Skip to main content
Top
Published in: Arthritis Research & Therapy 5/2014

Open Access 01-10-2014 | Research article

Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial

Authors: Axel Finckh, Geraldine M Mc Carthy, Anne Madigan, Daniel Van Linthoudt, Marcel Weber, David Neto, Georges Rappoport, Sandra Blumhardt, Diego Kyburz, Pierre-Andre Guerne

Published in: Arthritis Research & Therapy | Issue 5/2014

Login to get access

Abstract

Introduction

Calcium pyrophosphate deposition (CPPD) may cause severe arthropathy, major joint destruction and treatment options are limited. The aim of this study was to test the therapeutic efficacy of methotrexate (MTX) in chronic or recurrent CPPD arthropathy.

Methods

Patients with CPPD arthropathy were randomized to receive either weekly subcutaneous injections of 15 mg/week of MTX or placebo (PBO) for three months, in a double-blind, crossover randomized controlled trial. Inclusion criteria comprised definite CPPD disease, recurrent arthritis or persistent polyarthritis, and an insufficient response to NSAIDs, glucocorticoids or colchicine. The primary outcome was an improvement in the disease activity scores based on 44 joints (DAS44). The analysis was performed on an intent-to-treat basis.

Results

We randomized 26 patients, and compared 25 treatment periods on MTX with 21 treatment periods on PBO. Baseline characteristics were balanced between the groups. The evolution of the DAS44 was not statistically significantly different between groups (median DAS44 decreased by −0.08 on MTX versus −0.13 on PBO, after three months, P = 0.44). Furthermore, pain levels remained stable in both groups (median change in VAS Pain −1 unit on MTX and 0 on PBO, P = 0.43), and none of the secondary outcomes was significantly different between the two groups. Minor adverse events (AE) did not differ in frequency between the groups, but the only serious AE occurred on MTX (bicytopenia).

Conclusions

The results of this trial with MTX in this older population with chronic or recurrent CPPD arthropathy suggest no strong effect of MTX on disease activity.

Trial registration

EudraCT No: 2007-003479-37. Registered 26 April 2008
Appendix
Available only for authorised users
Literature
1.
go back to reference Zhang W, Doherty M, Bardin T, Barskova V, Guerne PA, Jansen TL, Leeb BF, Perez-Ruiz F, Pimentao J, Punzi L, Richette P, Sivera F, Uhlig T, Watt I, Pascual E: European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011, 70: 563-570. 10.1136/ard.2010.139105.CrossRefPubMed Zhang W, Doherty M, Bardin T, Barskova V, Guerne PA, Jansen TL, Leeb BF, Perez-Ruiz F, Pimentao J, Punzi L, Richette P, Sivera F, Uhlig T, Watt I, Pascual E: European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011, 70: 563-570. 10.1136/ard.2010.139105.CrossRefPubMed
2.
go back to reference Zhang W, Doherty M, Pascual E, Barskova V, Guerne PA, Jansen TL, Leeb BF, Perez-Ruiz F, Pimentao J, Punzi L, Richette P, Sivera F, Uhlig T, Watt I, Bardin T: EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis. 2011, 70: 571-575. 10.1136/ard.2010.139360.CrossRefPubMed Zhang W, Doherty M, Pascual E, Barskova V, Guerne PA, Jansen TL, Leeb BF, Perez-Ruiz F, Pimentao J, Punzi L, Richette P, Sivera F, Uhlig T, Watt I, Bardin T: EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis. 2011, 70: 571-575. 10.1136/ard.2010.139360.CrossRefPubMed
3.
go back to reference Announ N, Palmer G, Guerne PA, Gabay C: Anakinra is a possible alternative in the treatment and prevention of acute attacks of pseudogout in end-stage renal failure. Joint Bone Spine. 2009, 76: 424-426. 10.1016/j.jbspin.2009.01.001.CrossRefPubMed Announ N, Palmer G, Guerne PA, Gabay C: Anakinra is a possible alternative in the treatment and prevention of acute attacks of pseudogout in end-stage renal failure. Joint Bone Spine. 2009, 76: 424-426. 10.1016/j.jbspin.2009.01.001.CrossRefPubMed
4.
go back to reference Diamantopoulos AP, Brodin C, Hetland H, Haugeberg G: Interleukin 1beta blockade improves signs and symptoms of chronic calcium pyrophosphate crystal arthritis resistant to treatment. J Clin Rheumatol. 2012, 18: 310-311. 10.1097/RHU.0b013e31826149a2.CrossRefPubMed Diamantopoulos AP, Brodin C, Hetland H, Haugeberg G: Interleukin 1beta blockade improves signs and symptoms of chronic calcium pyrophosphate crystal arthritis resistant to treatment. J Clin Rheumatol. 2012, 18: 310-311. 10.1097/RHU.0b013e31826149a2.CrossRefPubMed
5.
go back to reference Chan ES, Cronstein BN: Methotrexate–how does it really work?. Nat Rev Rheumatol. 2010, 6: 175-178. 10.1038/nrrheum.2010.5.CrossRefPubMed Chan ES, Cronstein BN: Methotrexate–how does it really work?. Nat Rev Rheumatol. 2010, 6: 175-178. 10.1038/nrrheum.2010.5.CrossRefPubMed
6.
go back to reference Chollet-Janin A, Finckh A, Dudler J, Guerne PA: Methotrexate as an alternative therapy for chronic calcium pyrophosphate deposition disease: an exploratory analysis. Arthritis Rheum. 2007, 56: 688-692. 10.1002/art.22389.CrossRefPubMed Chollet-Janin A, Finckh A, Dudler J, Guerne PA: Methotrexate as an alternative therapy for chronic calcium pyrophosphate deposition disease: an exploratory analysis. Arthritis Rheum. 2007, 56: 688-692. 10.1002/art.22389.CrossRefPubMed
7.
go back to reference Andres M, Sivera F, Pascual E: Methotrexate is an option for patients with refractory calcium pyrophosphate crystal arthritis. J Clin Rheumatol. 2012, 18: 234-236. 10.1097/RHU.0b013e3182611471.CrossRefPubMed Andres M, Sivera F, Pascual E: Methotrexate is an option for patients with refractory calcium pyrophosphate crystal arthritis. J Clin Rheumatol. 2012, 18: 234-236. 10.1097/RHU.0b013e3182611471.CrossRefPubMed
8.
go back to reference Doan TH, Chevalier X, Leparc JM, Richette P, Bardin T, Forestier R: Premature enthusiasm for the use of methotrexate for refractory chondrocalcinosis: comment on the article by Chollet-Janin et al. Arthritis Rheum. 2008, 58: 2210-2211. 10.1002/art.23552.CrossRefPubMed Doan TH, Chevalier X, Leparc JM, Richette P, Bardin T, Forestier R: Premature enthusiasm for the use of methotrexate for refractory chondrocalcinosis: comment on the article by Chollet-Janin et al. Arthritis Rheum. 2008, 58: 2210-2211. 10.1002/art.23552.CrossRefPubMed
9.
go back to reference Kohn NN, Hughes RE, Mc CD, Faires JS: The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: the “pseudogout syndrome”. II. Identification of crystals. Ann Intern Med. 1962, 56: 738-745. 10.7326/0003-4819-56-5-738.CrossRefPubMed Kohn NN, Hughes RE, Mc CD, Faires JS: The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: the “pseudogout syndrome”. II. Identification of crystals. Ann Intern Med. 1962, 56: 738-745. 10.7326/0003-4819-56-5-738.CrossRefPubMed
11.
go back to reference Braun J, Kastner P, Flaxenberg P, Wahrisch J, Hanke P, Demary W, von Hinuber U, Rockwitz K, Heitz W, Pichlmeier U, Guimbal-Schmolck C, Brandt A: Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008, 58: 73-81. 10.1002/art.23144.CrossRefPubMed Braun J, Kastner P, Flaxenberg P, Wahrisch J, Hanke P, Demary W, von Hinuber U, Rockwitz K, Heitz W, Pichlmeier U, Guimbal-Schmolck C, Brandt A: Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008, 58: 73-81. 10.1002/art.23144.CrossRefPubMed
12.
go back to reference Fransen J, van Riel PL: The Disease Activity Score and the EULAR response criteria.Clin Exp Rheumatol 2005, Suppl 39:S93–S99., Fransen J, van Riel PL: The Disease Activity Score and the EULAR response criteria.Clin Exp Rheumatol 2005, Suppl 39:S93–S99.,
13.
go back to reference Schumacher HR, Edwards LN, Perez-Ruiz F, Becker M, Chen LX, Furst DE, Joseph-Ridge N, Schlesinger N, Horowitz Z, Saag K, Boice JA, Yamanaka H, Group OSI: Outcome measures for acute and chronic gout. J Rheumatol. 2005, 32: 2452-2455.PubMed Schumacher HR, Edwards LN, Perez-Ruiz F, Becker M, Chen LX, Furst DE, Joseph-Ridge N, Schlesinger N, Horowitz Z, Saag K, Boice JA, Yamanaka H, Group OSI: Outcome measures for acute and chronic gout. J Rheumatol. 2005, 32: 2452-2455.PubMed
14.
go back to reference Société Suisse de Rhumatologie/Schweizer Geselschaft für Rheumatologie: Recommendations pour les traitements de base de Methotrexate. 2004. Société Suisse de Rhumatologie/Schweizer Geselschaft für Rheumatologie: Recommendations pour les traitements de base de Methotrexate. 2004.
15.
go back to reference van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, de Boo TM, van der Wilt GJ, Severens JL, Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de Putte LB: Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001, 44: 1515-1524. 10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7.CrossRefPubMed van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, de Boo TM, van der Wilt GJ, Severens JL, Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de Putte LB: Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001, 44: 1515-1524. 10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7.CrossRefPubMed
16.
go back to reference Jones B, Kenward MG: Design and Analysis of Cross-Over Trials. In: Monographs on Statistics and Applied Probability. Chapman and Hall; 1989. Jones B, Kenward MG: Design and Analysis of Cross-Over Trials. In: Monographs on Statistics and Applied Probability. Chapman and Hall; 1989.
17.
go back to reference R Development Core Team: R: A language and environment for statistical computing.R Foundation for Statistical Computing: Vienna, Austria; 2008., R Development Core Team: R: A language and environment for statistical computing.R Foundation for Statistical Computing: Vienna, Austria; 2008.,
18.
go back to reference Kawabe Y, Eguchi K, Tsuboi M, Kita M, Tsukada T, Takashima H, Mizokami A, Kawakami A, Matsuoka N, Migita K, Nagataki S: Untoward effects of low dose methotrexate therapy in rheumatoid arthritis. Ryumachi [Rheumatism]. 1996, 36: 514-521. Kawabe Y, Eguchi K, Tsuboi M, Kita M, Tsukada T, Takashima H, Mizokami A, Kawakami A, Matsuoka N, Migita K, Nagataki S: Untoward effects of low dose methotrexate therapy in rheumatoid arthritis. Ryumachi [Rheumatism]. 1996, 36: 514-521.
19.
go back to reference Duxbury B, Combescure C, Chizzolini C: Rituximab in systemic lupus erythematosus: an updated systematic review and meta-analysis. Lupus. 2013, 22: 1489-1503. 10.1177/0961203313509295.CrossRefPubMed Duxbury B, Combescure C, Chizzolini C: Rituximab in systemic lupus erythematosus: an updated systematic review and meta-analysis. Lupus. 2013, 22: 1489-1503. 10.1177/0961203313509295.CrossRefPubMed
20.
go back to reference Zhang Y, Brown MA: Genetic studies of chondrocalcinosis. Curr Opin Rheumatol. 2005, 17: 330-335. 10.1097/01.bor.0000157042.19740.f4.CrossRefPubMed Zhang Y, Brown MA: Genetic studies of chondrocalcinosis. Curr Opin Rheumatol. 2005, 17: 330-335. 10.1097/01.bor.0000157042.19740.f4.CrossRefPubMed
Metadata
Title
Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial
Authors
Axel Finckh
Geraldine M Mc Carthy
Anne Madigan
Daniel Van Linthoudt
Marcel Weber
David Neto
Georges Rappoport
Sandra Blumhardt
Diego Kyburz
Pierre-Andre Guerne
Publication date
01-10-2014
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 5/2014
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-014-0458-4

Other articles of this Issue 5/2014

Arthritis Research & Therapy 5/2014 Go to the issue