Update on subcutaneous methotrexate for inflammatory arthritis and psoriasis

Figures & data

Table 1 Bioavailability of oral MTX compared with SC MTX

References	Sample	MTX weekly dose	Relevant results
^Citation10	12 patients with RA	7.5–17.5 mg	Mean relative bioavailability of SC MTX was significantly higher than oral MTX (0.97 vs 0.85)
^Citation12	15 patients with RA	25–40 mg (median, 30 mg)	Mean bioavailability of oral MTX was significantly lower (0.64, range 0.21–0.96) compared with SC MTX
^Citation13	49 RA patients enrolled in an 8-week, open-label, randomized-sequence, three-way crossover trial (47 completed the study)	10, 15, 20, and 25 mg in a random sequence of three treatments: oral, SC into the abdomen, and SC into the thigh	Greater systemic bioavailability of SC MTX at all dose levels (relative bioavailability at 10, 15, 20, and 25 mg was 121%, 114%, 131%, and 141%, respectively, of that seen with oral MTX)
^Citation14	17 patients with JIA	6.1–22.5 mg/m^2 for oral MTX; 8.8–28.6 mg/m^2 for SC MTX	Nonlinear pharmacokinetics of oral MTX. In four patients switched from oral to SC MTX at the same dose, the bioavailability of oral MTX was 11%–15% lower as compared with SC MTX
^Citation15	62 healthy subjects recruited in an open-label, randomized, two-sequence, two-period, single-dose, crossover study	Four dose groups (7.5, 15, 22.5, and 30 mg)	Bioavailability was generally higher with SC MTX (injected by prefilled autoinjector pen) compared with oral MTX for all dose groups (higher Cmax and AUC0–t values obtained with SC MTX)
^Citation16	10 patients with stable CD randomized to receive their regular maintenance dose	15–25 mg for 3 weeks	Bioavailability of oral MTX was highly variable and averages 73% of that of SC MTX
^Citation17	11 patients with CD	25 mg for 2 weeks	Mean relative bioavailability of 86% (62%–108%) of oral MTX compared with SC MTX

Abbreviations: AUC, area under the plasma-concentration curve; CD, Crohn’s disease; C_max, maximum plasma concentration; JIA, juvenile idiopathic arthritis; MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous.

Table 2 Comparison of efficacy results between oral MTX and SC MTX in patients with RA and JIA

References	Study design and patients	Treatment	Efficacy results
^Citation27	Six-month, multicenter, randomized, DB, double-dummy, controlled, two-arm, Phase IV trial in 384 MTX-naïve patients with active RA (DAS28 ≥4); 375 included in the efficacy analysis	15 mg/week of oral MTX (n=187) or SC MTX (n=188) for 24 weeks At week 16, switch from 15 mg of oral MTX to 15 mg of SC MTX and from 15 mg of SC MTX to 20 mg of SC MTX for 8 weeks in the absence of ACR20 response	At week 24, significantly more patients treated with SC MTX than with oral MTX showed ACR20 (78% vs 70%) and ACR70 (41% vs 33%) responses
^Citation28	Prospective study in 92 patients with active RA	Oral MTX (n=46) or SC MTX (n=46) at equivalent dose for 24 weeks	At 24 week, significant differences in favor of SC MTX in ACR20 and ACR50 response rates (93% vs 80%, and 89% vs 72%, respectively), with similar ACR70 response rates
^Citation29	Multicenter, prospective cohort study to compare oral vs SC MTX over the first year in 666 patients with early RA	Mean weekly dose over first 3 months of 17.2 mg for oral MTX (n=417) and 22.3 mg for SC MTX (n=249)	SC MTX associated with a lower rate of treatment failure (HR 0.55, 95% CI 0.39–0.79) and lower mean DAS28 scores
^Citation30	Retrospective analysis in 411 patients with JIA using the German MTX Registry	Oral MTX (n=259) and SC MTX (n=152) at a similar weekly dose (0.4 mg/kg vs 0.42 mg/kg)	Comparable response according to the ACR Pediatric 30 criteria after 6 months of treatment (73% vs 72%)
^Citation31	Prospective observational study of 55 patients with JIA	Initial median weekly dose of 11.7 mg/m^2 for oral MTX (n=10) and 14.4 mg/m^2 for SC MTX (n=45)	No differences in either the rate or the extent of therapeutic response between the two routes

Abbreviations: ACR, American College of Rheumatology; ACR20, ACR criteria for 20% improvement; ACR50, ACR criteria for 50% improvement; ACR70, ACR criteria for 70% improvement; DAS28, 28-joint Disease Activity Score; DB, double blind; HR, hazard ratio; JIA, juvenile idiopathic arthritis; MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous.

Table 3 Summary of efficacy results in series of patients with RA and JIA who were changed from oral to SC MTX

References	Study details and patients switched	Reasons for oral MTX failure	Mean weekly MTX dose (mg)		Relevant results obtained with SC MTX
			Oral	SC
^Citation33	Retrospective study of 196 RA patients	Inefficacy (50.5%), AEs (43.9%), other/unknown (5.6%)	17.7	16.3	Persistence of SC MTX therapy in 83% of patients at 1 year, 75.2% at 2 years, and 47.0% at 5 years
^Citation34	Post hoc analysis of 57 patients from the prospective, open-label CAMERA study	AEs (n=21), poor efficacy (n=36)	28±4	Equivalent dose	Improvement in 63% of patients Decrease in DAS28 of 0.3 points (P<0.05) after 1 month and of 0.5 points (P<0.01) over 4 months
^Citation35	Retrospective analysis of 80 RA patients	Gastrointestinal AEs	15.1±5.8	16.5±5.2	Significant decrease of DAS28, ESR, and CRP levels, and pain severity (VAS) after 1 and 3 months
^Citation36	Retrospective study of 103 RA patients	Inefficacy (n=40), intolerance (n=63)	15	15	Significant improvements in DAS28 scores, especially in patients who failed oral MTX therapy due to intolerance
^Citation37	Retrospective study of 78 RA patients	Inefficacy (n=38), AEs (n=40)	20	22	After 6 months, decrease in DAS28 ≥1.2 in 74% of cases; “good” or better response according to EULAR criteria in 58% of patients
^Citation38	Retrospective study of 50 RA patients	Lack of efficacy (69.6%), AEs (28.2%), or both (2.2%)	14.31	18.36	Lack of efficacy responsible for stopping SC MTX in only three patients The probabilities of discontinuation after 1, 2, and 3 years of SC MTX treatment are expected to be 6.10%, 8.50%, and 23.20%, respectively
^Citation39	Retrospective study of 31 JIA patients	Insufficient/no response (n=20), intolerance (n=11)	13.8/m^2*	15.4/m^2*	After 3 months, improvement** in 76% of patients
^Citation40	Single-center, questionnaire-based study of unselected JIA patients (switch required in 32 patients)	Intolerance (n=20), reluctance to take oral MTX (n=12)	12.6/m^2	12.8/m^2	After 6 months, no changes in the ACR score. Improvement in 12 children (37.5%), worsening in other 12 (37.5%)

Notes:

* Mean maximum dose.

** Defined as ≥30% improvement from baseline in three of five variables in the core set, with no more than one of the remaining variables worsening by >30%.

Abbreviations: ACR, American College of Rheumatology; AE, adverse event; CRP, C reactive protein; DAS28, 28-joint Disease Activity Score; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; JIA, juvenile idiopathic arthritis; MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous; VAS, visual analog scale.

Table 4 Tolerability data regarding oral MTX and SC MTX in patients with RA and JIA

References	Patients treated with MTX and study details	Summary of the tolerability data
SC MTX vs oral MTX
^Citation27	384 patients with RA*	Similar rate of total AEs and GI AEs. Diarrhea was more common with oral MTX (6.9% vs 2.6%) and loss of appetite was more common with SC MTX (7.3% vs 3.2%). Withdrawal due to AEs was more frequent with SC MTX
^Citation28	92 patients with RA*	AEs less frequent with SC MTX, eg, nausea (37% vs 63%), vomiting (11% vs 30%), dyspepsia (29% vs 48%), dizziness (41% vs 52%), and alopecia (72% vs 85%)
^Citation41	Online survey in RA patients SC MTX (n=49), oral MTX (n=115)	Prevalence of diarrhea was lower among patients receiving SC MTX. Nausea, mental fog, and hair loss were more frequent with SC MTX
^Citation29	666 patients with early RA*	No difference in failure due to toxicity
^Citation42	Questionnaire-based study in 106 unselected patients with inflammatory arthritis, 57 adults (33% on SC MTX) and 49 adolescents (49% on SC MTX)	Nausea reported in 77% of patients on SC MTX vs 37% in the oral group (P<0.0001) Risk of nausea was significantly associated with the use of SC MTX (OR 4.49, 95% CI 1.71–11.79)
^Citation30	411 patients with JIA*	At least one AE in 21% of cases with oral MTX and 27% with SC MTX (no statistical significance). Significantly more discontinuations due to AEs with SC MTX (11% vs 5%; type of AE not specified)
^Citation31	55 patients with JIA*	Trend toward increased odds for intolerance with SC MTX (OR 2.4; 95% CI 0.56–10.65, P=0.236)
^Citation43	Cross-sectional study of 179 JIA patients. Exclusive treatment with oral MTX in 95 patients and with SC MTX in 46 (similar median dose of 11.8–11.6 mg/m^2/week)	MTX intolerance was more frequent in patients with exclusive use of SC MTX (aOR 3.37, 95% CI 1.19–10.0). Significant differences were due to behavioral complaints with no difference in prevalence of nausea or vomiting between groups
Switch from oral MTX to SC MTX
^Citation33	196 RA patients*	After 2 years, drug discontinuation due to AEs was in 22.2% of patients who did not tolerate oral MTX
^Citation35	80 RA patients switched because of GI AEs*	Significantly less patients with GI AEs in the first (n=30) and third month (n=27) visits
^Citation38	50 RA patients*	Discontinuation of SC MTX because of AEs in six patients
^Citation44	Retrospective postal survey exploring GI AEs in 39 patients from dermatology/rheumatology centers; significant increase in weekly dose with change from oral MTX (14.2±5.1 mg) to SC MTX (16.2±5.0 mg)	Significant reductions were observed in VAS related to frequency and intensity of nausea and frequency of discomfort. Frequency of vomiting was not significantly reduced
^Citation39	31 JIA patients (switching in 11 due to nausea)*	Disappearance of nausea in nine patients (less severe in the other two who continued MTX therapy)
^Citation40	32 patients with JIA (20 with intolerance)*	Over 6 months, symptoms of drug intolerance (mostly GI symptoms) in three children
^Citation45	Survey in 70 RA patients initially treated with oral MTX (7.5 or 15 mg/week) and then switched to the same dose of SC MTX because of GI AEs	More intense GI AEs with oral MTX (in relation to MTX dose)

Note:

* For details regarding study design, patients, and MTX dose, see Tables 2 and 3.

Abbreviations: AE, adverse event; aOR, adjusted odds ratio; GI, gastrointestinal; JIA, juvenile idiopathic arthritis; MTX, methotrexate; OR, odds ratio; RA, rheumatoid arthritis; SC, subcutaneous; VAS, visual analog scale.

JundtJWBrowneBAFioccoGPSteeleADMockDA comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosingJ Rheumatol19932011184518498308768

 PubMed Web of Science ®Google Scholar

HoekstraMHaagsmaCNeefCProostJKnuifAvan de LaarMBioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritisJ Rheumatol200431464564815088287

 PubMed Web of Science ®Google Scholar

SchiffMHJaffeJSFreundlichBHead-to-head, randomized, crossover study of oral vs subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses $15 mg may be overcome with subcutaneous administrationAnn Rheum Dis20147381549155124728329

 PubMed Web of Science ®Google Scholar

TukováJChládekJNemcováDChládkováJDolezalováPMethotrexate bioavailability after oral and subcutaneous administration in children with juvenile idiopathic arthritisClin Exp Rheumatol20092761047105320149329

 PubMed Web of Science ®Google Scholar

PichlmeierUHeuerKUSubcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexateClin Exp Rheumatol201432456357124983446

 PubMed Web of Science ®Google Scholar

KurnikDLoebsteinRFishbeinEBioavailability of oral vs subcutaneous low-dose methotrexate in patients with Crohn’s diseaseAliment Pharmacol Ther2003181576312848626

 PubMed Web of Science ®Google Scholar

WilsonAPatelVChandeNPharmacokinetic profiles for oral and subcutaneous methotrexate in patients with Crohn’s diseaseAliment Pharmacol Ther201337334034523190184

 PubMed Web of Science ®Google Scholar

BraunJKästnerPFlaxenbergPMC-MT.6/RH Study Group. Comparison of the clinical efficacy and safety of subcutaneous vs oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trialArthritis Rheum2008581738118163521

 PubMed Web of Science ®Google Scholar

IslamMSHaqSAIslamMNComparative efficacy of subcutaneous vs oral methotrexate in active rheumatoid arthritisMymensingh Med J201322348348823982537

 PubMedGoogle Scholar

HazlewoodGSThorneJCPopeJECATCH InvestigatorsThe comparative effectiveness of oral vs subcutaneous methotrexate for the treatment of early rheumatoid arthritisAnn Rheum Dis20167561003100825979945

 PubMed Web of Science ®Google Scholar

KleinAKaulIFoeldvariIGanserGUrbanAHorneffGEfficacy and safety of oral and parenteral methotrexate therapy in children with juvenile idiopathic arthritis: an observational study with patients from the German Methotrexate RegistryArthritis Care Res (Hoboken)20126491349135622649024

 PubMed Web of Science ®Google Scholar

FráňováJFingerhutováŠKobrováKMethotrexate efficacy, but not its intolerance, is associated with the dose and route of administrationPediatr Rheumatol Online J20161413627301536

 PubMed Web of Science ®Google Scholar

ScottDGClaydonPEllisCRetrospective evaluation of continuation rates following a switch to subcutaneous methotrexate in rheumatoid arthritis patients failing to respond to or tolerate oral methotrexate: the MENTOR studyScand J Rheumatol201443647047624898259

 PubMed Web of Science ®Google Scholar

BakkerMFJacobsJWWelsingPMUtrecht Arthritis Cohort Study GroupAre switches from oral to subcutaneous methotrexate or addition of ciclosporin to methotrexate useful steps in a tight control treatment strategy for rheumatoid arthritis? A post hoc analysis of the CAMERA studyAnn Rheum Dis201069101849185220511610

 PubMed Web of Science ®Google Scholar

BormanPDemirGKaygısızFOkumuşMLETTER TO THE EDITOR Subcutaneous (SC) methotrexate (MTX) is better and well-tolerable than oral MTX in rheumatoid arthritis patients, switched from oral to SC administration due to gastrointestinal side effectsOpen Rheumatol J20148181925232363

 PubMedGoogle Scholar

HameedBJonesHSubcutaneous methotrexate is well tolerated and superior to oral methotrexate in the treatment of rheumatoid arthritisInt J Rheum Dis2010134e83e8421199461

 PubMed Web of Science ®Google Scholar

MainmanHMcClarenEHeycockCSaravananVHamiltonJKellyCWhen should we use parenteral methotrexate?Clin Rheumatol201029101093109820544244

 PubMed Web of Science ®Google Scholar

BrancoJCBarcelosAde AraújoFPUtilization of subcutaneous methotrexate in rheumatoid arthritis patients after failure or intolerance to oral methotrexate: a multicenter cohort studyAdv Ther2016331465726724937

 PubMed Web of Science ®Google Scholar

AlsufyaniKOrtiz-AlvarezOCabralDATuckerLBPettyREMallesonPNThe role of subcutaneous administration of methotrexate in children with juvenile idiopathic arthritis who have failed oral methotrexateJ Rheumatol200431117918214705239

 PubMed Web of Science ®Google Scholar

ŻuberZTurowska-HeydelDSobczykMMethotrexate efficacy and tolerability after switching from oral to subcutaneous route of administration in juvenile idiopathic arthritisReumatologia2016541192327407272

 PubMedGoogle Scholar

CurtisJRXieFMackeyDPatient’s experience with subcutaneous and oral methotrexate for the treatment of rheumatoid arthritisBMC Musculoskelet Disord201617140527669978

 PubMed Web of Science ®Google Scholar

PatilPParkerRARawcliffeCMethotrexate-induced nausea and vomiting in adolescent and young adult patientsClin Rheumatol201433340340724108504

 PubMed Web of Science ®Google Scholar

van DijkhuizenEHPouwJNScheuernAMethotrexate intolerance in oral and subcutaneous administration in patients with juvenile idiopathic arthritis: a cross-sectional, observational studyClin Exp Rheumatol2016341148154

 Web of Science ®Google Scholar

KromannCBLage-HansenPRKoefoedMJemecGBDoes switching from oral to subcutaneous administration of methotrexate influence on patient reported gastro-intestinal adverse effects?J Dermatolog Treat201526218819024852821

 PubMed Web of Science ®Google Scholar

Rutkowska-SakLRell-BakalarskaMLisowskaBOral vs subcutaneous low-dose methotrexate treatment in reducing gastrointestinal side effectsReumatologia200947207211

 Google Scholar