The Anti-Psoriatic Efficacy and Safety Profile of Topical and Intralesional Methotrexate: A Literature Review

Figures & data

Table 1 Previous Studies Related to Topical Methotrexate (MTX) in Aqueous Cream or Gel, and to Topical MTX with Chemical Enhancers

Authors (Year)	Type of Study	Patient Number	MTX Formulation	Frequency of MTX Application	Duration of Treatment	Comparators	Results	Adverse Events (AE)
Topical plain MTX in aqueous cream or gel in human
Fry et al (1967)^Citation12	Case series	9	0.2% MTX in aqueous cream	Once daily with a polythene occlusive dressing for the 24 hours.	4–14 days (until clear, discomfort to continue, no continuing improvement)	-	Majority of patients (90.4%) had considerable improvement.	- Local AE: erythema, purpura (88.8%), ulceration (33.3%) - Systemic AE: No
Stewart et al (1972)^Citation15	Intraindividual comparison	9	0.2% MTX cream under occlusion	N/A	5–7 days	Vanishing cream base	No improvement	- Local AE: erythema, superficial erosions, and burning sensation (11.1%) - Systemic AE: No
Syed et al (2001)^Citation17	RCT	60	0.25% MTX in hydrophilic gel	Twice daily for 5 consecutive days/week	4 weeks (maximum of 40 topical applications in 4 weeks)	Placebo	Numbers of healed chronic plaques were higher in MTX group (82.2%) than in placebo group (4.3%), P < 0.001	- Local AE: No - Systemic AE: No
Eskicirak et al (2006)^Citation10	SBPLC	40	1% MTX gel in hydroxymethylcellulose	Twice daily	8 weeks	Vaseline ointment	MTX gel was significantly more effective than placebo (P < 0.01).	- Local AE: No - Systemic AE: No
Faghihi et al (2012)^Citation11	RCT	65	1% MTX gel on glycerin base	Once daily	8 weeks	Placebo	No improvement	- Local AE: N/A - Systemic AE: N/A
Kumar et al (2004)^Citation13	Case series	14 PPP*	0.25% MTX in a hydroxygel base	Twice daily	12 weeks	-	Not very effective (42% of patients had at least 50% improvement)	- Local AE: No - Systemic AE: No
Topical MTX with chemical enhancer in human
Bjerring et al (1986)^Citation9	DBPLC	5	0.25% MTX cream in carbamide base	Twice daily	3 weeks	Placebo	No clinical and histological effects	- Local AE: N/A - Systemic AE: No
Weinstein et al (1989)^Citation18	DBPLC	42	0.1%, 0.5%, and 1% of MTX in a laurocapram-containing gel	Twice daily	6 weeks	Vehicle	At least 50% improvement was found in 60%, 59%, 50%, and 25% of patients with 0.1% MTX, 0.5% MTX, 1% MTX, and vehicle, respectively.	- Local AE: Some patients had mild irritation and temporary burning sensation. - Systemic AE: No
Sutton et al (2001)^Citation16	DBPLC	53	1% MTX in laurocapram (azone) gel formulation	Once daily	8 weeks	Placebo	Marked, moderate, and slight improvements were found in 27%, 7%, and 44% of MTX in azone, respectively. The majority (59%) of patients with placebo were only slight improved.	- Local AE: mild to moderate degree of pruritus, burning, irritation, and eruption (69.8%). - Systemic AE: headache (unlikely to related to treatment)
Ravi Kumar et al (1999)^Citation14	Case series	16 PPP*	1% MTX gel in propylene glycol	Twice daily	8 weeks	-	At least 50% improvement was obtained in 80% and 64% of patients with palmar and plantar psoriasis patients, respectively.	- Local AE: No - Systemic AE: No

Abbreviations: DBPLC, double-blind, placebo-controlled study; N/A, not available; PPP*, palmoplantar psoriasis; RCT, randomized, controlled study; SBPLC; single-blind, placebo-controlled study.

Table 2 Topical Methotrexate (MTX) Using Nanotechnology and Protein Transduction Domain

Authors (Year)	Type of Study		Patient Number	MTX Formulation		Frequency of MTX Application	Duration of Treatment	Comparators		Results	Adverse Events (AE)
Topical MTX using nanotechnology in human
Lakshmi et al (2007)^Citation25	RCT		30	0.25% niosomal MTX incorporated chitosan gel		Once daily	12 weeks	a. Marketed 0.25% MTX gel b. Placebo		- Niosomal MTX gel and marketed MTX gel were superior to placebo (P < 0.05). - Niosomal MTX gel was more efficacious than marketed MTX gel.	- Local AE: No - Systemic AE: No
Vanaja et al (2008)^Citation30	Open-label randomized parallel study		25	Ultra-deformable 0.25% liposomal MTX gel		N/A	10 weeks	1% plain MTX gel		- Liposomal MTX gel had comparable reduction in disease severity (45.3%), comparing to plain MTX gel (46.6%).	- Local AE: No - Systemic AE: No
Topical MTX using nanotechnology in animal mouse-model of psoriasis
Authors (Year)	N	MTX Formulation and Frequency of Application			Comparators		Duration of Treatment		Results		Adverse Events (AE)
Bahramizadeh et al (2019)^Citation21	72	MTX-entrapped deformable liposomes containing oleic acid in 3 concentrations a) 0.05% MTX daily b) 0.1% MTX daily c) 0.1% MTX every other day			d) Empty liposomes daily e) MTX subcutaneous injection single dose f) Betamethasone lotion daily g) MTX containing 0.1% carbomer gel daily h) Disease group with no treatment		7 days		Clinical: Among 3 concentrations of liposomal MTX, PASI score was decreased by 0.05% MTX liposome while it was increased by 0.1% MTX liposome. Histology: The reduction of epidermal thickness was only significantly in groups a, b (0.05% and 0.1% MTX-liposome daily) and f (betamethasone lotion daily). However, the inflammation index was significantly reduced in groups a-f. Cytokines: -		- Local AE: N/A - Systemic AE: No
Chandra et al (2019)^Citation23	12	a) 0.25% MTX-incorporated with ethosomal gel and 2% salicylic acid daily			b) Blank gel (Vaseline) c) Disease group with no treatment		7 days		Clinical: PASI scores decreased from 4 to 1, and from 4 to 3, in MTX ethosomal group and blank gel group, respectively. PASI score was not changed in the disease group with no treatment. Histology: MTX ethosomal gel treated group showed normal skin with very mild dyskeratosis. Blank gel treated group displayed moderate to high hyperkeratosis and orthokeratosis. Cytokines: -		- Local AE: N/A - Systemic AE: N/A
Authors (Year)	N	MTX Formulation and Frequency of Application			Comparators		Duration of Treatment		Results		Adverse Events (AE)
Yang et al (2021)^Citation36	48	a) MTX/nicotinamide cerosomes (0.05% w/ v and 6% w/v) daily			b) MTX/nicotinamide (0.05% w/ v and 6% w/v) solution c) MTX suspension (0.05% w/v) d) Oral MTX dose equivalent to 7.5 mg/ week for human e) Nicotinamide solution (6% w/ v) f) Blank cerosomes g) Imiquimod cream h) Normal control		7 days		Clinical: PASI score in MTX/nicotinamide cerosomes group was significantly lower than other treatment group (p < 0.01). Histology: Epidermal thickness in MTX/nicotinamide cerosomes group was significantly lower than other treatment groups (p < 0.001) Cytokines: MTX/nicotinamide cerosomes group exhibited the best effects in downregulating the levels of several proinflammatory cytokines.		- Local AE: N/A - Systemic AE: N/A
Panonnummal et al (2018)^Citation28	N/A	a) 100 μg/cm^2 MTX loaded chitin nanogel (MCNG) b) 150 μg/cm^2 of MCNG			c) 150 μg/cm^2 of MTX in carbopol gel d) Carbopol gel e) Control chitin nanogel f) Disease induced group with no treatment		3 weeks		Clinical: There was a significant reduction in PASI score by MCNG at both 150 μg/cm^2 dose (89.2%) and 100 μg/cm^2 dose (73.1%), compared to 33.9% reduction in PASI score in 150 μg/cm^2 of MTX in carbopol gel. Histology: MCNG treated group displayed less inflammatory cell infiltration, intact of granular layer, absence of parakeratosis and no micro abscess. MTX in carbopol gel and carbopol gel treated groups exhibited features of psoriasis histology such as regular acanthosis, intraepidermal neutrophilic abscess. Cytokines: -		- Local AE: No - Systemic AE: No
Asad et al (2021)^Citation32	25	a) MTX nanoparticles embedded into chitosan hydrogel			b) Free MTX hydrogel c) Marketed cream d) Imiquimod cream e) Normal control		10 days		Clinical: PASI score was decreased in group a-c, but a mark decreased was observed in group a Histology: Group a-c displayed the improvement in psoriatic lesion. Group b showed decrease in the thickness of both the dermis and epidermis but leukocytic infiltrations were present. Group c displayed a noticeable reduction in psoriatic lesions with better hyperkeratosis and parakeratosis feature. Group a showed a healthy keratin layer with decreased parakeratosis and hyperkeratosis level Cytokines: Group a showed better result in the reduction of TNF-α and IL–6, compared to group b and c.		- Local AE: N/A - Systemic AE: N/A
Avasatthi et al (2016)^Citation20	30	a) MTX-loaded nanostructured lipid carrier (MTX-NLC) gel Frequency: not available			b) MTX gel formulation c) Blank gel d) Disease induced group with no treatment e) Disease free control group with no treatment		7 days		Clinical: MTX-NLC gel showed highest reduction in average PASI score, followed by MTX gel and blank gel. Histology: Normal skin structure with very mild keratosis was found in MTX-NLC gel treated group whereas few hyperkeratosis and parakeratosis was exhibited in MTX gel treated group. Cytokines: -		- Local AE: N/A - Systemic AE: N/A
Agrawal et al (2020)^Citation19	24	a) MTX loaded nanostructured lipid carriers (MTXNLC) in carbopol gel daily			b) MTX in carbopol gel c) Disease group with soft paraffin d) No disease with soft paraffin		6 days		Clinical: The MTXNLC gel and MTX gel exhibited comparable efficacy of reduction in PASI score Histology: MTXNLC gel provided significant improvement in psoriatic histological alteration which was better than MTX gel Cytokines: MTXNLC showed significant decrease inflammatory cytokines including TNF-α, IL-1β and IL-6 which was better than MTX gel.		- Local AE: N/A - Systemic AE: N/A
Amarji et al (2016)^Citation8	24	a) 0.25% MTX loaded microemulsion in poloxamer gel daily			b) 0.1% topical dexamethasone c) Poloxamer gel with no active drug d) No treatment		5 days		Clinical: PASI score was significantly reduced in MTX loaded microemulsion in poloxamer gel (P < 0.001) from third day onwards whereas no cure was observed in groups c and d. Nevertheless, 0.1% dexamethasone showed the statistically most significant anti-psoriatic effect from second day onwards. Histology: - Cytokines: -		- Local AE: no irritation - Systemic AE: N/A
Rajitha et al (2019)^Citation29	36	a) MTX loaded nanoemulsion gel in Chaulmoogra oil (MTX-NE) daily			b) Bare nanoemulsion gel, daily for 1 month c) Chaulmogra oil, daily for 1 month d) Oral MTX tablet, once weekly for 1 month e) Disease group with no treatment f) No disease with no treatment		1 month		Clinical: MTX-NE showed highest average reduction in PASI score (95%), which was higher and even better than oral MTX group (91%). On the other hand, bare nanoemulsion gel and Chaulmoogra oil provided 70% and 46% reductions in PASI score. Histology: MTX-NE and oral MTX normalized epidermal thickness to the same level of normal skin (group f), which was significantly different from the bare nanoemulsion gel, Chaulmoogra oil, and disease groups. Cytokines: -		- Local AE: N/A - Systemic AE: N/A (low level of drug accumulation in vital organs with MTX-NE in comparison with oral MTX).
Rashid et al (2021)^Citation34	36	a) Olive oil based MTX loaded nanoemulsion gel (MTX NEG) daily			b) MTX plain gel c) Oral MTX tablet, once weekly for 1 month d) Olive oil e) Imiquimod cream f) Normal control		28 days		Clinical: MTX NEG and oral MTX demonstrated the highest percentage of PASI score reduction after 28 days (94.9% and 91.7%, respectively) While MTX plain gel and olive oil reduced PASI score by 61.3%, and 45.9%, respectively. Histology: - Cytokines: -		- Local AE: N/A - Systemic AE: N/A
Fratoddi et al (2019)^Citation24	16	a) Gold nanoparticles functionalized with sodium 3-mercaptopropane sulphonate (AuNPs-3MPS) loaded with MTX daily b) AuNPs-3MPS loaded with MTX daily			c) AuNPs-3MPS without MTX once daily for 2 days d) AuNPs-3MPS without MTX once daily for 1 day		a) 2 days b) 1 day		Clinical: AuNPs-3MPS loaded with MTX showed significant reduction in scaling and erythema scores, compared with AuNPs-3MPS alone. Histology: AuNPs-3MPS loaded with MTX displayed a reduction of epidermal thickness, parakeratosis and hyperkeratosis, compared with AuNPs-3MPS without MTX. Cytokines: -		- Local AE: No skin irritation - Systemic AE: No
Özcan et al (2020)^Citation27	53	a) MTX coupled with gold nanoparticles (MTX-GNPs) gel daily (MTX 12.5 mg/week)			b) MTX gel (12.5 mg/week) c) Gold nanoparticles (GNPs) gel d) Carbopol 980 gel carrier e) Disease group with no treatment f) No disease with no treatment		7 days		Clinical: MTX-GNPs showed significant reduction of ear inflammation, which was higher than GNPs gel. MTX gel lacked efficacy, despite the high dose, in reducing ear inflammation. Histology: MTX-GNPs exhibited uninflamed histologic feature, which was similar to the no-disease group. MTX gel and GNPs gel displayed features of psoriatic phenotype. Cytokines:		- Local AE: N/A - Systemic AE: No
	14	a) MTX-GNPs gel daily			b) Topical calcipotriol-betamethasone c) Vaseline		2 weeks		Clinical: - Histology: MTX-GNPs inhibited skin hyperplasia (acanthosis and papillomatosis) significantly better than topical calcipotriol-betamethasone Cytokines:		- Local AE: N/A - Systemic AE: N/A
Limon et al (2019)^Citation26	6	MTX in nanostructured supramolecular hydrogel every other day			MTX sodium salt in water (at the same concentration)		10 days		Clinical: MTX supramolecular hydrogel showed a decreased in ear thickness (50% reduction) from Day 8, while MTX solution showed a similar decrease at Day 11. Histology: - Cytokines: -		- Local AE: No skin rigidity, no hair loss, no exudate - Systemic AE: N/A
Xu et al (2022)^Citation35	36	a) MTX-Zinc oxide/Ag (ZA) embellished with nanomicelles (NMs) and further embedded with carbopol(Car); (Car@NMs@MTX-ZA hydrogels), therapeutic dosage: 0.5 mL/daily			b) Car@NMs@MTX hydrogel c) Car@NMs@ZA hydrogel d) Car@MTX hydrogel e) Car@ZA hydrogel f) Car@MTX-ZA hydrogel g) Zinc oxide h) Blank carbopol hydrogel i) Negative control		6 days		Clinical: Car@NMs@MTX-ZA hydrogels showed the highest reduction in PASI score. Histology: Car@NMs@MTX-ZA hydrogels displayed the highest reduction in epidermal thickness and HE Baker grading. Cytokines: The mRNA and protein expressions of TNF-α, IL-23, IL-1β and IL-6 was prominently suppressed by Car@NMs@MTX-ZA hydrogels compared with the other groups		- Local AE: N/A - Systemic AE: N/A
Topical MTX using protein transduction domains or cell-penetrating peptides
Byamba et al (2014)^Citation22	30	a) 0.1% topical skin-permeable MTX (SP-MTX) daily b) 1% topical SP-MTX daily			c) Disease free control group and disease induced group d) Intraperitoneal MTX treatment (IP-MTX) e) No treatment		3 days		Clinical: The cumulative PASI score was lowest in the 1% SP- MTX treatment group, followed by IP-MTX and 0.1% SP- MTX Histology: The increase in epidermal thickness was improved (compared with baseline) by intraperitoneal MTX and both concentrations of skin-permeable MTX (dose dependent). Cytokines: 1% SP-MTX almost completely reduced IL-17A-producing γδ T cell. IP-MTX partially reduced and 0.1% SP-MTX barely affected IL-17A-producing γδ T cell.		- Local AE: N/A - Systemic AE: No
Topical MTX using liquid crystalline systems
Bernandes et al (2021)^Citation33	42	a) MTX-loaded lamellar liquid crystal systems daily b) MTX-loaded hexagonal liquid crystal systems daily			c) MTX hydrogel daily d) 0.1% dexamethasone cream e) Negative control f) Imiquimod cream		5 days		Clinical: Erythema improved in the groups a, c, d. Peeling improved in the groups c, d. The lesion area improved in the groups a, c, d and f Histology: Group a, b, f showed the higher thickening of the epidermis compared to c, d, e groups (P <0.05). Cytokines: Group a, b, f showed higher cyclooxygenase-2 and myeloperoxidase activity and prostaglandin-2 production compared to the c, d, e groups (P <0.05) Group a, b showed higher level of IL-1 and IFN-γ in the skin of animals when compared with group d, e, f		- Local AE: N/A - Systemic AE: N/A
Alves et al (2022)^Citation31	35	a) Cholesterol/ceramide-based MTX-loaded liquid crystals daily b) Cholesterol-based MTX-loaded liquid crystals daily			c) Dexamethasone acetate d) Negative control e) Imiquimod cream		3 weeks		Clinical: - Histology: Both MTX-loaded liquid crystals formulation exhibited an increase in keratinization score, epidermis thickness, and inflammatory infiltrate. Cytokines: Both MTX-loaded liquid crystals formulations upregulated several pro-inflammatory cytokines (IL-1, IFN-γ, TNF-α)		- Local AE: N/A - Systemic AE: N/A

Table 3 Previous Studies Related to Topical Methotrexate (MTX) with Physical Enhancers/Laser/Photodynamic Therapy

Authors (Year)	Type of Study		Patients	MTX Formulation and Application	Assisted MTX Penetration	Comparators		Frequency of MTX Application	Duration of Treatment	Results	Adverse Events (AE)
Topical MTX with laser assisted-drug delivery/photodynamic therapy
Ali et al (2008)^Citation37	RCTs		30	0.25% liposomal MTX hydrogel with occlusive patch	650-nm diode laser (80 joules after MTX application and then 3 times/ week)	a. Plain MTX gel b. placebo		Once daily under occlusion for 30 minutes	12 weeks	- Complete clearance was found in 46.6% and 13.3% of patients with liposomal MTX and plain MTX gel, respectively. There was no improvement in placebo-treated lesions.	- Local AE: No - Systemic AE: No
Ramez et al (2018)^Citation41	Intraindividual comparison		30	0.1% nanoparticulated MTX microemulsion based on jojoba oil	Fractional erbium:YAG laser	MTX microemulsion based on jojoba oil without laser assisted		3 times weekly	8 weeks	Mocroemulsion/laser combination yielded a higher significant reduction in disease severity. (P < .05).	- Local AE: N/A - Systemic AE: No
Wang et al (2022)^Citation43	RCTs (mouse)		56	MTX and 5-aminoleavulinic acid (MTX-ALA) nanogels daily	635 nm laser (photodynamic therapy; PDT)	a) Topical 0.05% MTX-10% 5-ALA suspension + PDT b) Topical 10% ALA solution + PDT c) Topical 10% 5-ALA solution and oral 0.2 mL of the MTX suspension + PDT d) Oral 0.2 mL of the MTX suspension e) Imiquimod cream f) Normal control		Daily	7 days	Clinical: MTX-ALA nanogels + PDT exerted the best effect in decreasing the PASI score, compared to other groups. Histology: MTX-ALA nanogels + PDT; oral MTX; and oral MTX plus topical ALA + PDT group displayed the decreased of the thickened epidermis and alleviated inflammatory cell infiltration Cytokines: Only MTX-ALA nanogels + PDT can normalize TNF-α and IL-17A levels to those of normal control group	- Local AE: No skin erythema and no change in transpeidermal water loss in MTX-ALA nanogels mouse - Systemic AE: No histopathological changes in liver and kidney of mouse except in oral MTX group
Topical MTX with iontophoresis
Tiwari et al (2003)^Citation42	Intraindividual comparison		1 PPP*	MTX disodium solution (10 mg/ml)	Cotton gauze soaked in MTX solution with iontophoresis (12-15 mA)	No treatment		Once a week	4 weeks	The treated side had > 75% improvement while there was no clinical change on the control site.	- Local AE: No - Systemic AE: No
Haseena, et al (2017)^Citation40	Intraindividual comparison		28 PPP*	MTX solution (50 mg/2 ml) dissolved in 50 ml of water. approximately a total of 1 mg/ml of MTX)	Gauze soaked in MTX solution (1mg/ml) on the palm/sole that covered with aluminum foil plus iontophoresis (5-10 mA). White soft paraffin was applied on the other days.	White soft paraffin and iontophoresis. Coal tar ointment was applied on the other days.		Once weekly (4 sessions) and every 2 weeks (2 sessions)	8 weeks	- MTX solution significantly reduced disease severity (63.94%), comparing to the control (47.66%).	- Local AE: No - Systemic AE: No
Andanooru Chandrappa et al (2020)^Citation38	Open label study		50 PPP*	3-4 ml of 15 mg/ml MTX solution	Gauze soaked in MTX solution with iontophoresis (4.5 mA)	0.05% clobetasol propionate ointment twice daily		Once weekly	6 weeks	- There was no statistically significant difference in improvement between MTX and clobetasol groups.	- Local AE: Trivial and self‐limiting burn injury (48%) - Systemic AE: No
Topical MTX with microneedle patch made of hyaluronic acid in animal models of psoriasis
Du et al (2019)^Citation39	30	3 doses of MTX sodium aqueous solutions a) low dose (6.5 μg of MTX), b) medium dose (13.8 μg of MTX) c) high dose (30.6 μg of MTX) with dissolving microneedle patch made of hyaluronic acid (HA) daily for 5 days			d) blank HA microneedle patch e) disease group with no treatment f) disease free control group with no treatment Daily for 5 days		Clinical: The medium and high doses MTX with microneedle patch caused improvement. No improvement with blank HA microneedle application. Histology: Epidermal thickness was improved in all doses of MTX microneedle patch, especially in the medium dose and high dose MTX microneedle patches. Cytokines: IL-23 and IL-17 were downregulated by the MTX microneedle patch in a dose dependent manner.				- Local AE: N/A - Systemic AE: No
	25	a) MTX sodium aqueous solutions at medium dose (13.8 μg of MTX) with dissolving microneedle patch made of HA daily for 5 days			b) oral MTX (13.8 μg of MTX) c) oral MTX (27.6 μg of MTX) d) disease group with no treatment e) disease free control group with no treatment with dissolving microneedle patch made of HA daily for 5 days		Clinical: At the same MTX dosage (13.8 μg), MTX microneedle patch was superior to oral MTX in reducing psoriasiform dermatitis. Histology: Medium dose MTX microneedle patch and double dose of oral MTX exhibited comparable efficacy in reduction of epidermal thickness. Comparing to oral MTX, the thickness was reduced more in MTX microneedle with the same MTX dose. Cytokines: -				- Local AE: N/A - Systemic AE: No

Abbreviations: mA, milliampere; N/A, not available; PDT, photodynamic therapy; PPP*, palmoplantar psoriasis.

Table 4 Previous Studies Related to Intralesional Methotrexate (MTX) Injections

Author (Year)	Type of Study	Patients (Lesions)	Injection Site	MTX Dosage	Comparators	Frequency	Treatment Duration	Efficacy of MTX Group	Adverse Events of MTX
Stewart et al (1972)^Citation15	Intra-individual comparison	9 (45)	Plaque psoriasis	a) 0.1 ml of 0.5% MTX sodium solution (0.5 mg MTX)	b) 0.1 ml of 0.5% MTX sodium and 0.3% calcium leucovorin solution c) 0.1 ml sterile saline d) topical 5 mg of MTX sodium solution under occlusion e) occlusion of the skin without topical medication	- a, b and c. injected intralesionally every 12 hours for 36-hour period weekly - d. daily - e. continuous	3 weeks	No significant improvement in the areas treated by topical or intralesional methods	- Local AE: N/A - Systemic AE: Mild degree of transaminitis (11.1%)
Saricaoglu et al (2011)^Citation50	Case report	1 (1)	Nail matrix	2.5 mg MTX solution	-	Weekly	6 weeks	Improvement in subungual hyperkeratosis and pitting nails	- Local AE: No - Systemic AE: No
Grover et al (2017)^Citation46	Prospective study	4 (30)	Nail bed	0.1 mL of MTX 25 mg/mL	-	5 injections with an interval of 3 weeks.	15 weeks	There was a significant reduction in nail psoriasis severity index after MTX injections (P < 0.001).	-Local AE: pain, injection site pigmentation, nail bed hemorrhage - Systemic AE: No
Mittal et al (2018)^Citation48	Prospective, unblinded study	17 (90)	Nail matrix	a) 0.1 ml of MTX 25 mg/ml	b) 0.1 ml of 10 mg/ml triamcinolone acetonide, c) 0.1 ml of 50 mg/ml cyclosporine	2 injections with an interval of 6 weeks.	6 weeks	The efficacy of MTX was superior to cyclosporine but it was comparable to triamcinolone acetonide.	-Local AE: transient post-injection numbness (20%), pain (3.3%), Systemic AE: N/A
Mokni et al (2018)^Citation49	Case report	1 (6)	Nail matrix	0.1 ml of MTX 5 mg/2ml	-	Monthly	3 months	Nail dystrophy completely resolved except filiform hemorrhage.	- Local AE: N/A - Systemic AE: No
Duarte et al (2019)^Citation45	Case report	2 (2)	Nail matrix	0.1 ml of MTX 25 mg/ml	-	Every 30 days	3 months	Improvement	- Local AE: N/A - Systemic AE: N/A
Jindal et al (2020)^Citation47	Case report	1 (1) ACH	Nail matrix	0.2 ml of MTX 5 mg/ml	-	Monthly	4 months	Completely disappear of lesion	- Local AE: N/A - Systemic AE: N/A
Choudhary et al (2021)^Citation44	Prospective study	20 (89)	Nail matrix	2.5 mg	-	Weekly	6 weeks	NAPSI score decrease significantly from 3.70 (baseline) to 0.67 at 12 weeks.	- Local AE: Pain at injection site (10%), acute paronychia (5%) - Systemic AE: No
Starace et al (2022)^Citation53	Prospective study	12 (20)	Nail matrix	0.1 ml of MTX 25 mg/ml	0.1 ml of 10 mg/ml triamcinolone acetonide	4 injections with an interval of 6 weeks.	24 weeks	Nail psoriasis responded well to both treatment but more stability was noted at follow-up period in MTX group	- Local AE: Subungual hematoma - Systemic AE: N/A
Alakad et al (2022)^Citation52	RCT	28 (123)	Nail matrix and nail bed	0.02 ml of MTX 25 mg/ml	Fractional CO2 laser followed by topical application of 0.1 mL of MTX 25 mg/mL	Biweeky for 6 treatment sessions	3 weeks	Both treatments were associated with statistically significant improvement of nail psoriasis score. No statistically significant difference between both treatments was found.	- Local AE: Subungual hematoma and pain was less significantly found in Fractional CO2 group - Systemic AE: N/A
Abdelmeniem et al (2022)^Citation51	RCT	60	Nail matrix and nail bed	a) 0.1 ml of MTX (50 mg/2 ml)	b) 0.1 ml of 5-FU (250 mg/5 ml) c) 0.1 ml of triamcinolone acetonide (10 mg/ml) d) topical 0.005% calcipotriol cream plus 20% urea under occlusion twice daily	Monthly	3 months	The mean percentage of NAPSI improvement was highest in topical calcipotriol plus urea group, followed by intralesional triamcinolone, MTX and 5-FU.	-Local AE: Subungual hematoma, tolerable pain - Systemic AE: N/A

Abbreviations: ACH, acrodermatitis continua of Hallopeau; FU, fluorouracil; NAPSI, Nail Psoriasis Severity Index; N/A, not available;RCT, randomized, controlled study.

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