Methotrexate (MTX) is a nonbiological disease-modifying antirheumatic drug that has shown both a good control of clinical disease and a good safety. Usually drug-drug interactions (DDIs) represent the most limiting factor during the clinical management of any disease, in particular when several drugs are coadministered to treat the same disease. In this paper, we report the interactions among MTX and the other drugs commonly used in the management of rheumatoid arthritis. Using Medline, PubMed, Embase, Cochrane libraries, and Reference lists, we searched for the articles published until June 30, 2012, and we reported the most common DDIs between MTX and antirheumatic drugs. In particular, clinically relevant DDIs have been described during the treatment with MTX and NSAIDs, for example, diclofenac, indomethacin, or COX-2 inhibitors, and between MTX and prednisone or immunosuppressant drugs (e.g., leflunomide and cyclosporine). Finally, an increase in the risk of infections has been recorded during the combination treatment with MTX plus antitumor necrosis factor-α agents. In conclusion, during the treatment with MTX, DDIs play an important role in both the development of ADRs and therapeutic failure. 1. Introduction Rheumatoid arthritis (RA) is a chronic and autoimmune disease affecting about 1% of people, with the highest incidence between 40 and 70 years [1]. Drugs able to reduce inflammation and cells activation may be used in the management of RA. In particular, nonsteroidal anti-inflammatory drugs (NSAIDs) as well as immunosuppressive agents (i.e., glucocorticoids), disease-modifying antirheumatic drugs (DMARDs), and agents that are able to block the proinflammatory cytokine tumor necrosis factor-α (anti-TNF-α) may be used (Table 1). Table 1: Drugs used in the management of rheumatoid arthritis. NSAIDs, acting on cyclooxygenases, are able to control the inflammation and the clinical symptoms [2–4], but not the disease’s progression; their use as monotherapy for a long time is limited for the development of adverse drug reactions (ADRs) [5]. Glucocorticoids (e.g., dexamethasone and prednisone) are anti-inflammatory and immune suppressor agents that are able to reduce the inflammation and the progression of RA, through the inhibition of cytokines secretion and osteoclasts activation [6–15]. However, even if they represent a first-line treatment in patients with RA, their use is limited for the development of serious ADRs such as loss of bone mass, increased risk of fractures, infections, diabetes and hypertension [16–18]. The DMARDs group, includes
References
[1]
S. Tambar and E. M. Ruderman, “Current management of rheumatoid arthritis,” Managed Care Interface, vol. 20, no. 7, pp. 18–24, 2007.
[2]
S. De Fazio, L. Gallelli, P. Gareri, D. Mazzotta, P. A. Rende, and G. De Sarro, “Pharmacological properties of nonsteroideal anti-inflammatory drugs: a review,” Current Topics in Pharmacology, vol. 13, no. 1, pp. 75–83, 2009.
[3]
L. Gallelli, O. Galasso, A. Urzino, et al., “Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis,” Clinical Drug Investigation, vol. 32, pp. 827–833, 2012.
[4]
F. Oliva and L. Gallelli, “Ibuprofen pharmacology and its implications for musculoskeletal disorders,” Functional Neurology, vol. 25, no. 3, supplement 1, pp. 1–19, 2010.
[5]
L. Gallelli, M. Colosimo, D. Pirritano et al., “Retrospective evaluation of adverse drug reactions induced by nonsteroidal anti-inflammatory drugs,” Clinical Drug Investigation, vol. 27, no. 2, pp. 115–122, 2007.
[6]
J. W. Bijlsma, “Disease control with glucocorticoid therapy in rheumatoid arthritis,” Rheumatology, vol. 51, supplement 4, pp. 9–13, 2012.
[7]
M. Boers, “Prednisone for rheumatoid arthritis: the detriment of the doubt,” Nederlands Tijdschrift voor Geneeskunde, vol. 155, no. 32, p. A5069, 2012.
[8]
L. Clarke and J. Kirwan, “Efficacy, safety and mechanism of action of modified-release prednisone in rheumatoid arthritis,” Therapeutic Advances in Musculoskeletal Disease, vol. 4, no. 3, pp. 159–166, 2012.
[9]
G. Haugeberg, A. Strand, T. K. Kvien, and J. R. Kirwan, “Reduced loss of hand bone density with prednisolone in early rheumatoid arthritis: results from a randomized placebo-controlled trial,” Archives of Internal Medicine, vol. 165, no. 11, pp. 1293–1297, 2005.
[10]
D. Makrygiannakis, S. Revu, M. Engstrom, et al., “Local administration of glucocorticoids decreases synovial citrullination in rheumatoid arthritis,” Arthritis Research & Therapy, vol. 14, no. 1, p. R20, 2012.
[11]
E. McKeown, V. P. Bykerk, F. De Leon et al., “CATCH Investigators. Quality assurance study of the use of preventative therapies in glucocorticoid-induced osteoporosis in early inflammatory arthritis: results from the CATCH cohort,” Rheumatology, vol. 51, no. 9, pp. 1662–1669, 2012.
[12]
C. Montecucco, M. Todoerti, G. Sakellariou, C. A. Scirè, and R. Caporali, “Low-dose oral prednisone improves clinical and ultrasonographic remission rates in early rheumatoid arthritis: results of a 12-month open-label randomised study,” Arthritis Research & Therapy, vol. 14, no. 3, p. R112, 2012.
[13]
J. R. O'Dell, “Therapeutic strategies for rheumatoid arthritis,” The New England Journal of Medicine, vol. 350, no. 25, pp. 2591–2630, 2004.
[14]
R. A. Quax, J. W. Koper, P. H. de Jong, et al., “In vitro glucocorticoid sensitivity is associated with clinical glucocorticoid therapy outcome in rheumatoid arthritis,” Arthritis Research & Therapy, vol. 14, no. 4, p. R195, 2012.
[15]
D. L. Scott, K. Pugner, K. Kaarela et al., “The links between joint damage and disability in rheumatoid arthritis,” Rheumatology, vol. 39, no. 2, pp. 122–132, 2000.
[16]
U. Baschant, N. E. Lane, and J. Tuckermann, “The multiple facets of glucocorticoid action in rheumatoid arthritis,” Nature Reviews Rheumatology, vol. 8, no. 11, pp. 645–655, 2012.
[17]
S.-G. Lee, Y.-E. Park, S.-H. Park, et al., “Increased frequency of osteoporosis and BMD below the expected range for age among South Korean women with rheumatoid arthritis,” International Journal of Rheumatic Diseases, vol. 15, no. 3, pp. 289–296, 2012.
[18]
J. R. Curtis, A. Lanas, A. John, D. A. Johnson, and K. L. Schulman, “Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis,” Arthritis Care & Research, vol. 64, no. 12, pp. 1819–1828, 2012.
[19]
J. Zeidler, H. Zeidler, and J. M. Graf von der Schulenburg, “Therapy of rheumatoid arthritis with methotrexate : claims data analysis of treatment patterns,” Zeitschrift für Rheumatologie, vol. 71, no. 10, pp. 900–907, 2012.
[20]
K. Kruger, J. Wollenhaupt, K. Albrecht, et al., “guidelines for the sequential medical treatment of rheumatoid arthritis. Adapted EULAR recommendations and updated treatment algorithm,” Zeitschrift für Rheumatologie, vol. 71, no. 7, pp. 592–603, 2012.
[21]
A. D. Protogerou, E. Zampeli, and P. P. Sfikakis, “Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis,” Annals of Internal Medicine, vol. 157, no. 4, pp. 299–300, 2012.
[22]
S. K. Agarwal, “Biologic agents in rheumatoid arthritis: an update for managed care professionals,” Journal of Managed Care Pharmacy, vol. 179, supplement B, pp. S14–S18, 2011.
[23]
K. G. Saag, G. T. Gim, N. M. Patkar et al., “American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis,” Arthritis Care and Research, vol. 59, no. 6, pp. 762–784, 2008.
[24]
L. Gallelli, G. Ferreri, M. Colosimo et al., “Adverse drug reactions to antibiotics observed in two pulmonology divisions of Catanzaro, Italy: a six-year retrospective study,” Pharmacological Research, vol. 46, no. 5, pp. 395–400, 2002.
[25]
L. Gallelli, G. Ferreri, M. Colosimo et al., “Retrospective analysis of adverse drug reactions to bronchodilators observed in two pulmonary divisions of Catanzaro, Italy,” Pharmacological Research, vol. 47, no. 6, pp. 493–499, 2003.
[26]
L. Gallelli, V. Guadagnino, B. Caroleo, N. Marigliano, G. B. De Sarro, and A. Izzi, “Bilateral skin ulceration after injection of pegylated interferon-α -2b in a patient with chronic hepatitis C,” Clinical Drug Investigation, vol. 23, no. 9, pp. 615–619, 2003.
[27]
L. Gallelli, M. Nardi, T. Prantera et al., “Retrospective analysis of adverse drug reactions induced by gemcitabine treatment in patients with non-small cell lung cancer,” Pharmacological Research, vol. 49, no. 3, pp. 259–263, 2004.
[28]
L. Gallelli, V. Guadagnino, B. Caroleo, N. Marigliano, and G. De Sarro, “Cutaneous ulceration induced by interferon alfa,” Annals of Pharmacotherapy, vol. 38, no. 1, pp. 173–174, 2004.
[29]
L. Gallelli, S. Del Negro, S. Naty, M. Colosimo, R. Maselli, and G. De Sarro, “Levofloxacin-induced taste perversion, blurred vision and dyspnoea in a young woman,” Clinical Drug Investigation, vol. 24, no. 8, pp. 487–489, 2004.
[30]
P. Gareri, L. Gallelli, G. Ferreri Ibbadu, R. Lacava, E. Russo, and G. De Sarro, “Melaena following use of the cholinesterase inhibitor rivastigmine,” Clinical Drug Investigation, vol. 25, no. 3, pp. 215–217, 2005.
[31]
L. Gallelli, M. Ferraro, G. F. Mauro, and G. De Sarro, “Generalised dermatitis induced by pegylated interferon-α-2b in a patient infected with genotype-1 hepatitis C virus: presentation of a case,” Clinical Drug Investigation, vol. 25, no. 4, pp. 281–284, 2005.
[32]
L. Gallelli, M. Ferraro, G. F. Mauro, S. De Fazio, and G. De Sarro, “Nimesulide-induced hepatotoxicity in a previously healthy woman,” Clinical Drug Investigation, vol. 25, no. 6, pp. 421–424, 2005.
[33]
L. Gallelli, A. Gallelli, G. Vero et al., “Acute renal failure probably induced by prulifloxacin in an elderly woman: a first case report,” Clinical Drug Investigation, vol. 26, no. 1, pp. 49–53, 2006.
[34]
L. Gallelli, S. De Fazio, E. Corace, C. De Sarro, C. S. Garcia, and P. De Fazio, “Generalised urticaria in a young woman treated with clomipramine and after ingestion of codfish: a case report,” Pharmacopsychiatry, vol. 39, no. 4, pp. 154–156, 2006.
[35]
A. Siniscalchi, L. Gallelli, and G. De Sarro, “Combined topiramate and declorazepam therapy in a patient affected by essential tremor,” Parkinsonism and Related Disorders, vol. 13, no. 2, pp. 129–130, 2007.
[36]
P. Gareri, P. De Fazio, A. Cotroneo et al., “Anticholinergic drug-induced delirium in an elderly alzheimer's dementia patient,” Archives of Gerontology and Geriatrics, vol. 44, pp. 199–206, 2007.
[37]
A. Siniscalchi, L. Gallelli, S. De Fazio, and G. De Sarro, “Psychic disturbances associated with sodium valproate plus levetiracetam,” Annals of Pharmacotherapy, vol. 41, no. 3, pp. 527–528, 2007.
[38]
P. Gareri, P. De Fazio, L. Gallelli et al., “Venlafaxine-propafenone interaction resulting in hallucinations and psychomotor agitation,” Annals of Pharmacotherapy, vol. 42, no. 3, pp. 434–438, 2008.
[39]
L. Gallelli, O. Staltari, C. Palleria, G. De Sarro, and M. Ferraro, “Hepatotoxicity induced by methimazole in a previously health patient,” Current Drug Safety, vol. 4, no. 3, pp. 204–206, 2009.
[40]
A. Siniscalchi, L. Gallelli, G. Calabrò, G. A. Tolotta, and G. De Sarro, “Phenobarbital/lamotrigine coadministration-induced blood dyscrasia in a patient with epilepsy,” Annals of Pharmacotherapy, vol. 44, no. 12, pp. 2031–2034, 2010.
[41]
G. Di Mizio, L. Gallelli, V. Barbieri et al., “Capecitabine-induced, rapid decrease of renal function due to drug dispensing error in a hospital pharmacy,” Journal of Clinical Pharmacology, vol. 51, no. 1, pp. 117–119, 2011.
[42]
F. Scicchitano, C. Giofrè, C. Palleria et al., “Pharmacovigilance and drug safety 2011 in Calabria (Italy): adverse events analysis,” Journal of Research in Medical Sciences, vol. 17, no. 9, pp. 872–875, 2012.
[43]
J. M. Dalrymple, L. K. Stamp, J. L. O'Donnell, P. T. Chapman, M. Zhang, and M. L. Barclay, “Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis,” Arthritis and Rheumatism, vol. 58, no. 11, pp. 3299–3308, 2008.
[44]
P. Seideman, O. Beck, S. Eksborg, and M. Wennberg, “The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis,” British Journal of Clinical Pharmacology, vol. 35, no. 4, pp. 409–412, 1993.
[45]
R. Segal, E. Mozes, M. Yaron, and B. Tartakovsky, “The effects of methotrexate on the production and activity of interleukin-1,” Arthritis and Rheumatism, vol. 32, no. 4, pp. 370–377, 1989.
[46]
R. Segal, M. Yaron, and B. Tartakovsky, “Methotrexate: mechanism of action in rheumatoid arthritis,” Seminars in Arthritis and Rheumatism, vol. 20, no. 3, pp. 190–200, 1990.
[47]
K. W. Tan and Y. K. Tay, “A case of acute methotrexate toxicity,” Annals of the Academy of Medicine Singapore, vol. 40, no. 2, pp. 97–99, 2011.
[48]
J. I. Schwartz, N. G. B. Agrawal, P. H. Wong et al., “Examination of the effect of increasing doses of etoricoxib on oral methotrexate pharmacokinetics in patients with rheumatoid arthritis,” Journal of Clinical Pharmacology, vol. 49, no. 10, pp. 1202–1209, 2009.
[49]
H. Honjo, Y. Uwai, and K. Iwamoto, “Inhibitory effect of selective cyclooxygenase-2 inhibitor etoricoxib on human organic anion transporter 3 (hOAT3),” Drug Metabolism Letters, vol. 5, no. 2, pp. 140–137, 2011.
[50]
A. Karim, D. S. Tolbert, T. L. Hunt, R. C. Hubbard, K. M. Harper, and G. S. Geis, “Celecoxib, a specific COX-2 inhibitor, has no significant effect on methotrexate pharmacokinetics in patients with rheumatoid arthritis,” Journal of Rheumatology, vol. 26, no. 12, pp. 2539–2543, 1999.
[51]
S. N. Hartmann, C. M. Rordorf, S. Milosavljev et al., “Lumiracoxib does not affect methotrexate pharmacokinetics in rheumatoid arthritis patients,” Annals of Pharmacotherapy, vol. 38, no. 10, pp. 1582–1587, 2004.
[52]
C. Palleria, A. Di Paolo, C. Giofrè et al., “Pharmacokinetic drug-drug interaction and their implication in clinical management,” Journal of Research in Medical Sciences, 2013.
[53]
A. N. Colebatch, J. L. Marks, D. M. van der Heijde, and C. J. Edwards, “Safety of nonsteroidal antiinflammatory drugs and/or paracetamol in people receiving methotrexate for inflammatory arthritis: a Cochrane systematic review,” Journal of Rheumatology. Supplement, vol. 90, pp. 62–73, 2012.
[54]
Arava (Leflunomide), Sanofi-Aventis. UK Summary of product characteristics, September 2009.
[55]
EMEA, “EMEA public statement on leflunomide (Arava)—severe and serious hepatic reactions,” London, UK, March 2001, http://www.emea.europa.eu/docs/en_GB/document_library/Public_statement/2009/12/WC500018389.pdf.
[56]
R. L. Hill, D. J. Topliss, and P. M. Purcell, “Pancytopenia associated with leflunomide and methotrexate,” Annals of Pharmacotherapy, vol. 37, no. 1, p. 149, 2003.
[57]
J. McEwen, P. M. Purcell, R. L. Hill, L. J. Calcino, and C. G. Riley, “The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate,” Pharmacoepidemiology and Drug Safety, vol. 16, no. 1, pp. 65–73, 2007.
[58]
J. Chan, D. C. Sanders, L. Du, and P. I. Pillans, “Leflunomide-associated pancytopenia with or without methotrexate,” Annals of Pharmacotherapy, vol. 38, no. 7-8, pp. 1206–1211, 2004.
[59]
J. Londono, A. M. Santos, P. I. Santos, M. F. Cubidez, C. Guzman, and R. Valle-O？ate, “Therapeutic efficacy and safety of methotrexate + leflunomide in Colombian patients with active rheumatoid arthritis refractory to conventional treatment,” Revista Brasileira de Reumatologia, vol. 52, no. 6, pp. 837–845, 2012.
[60]
S. W. Lee, H. J. Park, B. K. Kim et al., “Leflunomide increases the risk of silent liver fibrosis in patients with rheumatoid arthritis receiving methotrexate,” Arthritis Research & Therapy, vol. 14, no. 5, p. R232, 2012.
[61]
W. Katchamart, J. Trudeau, V. Phumethum, and C. Bombardier, “Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis,” Annals of the Rheumatic Diseases, vol. 68, no. 7, pp. 1105–1112, 2009.
[62]
R. Elsby, L. Fox, D. Stresser et al., “In vitro risk assessment of AZD9056 perpetrating a transporter-mediated drug-drug interaction with methotrexate,” European Journal of Pharmaceutical Sciences, vol. 43, no. 1-2, pp. 41–49, 2011.
[63]
A. H. Gerards, R. B. M. Landewé, A. P. A. Prins et al., “Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial,” Annals of the Rheumatic Diseases, vol. 62, no. 4, pp. 291–296, 2003.
[64]
P. Sarzi-Puttini, E. D'Ingianna, M. Fumagalli et al., “An open, randomized comparison study of cyclosporine A, cyclosporine A + methotrexate and cyclosporine A + hydroxychloroquine in the treatment of early severe rheumatoid arthritis,” Rheumatology International, vol. 25, no. 1, pp. 15–22, 2005.
[65]
L. Fuksa, E. Brcakova, G. Kolouchova et al., “Dexamethasone reduces methotrexate biliary elimination and potentiates its hepatotoxicity in rats,” Toxicology, vol. 267, no. 1–3, pp. 165–171, 2010.
[66]
J. E. A. Wolff, H. Hauch, J. Kühl, R. M. Egeler, and H. Jürgens, “Dexamethasone increases hepatotoxicity of MTX in children with brain tumors,” Anticancer Research, vol. 18, no. 4B, pp. 2895–2899, 1998.
[67]
O. A. Malysheva, M. Wahle, U. Wagner et al., “Low-dose prednisolone in rheumatoid arthritis: adverse effects of various disease modifying antirheumatic drugs,” Journal of Rheumatology, vol. 35, no. 6, pp. 979–985, 2008.
[68]
M. E. Weinblatt, J. M. Kremer, J. S. Coblyn et al., “Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis,” Arthritis & Rheumatism, vol. 42, pp. 1322–1328, 1999.
[69]
P. Bird, H. Griffiths, K. Tymms, et al., “The SMILE study—safety of methotrexate in combination with leflunomide in rheumatoid arthritis,” The Journal of Rheumatology, vol. 40, no. 3, pp. 228–235, 2013.
[70]
J. P. Callen, “Complications and adverse reactions in the use of newer biologic agents,” Seminars in Cutaneous Medicine and Surgery, vol. 26, no. 1, pp. 6–14, 2007.
[71]
B. T. Luong, B. S. Chong, and D. M. Lowder, “Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab,” Annals of Pharmacotherapy, vol. 34, no. 6, pp. 743–760, 2000.
[72]
H. Zhou, P. R. Mayer, J. Wajdula, and S. Fatenejad, “Unaltered etanercept pharmacokinetics with concurrent methotrexate in patients with rheumatoid arthritis,” Journal of Clinical Pharmacology, vol. 44, no. 11, pp. 1235–1243, 2004.
[73]
M. H. Weisman, L. W. Moreland, D. E. Furst et al., “Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study,” Clinical Therapeutics, vol. 25, no. 6, pp. 1700–1721, 2003.
[74]
RoActemra (Tocilizumab), Roche Registration Ltd. Summary of product characteristics, January 2009.
[75]
Cimzia (Certolizumab pegol), UCB Inc. US Prescribing information, December 2008.
[76]
Simponi (Golimumab), Centocor Ortho Biotech Inc. US Prescribing information, April 2009.
[77]
J. Von Kempis, J. Dudler, P. Hasler et al., “Use of abatacept in rheumatoid arthritis,” Swiss Medical Weekly, vol. 142, 2012.
[78]
B. Dijkmans and A. Gerards, “Cyclosporin in rheumatoid arthritis: monitoring for adverse effects and clinically significant drug interactions,” BioDrugs, vol. 10, no. 6, pp. 437–445, 1998.
[79]
M. Baraldo, G. Ferraccioli, F. Pea, E. Gremese, and M. Furlanut, “Cyclosporine a pharmacokinetics in rheumatoid arthritis patients after 6 months of methotrexate therapy,” Pharmacological Research, vol. 40, no. 6, pp. 483–486, 1999.
[80]
R. B. Velagapudi, P. A. Noertersheuser, W. M. Awni et al., “Effect of methotrexate coadministration on the pharmacokinetics of adalimumab (Humira, Abbott) following a single intravenous injection,” Arthritis & Rheumatism, vol. 48, p. S141, 2003.
[81]
Humira (Adalimumab), Abbott Laboratories. US Prescribing information, March 2009.
[82]
B. Davies and T. Shaw, “Rituximab pharmacokinetic characteristics are not influenced by combination with methotrexate or cyclophosphamide,” Annals of the Rheumatic Diseases, vol. 63, p. FRI0128, 2004.
[83]
J. A. Singh, G. A. Wells, R. Christensen et al., “Adverse effects of biologics: a network meta-analysis and cochrane overview,” Cochrane Database of Systematic Reviews, vol. 2, Article ID CD008794, 2011.
[84]
A. E. Thompson and P. G. Bashook, “Rheumatologists' recommended patient information when prescribing methotrexate for rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 28, no. 4, pp. 539–545, 2010.
[85]
E. N. van Roon, P. M. L. A. van den Bemt, T. L. T. A. Jansen, N. M. Houtman, M. A. F. J. van de Laar, and J. R. B. J. Brouwers, “An evidence-based assessment of the clinical significance of drug-drug interactions between disease-modifying antirheumatic drugs and non-antirheumatic drugs according to rheumatologists and pharmacists,” Clinical Therapeutics, vol. 31, no. 8, pp. 1737–1746, 2009.
