Combe B: Understanding emerging treatment paradigms in rheumatoid arthritis. Arthritis Res Ther. 2011, 13 (Suppl 1): S3-10.1186/1478-6354-13-S1-S3.
Davila L, Ranganathan P: Pharmacogenetics: implications for therapy in rheumatic diseases. Nat Rev Rheumatol. 2011, 7: 537-550. 10.1038/nrrheum.2011.117.
Mitchell KL, Pisetsky D: Early rheumatoid arthritis. Curr Opin Rheumatol. 2007, 19: 278-283. 10.1097/BOR.0b013e32805e87bf.
Dougados M, et al: Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2012, 10.1136/annrheumdis-2011-201282.
Kavanaugh A, et al: Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis. 2012, 33: 3779-3784. 10.1136/annrheumdis-2011-201247.
Detert J, et al: Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann Rheum Dis. 2012, 10.1136/annrheumdis-2012-201612. Jul 7. [Epub ahead of print]
DOI: 10.1186
Published on: 20120210
Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study
Abstract
Background
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of bone and cartilage. Although its etiology is unclear, hydroxyl radicals have been proposed to be involved in the pathogenesis of RA. Molecular hydrogen (H2) has recently been shown to be a selective scavenger for hydroxyl radicals. A method has also been developed to treat water containing extremely high concentrations of H2. We hypothesized that H2 in water could complement conventional treatments by reducing oxidative stress in RA.
Methods
Twenty rheumatoid arthritis (RA) patients drank 530 ml of water containing 4 to 5 ppm molecular hydrogen (water high in H2) daily for 4 weeks. After a 4-week washout period, patients continued to drink high-H2 water for 4 weeks. Urinary 8-hydroxydeoxyguanine (8-OHdG) and disease activity (DAS28, using C-reactive protein [CRP] levels) were estimated at the end of every 4 weeks.
Results
Drinking water high in H2 appears to increase H2 concentrations in the body more than water saturated with H2 (1.6 ppm). On average, urinary 8-OHdG was significantly reduced by 14.3% (p < 0.01). DAS28 also decreased from 3.83 to 3.02 over the same period (p < 0.01). After the washout period, both urinary 8-OHdG and mean DAS28 decreased compared with the end of the drinking period. During the second drinking period, the mean DAS28 decreased from 2.83 to 2.26 (p < 0.01). Urinary 8-OHdG did not decrease further but remained below baseline. All 5 patients with early RA (duration < 12 months) who did not show antibodies to cyclic citrullinated peptide (ACPA) achieved remission, and 4 of them were asymptomatic at the end of the study.
Conclusion
The results show that the hydroxyl radical scavenger H2 is effective in reducing oxidative stress in patients with this disease. High H2 water can significantly improve symptoms of RA.
References
Smith HS, Smith AR, Seidner P: Painful rheumatoid arthritis. Pain Physician. 2011, 14: E427-E458.
McInnes IB, Schett G: The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011, 365: 2205-2219. 10.1056/NEJMra1004965.
Chinopoulos C, Adam-Vizi V: Calcium, mitochondria and oxidative stress in neuronal pathology. Novel aspects of an enduring theme. FEBS J. 2006, 273: 433-450. 10.1111/j.1742-4658.2005.05103.x.
Papa S: Mitochondrial oxidative phosphorylation changes in the life span. Molecular aspects and physiopathological implications. Biochim Biophys Acta. 1996, 1276: 87-105. 10.1016/0005-2728(96)00077-1.
Quinn MT, Gauss KA: Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J Leukoc Biol. 2004, 76: 760-781. 10.1189/jlb.0404216.
Cross AR, Segal AW: The NADPH oxidase of professional phagocytes–prototype of the NOX electron transport chain systems. Biochim Biophys Acta. 2004, 1657: 1-22. 10.1016/j.bbabio.2004.03.008.
Filippin LI, Vercelino R, Marroni NP, Xavier RM: Redox signalling and the inflammatory response in rheumatoid arthritis. Clin Exp Immunol. 2008, 152: 415-422. 10.1111/j.1365-2249.2008.03634.x.
Winyard PG, et al: Measurement and meaning of markers of reactive species of oxygen, nitrogen and sulfur in healthy human subjects and patients with inflammatory joint disease. Biochem Soc Trans. 2011, 39: 1226-1232. 10.1042/BST0391226.
Hadjigogos K: The role of free radicals in the pathogenesis of rheumatoid arthritis. Panminerva Med. 2003, 45: 7-13.
Kasai H, et al: Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. Carcinogenesis. 1986, 7: 1849-1851. 10.1093/carcin/7.11.1849.
Maki H, Sekiguchi M: MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis. Nature. 1992, 355: 273-275. 10.1038/355273a0.
Ishibashi T, Hayakawa H, Sekiguchi M: A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides. EMBO Rep. 2003, 4: 479-483. 10.1038/sj.embor.embor838.
Negishi H, et al: The relation of oxidative DNA damage to hypertension and other cardiovascular risk factors in Tanzania. J Hypertens. 2001, 19: 529-533. 10.1097/00004872-200103001-00002.
Nishikawa T, et al: Evaluation of urinary 8-hydroxydeoxy-guanosine as a novel biomarker of macrovascular complications in type 2 diabetes. Diabetes Care. 2003, 26: 1507-1512. 10.2337/diacare.26.5.1507.
Shen J, et al: Telomere length, oxidative damage, antioxidants and breast cancer risk. International journal of cancer. Journal international du cancer. 2009, 124: 1637-1643. 10.1002/ijc.24105.
Bashir S, Harris G, Denman MA, Blake DR, Winyard PG: Oxidative DNA damage and cellular sensitivity to oxidative stress in human autoimmune diseases. Ann Rheum Dis. 1993, 52: 659-666. 10.1136/ard.52.9.659.
Miyamoto M, Kotani K, Ishibashi S, Taniguchi N: The relationship between urinary 8-hydroxydeoxyguanosine and metabolic risk factors in asymptomatic subjects. Medical principles and practice: international journal of the Kuwait University, Health Science Centre. 2011, 20: 187-190. 10.1159/000319774.
Masugata H, et al: Association between Urinary 8-Hydroxydeoxyguanosine, an Indicator of Oxidative Stress, and the Cardio-Ankle Vascular Index in Hypertensive Patients. J Atheroscler Thromb. 2012, 19: 747-755. 10.5551/jat.12716.
Ohsawa I, et al: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007, 13: 688-694. 10.1038/nm1577.
Gharib B, et al: Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. Comptes rendus de l’Academie des sciences. Serie III. Sciences de la vie. 2001, 324: 719-724.
Abraini JH, Gardette-Chauffour MC, Martinez E, Rostain JC, Lemaire C: Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture. J Appl Physiol. 1994, 76: 1113-1118.
Fontanari P, et al: Changes in maximal performance of inspiratory and skeletal muscles during and after the 7.1-MPa Hydra 10 record human dive. Eur J Appl Physiol. 2000, 81: 325-328. 10.1007/s004210050050.
Ohta S: Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des. 2011, 17: 2241-2252. 10.2174/138161211797052664.
Kajiyama S, et al: Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 2008, 28: 137-143. 10.1016/j.nutres.2008.01.008.
Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N: Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr. 2010, 46: 140-149. 10.3164/jcbn.09-100.
Schellekens GA, et al: The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000, 43: 155-163. 10.1002/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2–3.
Van Gaalen FA, et al: Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis Rheum. 2004, 50: 2113-2121. 10.1002/art.20316.
Seo T, Kurokawa R, Sato B: A convenient method for determining the concentration of hydrogen in water: use of methylene blue with colloidal platinum. Medical gas research. 2012, 2: 1-10.1186/2045-9912-2-1.
Ito M, et al: Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Medical gas research. 2012, 2: 15-10.1186/2045-9912-2-15.
Saito S, et al: Quantitative determination of urinary 8-hydroxydeoxyguanosine (8-OH-dg) by using ELISA. Res Commun Mol Pathol Pharmacol. 2000, 107: 39-44.
Ghoshal UC: How to interpret hydrogen breath tests. Journal of neurogastroenterology and motility. 2011, 17: 312-317. 10.5056/jnm.2011.17.3.312.
Goebel KM, Storck U, Neurath F: Intrasynovial orgotein therapy in rheumatoid arthritis. Lancet. 1981, 1: 1015-1017.
Salvemini D, Cuzzocrea S: Therapeutic potential of superoxide dismutase mimetics as therapeutic agents in critical care medicine. rit Care Med. 2003, 31: S29-38. 10.1097/01.CCM.0000042468.64712.21.
Afonso V, Champy R, Mitrovic D, Collin P, Lomri A: Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine. 2007, 74: 324-329. 10.1016/j.jbspin.2007.02.002.
Edaravone Acute Infarction Study Group: Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis. 2003, 15: 222-229.
Arii K, Kumon Y, Ikeda Y, Suehiro T, Hashimoto K: Edaravone inhibits the disease activity in rheumatoid arthritis. J Clin Pharm Ther. 2006, 31: 197-199. 10.1111/j.1365-2710.2006.00722.x.
Buchholz BM, et al: Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2008, 8: 2015-2024. 10.1111/j.1600-6143.2008.02359.x.
Suzuki YJ, Forman HJ, Sevanian A: Oxidants as stimulators of signal transduction. Free Radic Biol Med. 1997, 22: 269-285. 10.1016/S0891-5849(96)00275-4.
Finkel T: Oxygen radicals and signaling. Curr Opin Cell Biol. 1998, 10: 248-253. 10.1016/S0955-0674(98)80147-6.
Qin ZX, et al: Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. Atherosclerosis. 2012, 220: 343-350. 10.1016/j.atherosclerosis.2011.11.002.
Ishibashi T, et al: Mammalian enzymes for preventing transcriptional 598 errors caused by oxidative damage. Nucleic Acids Res. 2005, 33: 3779-3784. 10.1093/nar/gki682.
Bang H, et al: Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum. 2007, 56: 2503-2511. 10.1002/art.22817.
Remans PH, et al: Clinical, Intracellular free radical production in synovial T lymphocytes from patients with rheumatoid arthritis. Arthritis Rheum. 2005, 52: 2003-2009. 10.1002/art.21111.
Breedveld FC, Combe B: Understanding emerging treatment paradigms in rheumatoid arthritis. Arthritis Res Ther. 2011, 13 (Suppl 1): S3-10.1186/1478-6354-13-S1-S3.
Davila L, Ranganathan P: Pharmacogenetics: implications for therapy in rheumatic diseases. Nat Rev Rheumatol. 2011, 7: 537-550. 10.1038/nrrheum.2011.117.
Mitchell KL, Pisetsky D: Early rheumatoid arthritis. Curr Opin Rheumatol. 2007, 19: 278-283. 10.1097/BOR.0b013e32805e87bf.
Dougados M, et al: Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2012, 10.1136/annrheumdis-2011-201282.
Kavanaugh A, et al: Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis. 2012, 33: 3779-3784. 10.1136/annrheumdis-2011-201247.
Detert J, et al: Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann Rheum Dis. 2012, 10.1136/annrheumdis-2012-201612. Jul 7. [Epub ahead of print]
