Dear Editor,
Nail involvement occurs in 80–90% of psoriasis patients during their lifetimes [1, 2]. Nail psoriasis is more than a cosmetic concern, often causing pain, difficulty with functionality, and psychosocial problems [1]. Despite the substantial burden of nail involvement on psoriasis patients, clinical trials assessing efficacy and safety of nail psoriasis therapeutics are limited, and the most recent nail psoriasis Cochrane review is now over a decade old.
The 2013 nail psoriasis Cochrane review [3] examined data from 18 randomized controlled clinical trials (1,266 adult patients) for nail psoriasis treatments, assessing for efficacy, adverse events (AEs), and quality of evidence. Treatment efficacy was measured via primary outcomes, including clinician-assessed global improvement, nail psoriasis score improvement, and patient-reported improvement. Most of the included studies (55.6%) assessed topical treatments, 27.8% assessed systemic treatments, and 16.7% assessed radiotherapy. The quality of trials was generally poor due to risk of bias and failure to report nail improvement compared to controls in some studies. The heterogenous nature of most trials prevented performing a meta-analysis. Evidence for efficacy and safety was typically limited to one study per therapy.
For topical therapies, there were no significant improvements in nail scores compared to controls. There were only significant nail improvements compared to baseline for cyclosporine 70% in maize oil, tazarotene 0.1% cream, and clobetasol 0.05%, as measured by clinical severity score, Nail Psoriasis Severity Index (NAPSI), and therapeutic results score, respectively (Table 1). Topical therapies with the highest AE rates included tazarotene 0.1% gel (23.8%), tazarotene 0.1% cream (18.8%), and 5-fluorouracil (10.5%) (Table 2).
Mean percent improvement of fingernail severity and level of evidence
| Intervention versus controla | Baseline fingernail severity scoreb | % improvement from baselinec | Level of evidenced |
|---|---|---|---|
| Topical cyclosporine 70% in maize oil versus maize oil | 8.0 versus 8.0 (PS) | At 12 weeks: 77.0% (n = 8)sb versus 12.0% (n = 8)nsb | A2 |
| 5-fluorouracil in Belanyx® versus Belanyx® lotion | 7.1 versus 7.1 (NAS) | At 12 weeks: 32.0% (n = 57)sb versus 39.0% (n = 57)sb | A2 |
| Tazarotene 0.1% cream versus clobetasol propionate 0.05% | 1.5 versus 1.4 (NAPSI) | At 12 weeks: 75.0% (n = 16)ns,sb versus 68.0% (n = 14)ns,sb | A2 |
| Topical calcipotriol 50 μg/g versus betamethasone dipropionate 64 mg/g + salicylic acid 0.03 g/g | 2.3 versus 2.3 (NT) | At 12 weeks: 26.5% (n = 13)ns versus 30.4% (n = 16)ns | B |
| At 20 weeks (week 12 responders only): 49.2% (n = 8)ns,sb versus 51.7 (n = 10)ns,sb | |||
| Methotrexate 15 mg/week versus cyclosporine 5 mg/kg | 39.1 versus 42.1 (NAPSI) | At 24 weeks: 43.3% (n = 17)ns,nsb versus 37.2% (n = 17)ns,nsb | A2 |
| Systemic cyclosporine 2.5 mg/kg versus topical dithranol + salicylic acid + UVB | 5.5 versus 5.0 (PS) | 82.0% (n = 10) at median 10 weeksnsb versus 0.0% (n = 15) at median 8 weeksnsb | A2/B |
| Systemic cyclosporine 2.5 mg/kg versus etretinate | N/A | At 10 weeks: <25% improvement in nail involvement in both groupsns | B |
| Ustekinumab 45 mg versus placebo | 3.7 versus 4.6 (NAPSI) | At 12 weeks: <25% improvement in nail involvement in both groupsns | A2 |
| Ustekinumab 90 mg versus placebo | 4.1 versus 4.6 (NAPSI) | At 12 weeks: <25% improvement in nail involvement in both groupsns | A2 |
| Golimumab 50 mg versus placebo | 4.7 versus 4.4 (NAPSI) | At 14 weeks: 25.0% (n = 95)s versus 0.0% (n = 83)s | B |
| At 24 weeks: 33.0% (n = 95)s versus 0.0% (n = 83)s | |||
| Golimumab 100 mg versus placebo | 4.6 versus 4.4 (NAPSI) | At 14 weeks: 43.0% (n = 109)s versus 0.0% (n = 83)s | B |
| At 24 weeks: 54.0% (n = 109)s versus 0.0% (n = 83)s | |||
| Infliximab 5 mg/kg versus placebo | 4.6 versus 4.3 (NAPSI) | At 10 weeks: 26.8% (n = 240)s versus −7.7% (n = 65)s | A2 |
| At 24 weeks: 57.2%s versus −4.1%s | |||
| Electron beam 0.75 Gy versus placebo | N/A | At 3 months, improvement after 8 weeks of therapys,sb | B |
| Grenz rays 5 Gy versus placebo | N/A | At 10 weeks: moderate therapeutic responses | A2/B |
| Superficial radiotherapy 450 cGy versus “sham radiotherapy” | 5.5 versus 5.4 (PS) | At 10 weeks, after 2 weeks of therapy: <25% improvement for both groups (both n = 8)s,sb | B |
| Intervention versus controla | Baseline fingernail severity scoreb | % improvement from baselinec | Level of evidenced |
|---|---|---|---|
| Topical cyclosporine 70% in maize oil versus maize oil | 8.0 versus 8.0 (PS) | At 12 weeks: 77.0% (n = 8)sb versus 12.0% (n = 8)nsb | A2 |
| 5-fluorouracil in Belanyx® versus Belanyx® lotion | 7.1 versus 7.1 (NAS) | At 12 weeks: 32.0% (n = 57)sb versus 39.0% (n = 57)sb | A2 |
| Tazarotene 0.1% cream versus clobetasol propionate 0.05% | 1.5 versus 1.4 (NAPSI) | At 12 weeks: 75.0% (n = 16)ns,sb versus 68.0% (n = 14)ns,sb | A2 |
| Topical calcipotriol 50 μg/g versus betamethasone dipropionate 64 mg/g + salicylic acid 0.03 g/g | 2.3 versus 2.3 (NT) | At 12 weeks: 26.5% (n = 13)ns versus 30.4% (n = 16)ns | B |
| At 20 weeks (week 12 responders only): 49.2% (n = 8)ns,sb versus 51.7 (n = 10)ns,sb | |||
| Methotrexate 15 mg/week versus cyclosporine 5 mg/kg | 39.1 versus 42.1 (NAPSI) | At 24 weeks: 43.3% (n = 17)ns,nsb versus 37.2% (n = 17)ns,nsb | A2 |
| Systemic cyclosporine 2.5 mg/kg versus topical dithranol + salicylic acid + UVB | 5.5 versus 5.0 (PS) | 82.0% (n = 10) at median 10 weeksnsb versus 0.0% (n = 15) at median 8 weeksnsb | A2/B |
| Systemic cyclosporine 2.5 mg/kg versus etretinate | N/A | At 10 weeks: <25% improvement in nail involvement in both groupsns | B |
| Ustekinumab 45 mg versus placebo | 3.7 versus 4.6 (NAPSI) | At 12 weeks: <25% improvement in nail involvement in both groupsns | A2 |
| Ustekinumab 90 mg versus placebo | 4.1 versus 4.6 (NAPSI) | At 12 weeks: <25% improvement in nail involvement in both groupsns | A2 |
| Golimumab 50 mg versus placebo | 4.7 versus 4.4 (NAPSI) | At 14 weeks: 25.0% (n = 95)s versus 0.0% (n = 83)s | B |
| At 24 weeks: 33.0% (n = 95)s versus 0.0% (n = 83)s | |||
| Golimumab 100 mg versus placebo | 4.6 versus 4.4 (NAPSI) | At 14 weeks: 43.0% (n = 109)s versus 0.0% (n = 83)s | B |
| At 24 weeks: 54.0% (n = 109)s versus 0.0% (n = 83)s | |||
| Infliximab 5 mg/kg versus placebo | 4.6 versus 4.3 (NAPSI) | At 10 weeks: 26.8% (n = 240)s versus −7.7% (n = 65)s | A2 |
| At 24 weeks: 57.2%s versus −4.1%s | |||
| Electron beam 0.75 Gy versus placebo | N/A | At 3 months, improvement after 8 weeks of therapys,sb | B |
| Grenz rays 5 Gy versus placebo | N/A | At 10 weeks: moderate therapeutic responses | A2/B |
| Superficial radiotherapy 450 cGy versus “sham radiotherapy” | 5.5 versus 5.4 (PS) | At 10 weeks, after 2 weeks of therapy: <25% improvement for both groups (both n = 8)s,sb | B |
PS, point scale; NAS, nail area severity; NAPSI, Nail Psoriasis Severity Index; NT, nail thickness; s, significant between groups; ns, not significant between groups; sb, significant compared to baseline; nsb, not significant compared to baseline.
aComparisons without recorded significance omitted.
bWhere provided, fingernail severity scores were recorded as follows: PS, NAS, NAPSI, NT (mm).
cWhere provided, significance was recorded as follows: s, ns, sb, nsb.
dStudy levels of evidence: A2, randomized controlled trial of good quality; B, randomized clinical trial of low quality.
Treatment-related AEs
| Intervention versus controla | AEs (% of patients) |
|---|---|
| Topical cyclosporine 70% in maize oil versus maize oil | I: 0.0% (0/8) – no AE |
| C: 0.0% (0/8) – no AE | |
| 5-fluorouracil in Belanyx® versus Belanyx® lotion | I: 10.5% (6/57) – pain, swelling, discoloration, inflammation, onycholysis, perforation |
| C: 0.0% (0/57) – no AE | |
| Tazarotene 0.1% cream versus clobetasol propionate 0.05% | I: 18.8% (3/16) – desquamation, erythema, irritation |
| C: 7.1% (1/14) – burning on the nail fold skin | |
| Topical calcipotriol 50 μg/g versus betamethasone dipropionate 64 mg/g + salicylic acid 0.03 g/g | I: 12.0% (3/25) – erythema, irritation, burning, urticaria |
| C: 14.3% (3/21) – erythema | |
| Methotrexate 15 mg/week versus cyclosporine 5 mg/kg | I: 22.2% (4/18) – nausea, telogen effluvium, increased hepatic enzymes |
| C: 26.3% (5/19) – hypercholesterolemia, hirsutism, menstrual abnormalities, mild pain on the distal nail, increased creatinine, increased lipids | |
| Systemic cyclosporine 2.5 mg/kg versus topical dithranol 2–8% + 0.5% salicylic acid + UVB | I: (NR) – minimal toxicity |
| C: (NR) – burning | |
| Systemic cyclosporine 2.5 mg/kg versus etretinate | I: 32.1% (45/140) – gastrointestinal, skin and mucous membrane symptoms, nervous system, and psychiatric disorders |
| C: 57.1% (40/70) – skin and mucous membrane symptoms | |
| Ustekinumab 45 or 90 mg versus placebo | I: 97.4% (150/154) – nasopharyngitis, increased triglycerides, increased creatine phosphokinase, seasonal allergy, infections |
| C: 65.6% (21/32) - Exacerbation of skin psoriasis, infections | |
| Golimumab 50 and 100 mg versus placebo | I: 65% (222/343) – upper respiratory tract infections, nasopharyngitis |
| C: 59% (67/113) – upper respiratory tract infections, headache, unspecified serious AEs | |
| Infliximab 5 mg/kg versus placebo | I: 82.0% (244/298) – infections, headache, increased hepatic enzymes, fatigue |
| C: 71% (54/76) – infections, headache, psoriasis, pharyngitis | |
| Electron beam 0.75 Gy versus placebo | I: 100.0% (12/12) – temporary brownish-black discolorations |
| C: 0.0% (0/12) – no AE | |
| Grenz rays 5 Gy versus placebo | I: 22.7% (5/22) – slight pigmentation of nail fold |
| C: 0.0% (0/22) – no AE | |
| Superficial radiotherapy 450 cGy versus “sham radiotherapy” | I: 0.0% (0/8) – no AE |
| C: 0.0% (0/8) – no AE |
| Intervention versus controla | AEs (% of patients) |
|---|---|
| Topical cyclosporine 70% in maize oil versus maize oil | I: 0.0% (0/8) – no AE |
| C: 0.0% (0/8) – no AE | |
| 5-fluorouracil in Belanyx® versus Belanyx® lotion | I: 10.5% (6/57) – pain, swelling, discoloration, inflammation, onycholysis, perforation |
| C: 0.0% (0/57) – no AE | |
| Tazarotene 0.1% cream versus clobetasol propionate 0.05% | I: 18.8% (3/16) – desquamation, erythema, irritation |
| C: 7.1% (1/14) – burning on the nail fold skin | |
| Topical calcipotriol 50 μg/g versus betamethasone dipropionate 64 mg/g + salicylic acid 0.03 g/g | I: 12.0% (3/25) – erythema, irritation, burning, urticaria |
| C: 14.3% (3/21) – erythema | |
| Methotrexate 15 mg/week versus cyclosporine 5 mg/kg | I: 22.2% (4/18) – nausea, telogen effluvium, increased hepatic enzymes |
| C: 26.3% (5/19) – hypercholesterolemia, hirsutism, menstrual abnormalities, mild pain on the distal nail, increased creatinine, increased lipids | |
| Systemic cyclosporine 2.5 mg/kg versus topical dithranol 2–8% + 0.5% salicylic acid + UVB | I: (NR) – minimal toxicity |
| C: (NR) – burning | |
| Systemic cyclosporine 2.5 mg/kg versus etretinate | I: 32.1% (45/140) – gastrointestinal, skin and mucous membrane symptoms, nervous system, and psychiatric disorders |
| C: 57.1% (40/70) – skin and mucous membrane symptoms | |
| Ustekinumab 45 or 90 mg versus placebo | I: 97.4% (150/154) – nasopharyngitis, increased triglycerides, increased creatine phosphokinase, seasonal allergy, infections |
| C: 65.6% (21/32) - Exacerbation of skin psoriasis, infections | |
| Golimumab 50 and 100 mg versus placebo | I: 65% (222/343) – upper respiratory tract infections, nasopharyngitis |
| C: 59% (67/113) – upper respiratory tract infections, headache, unspecified serious AEs | |
| Infliximab 5 mg/kg versus placebo | I: 82.0% (244/298) – infections, headache, increased hepatic enzymes, fatigue |
| C: 71% (54/76) – infections, headache, psoriasis, pharyngitis | |
| Electron beam 0.75 Gy versus placebo | I: 100.0% (12/12) – temporary brownish-black discolorations |
| C: 0.0% (0/12) – no AE | |
| Grenz rays 5 Gy versus placebo | I: 22.7% (5/22) – slight pigmentation of nail fold |
| C: 0.0% (0/22) – no AE | |
| Superficial radiotherapy 450 cGy versus “sham radiotherapy” | I: 0.0% (0/8) – no AE |
| C: 0.0% (0/8) – no AE |
AEs, adverse events; I, intervention; C, control; NR, not reported.
aComparisons based on Table 1.
For systemic therapies, there were only significant improvements in the primary outcomes “clinician-assessed global improvement” and “nail psoriasis score improvement” for infliximab 5 mg/kg and golimumab 50 mg and 100 mg compared to placebo (Table 1). Systemic therapies with the highest AE rates included ustekinumab (97.4%), infliximab (82%), and golimumab (65%) (Table 2).
Despite a plethora of advances in cutaneous psoriasis therapeutics, progress in nail psoriasis therapeutics has been relatively stagnant due to the unique challenges in nail research, including the physiologically slow nail growth compared to skin turnover rate. Outcome assessments for fingernails and toenails generally require a minimum 6 months and 1 year, respectively, making patient enrollment periods in nail trials significantly longer than those in cutaneous trials. Most psoriasis clinical trials have focused on skin outcomes as primary endpoints, with very few trials specifically analyzing nail psoriasis patients. There is also heterogeneity in the use of outcomes to assess the effect of interventions on nail psoriasis [4]. An expert consensus on a standardized set of nail psoriasis treatment outcomes which may be used to directly compare therapeutic outcomes has not yet been established. The 2013 outdated nail psoriasis Cochrane review, with its limited quality of evidence, is a testament to this overarching problem in not only nail psoriasis research, but nail disease research in general.
Due to the lack of clinical trials specifically analyzing nail psoriasis patients, expert nail psoriasis treatment guidelines [5] were published in 2019 to help guide treatment based on available evidence. These guidelines recommend topical therapies and intralesional injections as first-line therapies, with systemic treatments reserved for patients with greater extent of nail involvement (>3 nails) and significant QOL burden [5].
A number of systematic reviews assessing the efficacy and safety of targeted nail psoriasis therapies have been conducted [1, 6, 7]. However, no systematic reviews have directly compared systemic, topical, and intralesional therapies for nail psoriasis since the 2013 Cochrane review.
In conclusion, the quality of trials in this review was generally poor. Among topical and systemic therapies, infliximab and golimumab demonstrated significant nail improvement compared to controls. Evidence for topical therapies was inconclusive and of low quality. Systemic therapies were associated with the highest rates of AEs. Well-designed randomized psoriasis clinical trials analyzing nail changes as the primary outcome and a Cochrane review including more recently studied systemic therapies are needed. The 2013 nail psoriasis Cochrane review is a testament to the unique challenges of nail disease research, and a reassessment of research standards for nail disease may be warranted.
Conflict of Interest Statement
PS receives departmental independent research grants for TREAT NL registry from Pharma since December 2019, is Chief Investigator (CI) of the systemic and phototherapy atopic eczema registry (TREAT NL) for adults and children, and is involved in performing clinical trials with many pharmaceutical industries that manufacture drugs used for the treatment of, e.g., psoriasis and atopic dermatitis, for which financial compensation is paid to the department/hospital. She was involved in the development of one of the HOME core outcome instruments (Recap of atopic eczema [RECAP]) and in the development of the Outcome Measures for Vascular Malformations (OVAMA) questionnaire for vascular malformations. MMEW currently serves as principal investigator in clinical trials sponsored by Incyte. SRL has served as a consultant for Ortho Dermatologics, Eli Lilly, BelleTorus Corporation, and Moberg Pharmaceuticals.
Funding Sources
There are no funding sources.
Author Contributions
Michael J. Diaz and Kaya L. Curtis: formal analysis, methodology, and writing – original draft preparation, review, and editing; Jasmine T. Tran: formal analysis and writing – original draft preparation, review, and editing; Phyllis I. Spuls: conceptualization, investigation, methodology, data curation, and validation; Marjorie E. Montanez-Wiscovich and Shari R. Lipner: supervision, project administration, and writing – review and editing.
References
