Palmoplantar Pustulosis: A Systematic Review of Risk Factors and Therapies

Figures & data

Figure 1 Identification of studies via databases.

Table 1 Risk Factors for Development of PPP and Disease Severity

Author, Year	Study Type	Level of Evidence	Risk Factor	Number of Patients	Character-Istics of Population	Outcome	Rating of Study (NIH)
Ataş H, 2017^Citation16	Case-control study	3	Sex, smoking, thyroid pathologies, thyroid autoantibodies, insulin resistance	33 patients with PPP and 27 age and gender-matched controls	1 female, 2 male	Predictive risk factors: female sex (8.8-fold increased risk; OR = 141.7, p < 0.0001); tobacco use: smokers (32.7-fold increased risk (OR = 147.6, p = 0.006); anti-TPO level > 35 U/mL (OR = 4.2, p = 0.025) and thyroid dysfunction (OR = 5.4, p = 0.004) risk factors in univariate, but not multivariate analysis insulin resistance: no correlation (p > 0.05)	Medium
Serizawa N, 2021^Citation17	Case-control study	2	Dietary habits	72	72 cases and 72 controls (each 25 men and 47 women), Japanese patients	PPP was associated with high BMI (OR 1.21; 95% confidence interval 1.08–1.35; p = 0.000879), high intake of pulses (OR 1.18; 95% confidence interval 1.02–1.36; p = 0.0225), and low intake of vitamin A (OR 0.998; 95% confidence interval 0.996–0.999; p = 0.0482). PPPASI was predicted by BMI (β = 0.4405, t = 2.048, p = 0.0444) and sodium (Na) intake (β = 2.6959, t = 2.013, p = 0.0480)	Medium
Kim DH, 2022^Citation18	Cross-sectional analysis	3	Comorbidities	37,399	37,399 patients with PPP, 332,279 patients with psoriasis vulgaris, 365,415 patients with pompholyx extracted from Korean National Health Insurance database	51.7% female, significantly higher risk of AS (p< 0.001) and thyroid disorder (p < 0.001) compared to PsV patients. Risk of PsA was significantly higher in patients with PsV (p<0.001). History of smoking in 49.0%, 38.7% were overweight or obese. 22.5% had PsV. Those with PsV had older age (p < 0.001) with fewer women (p < 0.001). Current smokers (p<0.001) and obese patients (p=0.001) had a higher risk of developing PPP than Pso. Heavy drinkers had lower risk for PPP than PsV (p<0.001). Smoking and obesity are significant risk factors for development of PPP	High
Misiak-Galazka M 2018^Citation7	Case-control study	3	Comorbidities, compared to Pso	63	63 patients with PPP (92.06% female; mean age 58.51 years), 37 controls with PsV sex/age matched	Significantly more smokers 95.23% (p= 0.001) with significantly higher py and longer period of smoking, higher rate of thyroid disease 31.75% (p=0.0421); higher intensity of pain in PPP (p=0.0001); infections, high BMI, prevalence of arthralgias (57.14%), psychiatric disorders and stress not higher than in PsV, menopause and pregnancy do not influence PPP; pos FA for PPP in 4.76% and for PsV in 22.22%; 44.44% had hypertension, 11.11% had diabetes mellitus, 30.16% had metabolic syndrome, no difference to control. 30.77% had positive patch test, most frequently nickel, chlorides, and fragrances; significantly higher than PsV (p<0.05). No higher frequency of atopic diseases. No differences in calcium and mg levels; none had increased level of anti-endomysial IgG/IgA; 25–30% had PsV features	High
Mazloom SE, 2014^Citation19	Retrospective cohort study	3	TNF-α inhibitor	102	102 patients with TNF-α inhibitor-induced psoriasis; 41/102 developed PPP	41% of TNF-α inhibitor-induced psoriasis was PPP; INX (18/41), ADA (14/41), ETA (9/41); 43% smokers, smoking was significantly associated with risk of PPP but not other types of psoriasis	Medium
López-Robles A, 2012^Citation20	Retrospective cohort study	3	TNF-α inhibitor	450	450 rheumatic patients exposed to TNF-α inhibitor in a tertiary care center in Spain	1.56% developed psoriasiform lesion within 4–38 months (mean 9); 3/7 (71,3%) were PPP, 2 ADA, 1 INX	High
Bae JM, 2018^Citation21	Case control	3	TNF-α inhibitor agents in patients with IBD	5428 patients treated with anti-TNF > 6 months and 10,856 matched controls	50,502 IBD patients from the Korea National Health Insurance Claims database from January 2007 to December 2016	Highly increased risk of palmoplantar pustulosis in males with TNF-α inhibitor compared to control (HR 19.682, 95% CI 3.867–100.169), but not females (HR 1.181, 95% CI 0.101–13.783). Increased risk predominant in younger patients (HR 14.318, 95% CI 2.915–70.315). Infliximab but not adalimumab showed significant associations with risk of PPP: HR 9.504, 95% CI 2.767–32.648	High
Thein D, 2022^Citation22	Cohort study	3	TNF-α inhibitor	109,085	108,024 patients received conventional therapy and 20,910 received TNF-α inhibitor, 62% female, median age 50 (34–64) years with TNF-α inhibitor for IBD or RA	0.12% development of new PPP. TNF-α inhibitor-associated Pso: Non-pustular Pso is more prevalent but pustular Pso has the highest relative risk (HR of developing a pustular type of psoriasis 6.50 (95% CI, 4.60–9.23; P < 0.001))	High
Kim M, 2021^Citation23	Retrospective cohort study	3	Nail involvement	116	116 patients with PPP from Seoul University Hospital, 59.9% female, 14.7% had concomitant Pso and 8.6% had concomitant PsA, 66.3% had Involvement	NAPSI is correlated with PPPASI (p=0.01) and involvement area (p=0.04); Crumbling was associated with higher PPPASI (p = 0.01) and onycholysis was associated with lower PPPASI (P = 0.03). Risk factors for nail involvement: female sex (p < 0.001), younger age at diagnosis (p = 0.01), and higherPPPASI (p = 0.01).	High

Abbreviations: OR, odds ratio; PsV, psoriasis vulgaris; AS, Acrodermatitis suppurativa Hallopeau.

Table 2 Laser-and Light Therapies, Topical Treatments, Surgical Interventions, and Other Systemic Therapies

Author, Year	Study Type	Therapy (Drug/ Intervention, Dosage)	Treatment Duration	Number of Patients	Scoring Tool	Outcome	Adverse Events	Rating of Study (NIH)
Layton AL, 1990^Citation32	RCT	PUVA vs placebo	8 weeks	27	Clinical score	No significant difference btw groups	PUVA group (blistering, erythema, pruritus)	Medium
Murray D, 1979^Citation33	RCT	PUVA vs control (4x/week)	8 weeks (30 treatments)	22	Clinical score	Total clearance in PUVA (12/22); control (0/22)	4 burn in topical psoralen, in oral psoralen: 1 burn, 4 ankle swelling, 4 nausea, 6 conjunctivitis	High
Paul R, 1983^Citation35	Clinical trial	PUVA	5–20 treatment sessions	9	4-point clinical score	4/5 completed treatment with good or excellent improvement	Nausea (1/9)	Low
Jansen CT, 1981^Citation34	Clinical trial	PUVA	NA	10	Clinical evaluation	1/10 good improvement, 2/10 moderate improvement, 5/10 unchanged and 2/10 exacerbation of disease	Disease exacerbation, burning sensation, erythema	Low
Riad K, 2006^Citation36	Retrospective cohort study	PUVA; 3x/week	1–42 weeks	11	Clinical evaluation	46.7% complete or partial response	Superficial burn of the skin, hyperpigmentation	Low
Agren-Jonsson S, 1985^Citation37	Clinical trial	PUVA, 1–3x/week	Max 2–3 months	40	Clinical evaluation	Complete clearance 31/36 palmar lesions, 5/34 patients plantar lesions	Nausea (24/40), subungual petechiae (1/40)	Low
Su LN, 2017^Citation39	RCT	UVA1 vs UVBnb; 3x/week	10 weeks	64	PPPASI	Significant reduction in both groups (P < 0.05). Significantly greater in the UVA1 group (p < 0.05)	UVA1: burning sensation and hyperpigmentation; UVBnb: xerosis	High
Su LN, 2016^Citation38	Clinical trial	UVA1 (80 J/cm^2), 3x/week	10 weeks, 3 months follow up	62	PPPASI	PPPASI 50 (90.3%), PPPASI 75 (72.6%)	Burning sensation, pruritus, hyperpigmentation	Medium
Engin B, 2005^Citation40	Left–right comparison clinical trial	PUVA vs UVA	6 weeks	5	Severity index	Significantly better reduction after PUVA (P<0.05).	Localized phototoxicity (1/5)	Medium
Peng C, 2021^Citation44	RCT	308-nm Excimer laser 2 MED vs 4 MED vs 6 MED, 3x/week	12 weeks	73	PPPASI, DLQI	PPPASI 75 at week 12: 8.3% (low dose), 29.17% (medium dose), 95% (high dose)	Erythema, blistering, erosions, pain (more frequent at high dose)	High
Fumimori T, 2013^Citation42	Clinical trial	Excimer Light, 2x/week	2x/week	34	PPPASI	PPPASI 50 (19/34), PPPASI 75 (6/34)	NA	Medium
Furuhashi T, 2011^Citation43	Clinical trial	Excimer light (308 nm); 1x/week	30 weeks	15	PPPASI	PPASI 50 (60%), PPPASI 90 (20%)	NA	Medium
Kawada A, 2013^Citation41	Clinical trial	nbUVB	Max 12 week	15	mPPPASI	mPPPASI 75 (40.0%); mPPPPSI 50 (73.3.%)	Slight pain (1)	Medium
Fairris GM, 1984^Citation46	RCT	Superficial X-ray therapy (100 rad; 1 Gy; 50 kV) vs placebo; 3 treatment	63 d (intervals of 21 days)	9	Clinical evaluation	X-ray therapy has little or no therapeutic effect	NA	Low
Fenton L, 2016^Citation45	Retrospective cohort study	Grenz rays weekly, 5 Gy per treatment, 9 total courses	NA	9	Clinical evaluation	Marked improvement after three courses in 100%	NA	Low
Umezawa Y, 2016^Citation26	RCT	Maxacalcitol ointment vs placebo, 2x/d	8 weeks	188	Clinical score	Significant medication group compared placebo group (P < 0.0001)	Comparable to placebo (irritation, swelling)	High
Muro M, 2014^Citation27	RCT	1) Maxacalcitol ointment+ betamethasone butyrate propionate ointment (MBBP) vs 2) betamethasone butyrate propionate ointment (BBP) 1x/d	8 weeks	21	mPPPASI	Significant improvement both groups (p<0.01); significantly higher improvement of pustules and erythema (p<0.05)	No AEs	High
Volden G, 1992^Citation25	Clinical trial	Clobetasol propionate occlusive, 1x/ week	1–7 weeks (mean 2.2 weeks)	19	Clinical evaluation	Complete resolution in 18/19	NA	Low
Kragballe K, 1991^Citation29	RCT	1) Triamcinolone acetonide 0.1% cream+ hydrocolloid dressing 3x/week vs 2) clobetasol propionate 0.05% 2x/d	4 weeks	19	5-point severity score	Complete clearance 1) 63%, 2) 21% w (p=0.001)	No AEs	Medium
Goette D, 1982^Citation28	Case series	Triamcinolone acetonide; 3.3–5.0 mg/mL (local injection)	Single treatment	5	Clinical evaluation	5/5 clear or near clear within 3 weeks	Hypopigmentation, atrophy, tinea pedis	Low
Horiuchi Y, 2020^Citation30	Case series	Ozone nanobubble water oral rinse; 10–20 mL rinse 1x/d	6 months	7	Clinical scale (5 point)	6/7 complete clearance	NA	Low
Mizawa M, 2016^Citation31	Clinical trial	Jumihaidokuto (EKT-6) 6.0 g/d as adjuvant therapy	4–8 weeks	10	PPPASI	Significant reduction (p < 0.01)	No AEs	Medium
Takahara M, 2018^Citation47	Retrospective cohort study	Tonsillectomy	Single treatment, 24 months follow-up	138	PPPASI, Skin severity score (SSS)	12/24 months after tonsillectomy: PPPASI 100 in 44%/78%	NA	Medium
Kouno M, 2017^Citation48	Retrospective cohort study	Dental infection control, tonsillectomy, dental filling removal	Single treatment	85 (70 dental infection control; 9 dental filling removal; 6 tonsillectomy)	PPPASI	PPPASI 75 reached by 63% after dental infection control, 11% after dental metal removal and 84% after tonsillectomy	NA	Medium
V’Lckova-Laskoska MT, 2009^Citation49	Clinical trial	Itraconazole, 100 mg/d for 4 weeks, then 100 mg 1x/2d for 4 weeks	8 weeks	6	Clinical evaluation	3/6 complete clearance of pustules, 100% relapse within 1 months after therapy	None	Low
Ward J, 1976^Citation50	RCT	Clomocycline, 170 mg po 3x/d	3 months treatment, 3 months placebo	40	Clinical score	Significantly higher rate of responders to clomocycline (p=0.003)	Nausea and vomiting (6), vaginal thrush (1), constipation (1), heartburn (1), miscellaneous symptoms (4)	High
Bhushan M, 2001^Citation51	RCT	Liarozole, 75 mg po, 2x/d	12 weeks	15	PPPASI	Significant improvement (P = 0.02) in treatment group	Pruritus, cheilitis, xerosis	High

Abbreviations: RCT, randomized controlled trial; PPPASI, palmoplantar pustulosis area and severity index; mPPPASI, modified palmoplantar pustulosis area and severity index; MED, minimal erythema dose.

Table 3 Conventional Therapies for the Treatment of PPP

Author, Year	Study Type	Therapy (Drug/ Intervention, Dosage)	Treatment Duration	Number of Patients	Scoring Tool	Outcome	Adverse evenTs	Rating of Study (NIH)
Ettler K, 2001^Citation64	Clinical trial	Acitretin 25–50 mg/d po, followed by PUVA	3 months	10	mPASI	Average PASI reduction 87%; significant improvement. Relapses within 2 weeks despite PUVA in all patients	Exanthema, cheilitis, dry mucosa, hyperlipidemia	Low
Lassus A, 1988^Citation52	Clinical trial	Acitretin 30 mg/d po	12 weeks	30	Pustule count	Decrease of mean number of pustules from 57.8 (±8.6) to 3.9 (±1.6)	Cheilitis, scaling, hair loss
van de Kerskhov PCM, 1988^Citation53	Clinical trial	Acitretin 25–55 mg/d po	6 months	6	Clinical score 0–4 for erythema, scaling, pustules	Prompt improvement, better at higher dosage, relapse within 2 weeks after cessation	Dry skin, dry lips, hair loss, pruritus, transient increase in triglycerides and transaminases	Low
Reich K, 2016^Citation56	RCT	Alitretinoin 30 mg/d po	24 weeks	33 (24 alitretinoin, 9 placebo)	PPPASI, mPASI, number of pustules, NAPSI	No significant difference between alitretinoin and placebo	1 SAE (dizziness), 4 AE leading to dose interruption (dizziness, headache, loss of appetite)	High
Lee SJ, 2019^Citation57	Retrospective cohort study	Alitretinoin 30 mg/d po	NA	10	PGA	PGA clear/almost clear (4/10), higher response rate in hyperkeratotic PPP (p=0.033)	NA	Medium
Erkko P, 1998^Citation58	RCT	Ciclosporin 1–4 mg/kg/d po	18 weeks, 12 months	58 (CyA 27, placebo 31)	Number of fresh pustules	Significant reduction of number of fresh pustules (p < 0.001)	Increased serum creatinine levels (2), hypertension (7), hypertrichosis (6)	High
Reitamo S., 1993^Citation59	RCT	Ciclosporin 2.5 mg/kg/d po	4 weeks	38 (19 CyA and 19 control)	Number of pustules	Significant reduction of pustules in CyA but not placebo (p= 0.001).	Headache, cold feet, common cold, nausea, diarrhea, dryness of mouth, weakness/ stiffness, arthralgia, paronychia, sinusitis, hypertension, hypertrichosis, vaginitis, paresthesia, secretion of the eyes, dizziness, sweating, abdominal pain	Medium
Jin XH, 2019^Citation60	Clinical trial	Ciclosporin, 3 mg/kg /d po	15 days-6 months	48	PPPASI	PPPASI 90 (16.7%), PPPASI 60 (45.8%)	Hypertension 6/48, frequent urination and enuresis nocturna 6/48, gastrointestinal reactions 6/48, hypertrichosis 3/48, increased creatinine 1/48	Medium
Remitz A, 1996^Citation61	Controlled clinical trial	Ciclosporin 2.5 mg/kg/d po Vs placebo	4 weeks	14 vs 14	Clinical evaluation	Clinical improvement only in CyA group	NA	Medium
Mann RJ, 1982^Citation63	RCT	Colchicine, 0.5 mg po, 2x/d	6 weeks	12	Clinical evaluation	No significant improvement with colchicine	Neck pain, headache, diarrhea, nausea	Medium
English JSC, 1983^Citation62	RCT	Colchicine 0.5 mg po, 2x/d vs placebo	3 months	10	Number of pustules	No significant difference between colchicine and placebo.	The only side-effect reported was diarrhea for 1 week in one patient on colchicine but this settled spontaneously. No hematological abnormality was found throughout the trial period.	Low
Aichelburg MC, 2021^Citation55	RCT	1) Dimethylfumarate, max 720 mg po/d +PUVA vs 2) acitretin (50 mg/day) +PUVA	38 weeks	21	PPPASI	PPPASI 90 1) 81.8%, 2) 90% (P = 0.593)	Nausea (1)	Medium

Abbreviations: RCT, randomized controlled trial; PPPASI, palmoplantar pustulosis area and severity index; mPPPASI, modified palmoplantar pustulosis area and severity index; PGA, physician global assessment; CyA, ciclosporin A; SAE, severe adverse event.

Table 4 Biologics and Small Molecules for the Treatment of PPP

Author, year	Study Type	Therapy (Drug/ Intervention, Dosage)	Treatment Duration	Number of Patients	Scoring Tool	Outcome	Adverse Events	Rating of Study (NIH)
Poortinga S, 2021^Citation65	Retrospective cohort study	IL-23p19 antibodies	Median 12.5 months	16 (12 gus, 3 ris, 1 til)	PPPASI	Week 12: PPASI 50 56.3%, PPASI 75 25.0%; 1 year; PPPASI 50 62.5% PPPASI 75 43.8%	No relevant AE	High
Terui T, 2018^Citation67	RCT	Guselkumab 200 mg sc; week 0 and 4	24 weeks	41	PPSI, PPPASI, PGA	Week 16: PPPASI 50 60%, significantly higher than placebo (0.009)	No severe AE, frequency of treatment-emerged AE (75%) comparable to placebo	High
Terui T, 2019^Citation68	RCT	Guselkumab 200 mg vs 100 mg sc vs placebo (week 0, 4, 12, then every 8 weeks)	52 weeks	159	PPPASI, PPSI, PGA, DLQI	Week 16: PPPASI 75 (compared to placebo) GUS100 (20.4%; p = 0.01) GUS 200 mg (11.5%, p =0.12). Week 52: PPPASI 75 GUS 100 (55.6%) and GUS 200 (59.6%)	TAES Gus100 mg < than placebo and Gus200	High
Okubo Y, 2021^Citation66	RCT	Gusekumab 100 mg vs 200 mg vs placebo (week 0, 4, 12, then every 8 weeks)	60 weeks (24 weeks follow up)	133 with 4 groups; 1) 45 GUS 100 mg, 2)43 GUS 200 mg, 3)21 placebo switch to GUS 100 mg at weeks 16, 4) 24 placebo switch to GUS 200 mg at weeks 16	PPPASI, PPSI, PGA, patients reported outcomes	Week 16: significantly higher number of PPPASI 50 responders with GUS 100 mg (p=0.02) but not GUS 200 mg compared to placebo. At week 84 PPPASI 75: 1) 61.9%, 2) 66.7%, 3) 68.9%, 4) 81.4% (all groups 71.4%)	SAE 7.6%, most frequent TEAE: nasopharyngitis, oral herpes, eczema, urticaria, dental caries, injection site swelling/ pruritus/erythema, hyperlipidemia, AE of special interest: severe infection 1.3%	High
Mrowietz U, 2019^Citation69	RCT	Secukinumab standard dose (phase 1: 300 mg vs 150 mg vs placebo; Phase 2: non-responders to placebo randomized to secu 300 or 150)	Phase 1: 16 weeks; phase 2: 52 weeks	1) 237 (sec 300 mg: 79, sec 150: 80, placebo: 78); 2) 184 (sec 300: 92 and sec 150:92)	PPPASI, DLQI	Week 16: PPPASI 50 52.2% by SEC 300 vs 32.9 by placebo (p= 0.0159); PPPASI 75 26.6% by SEC 300 mg vs 14.1% in placebo (p = 0.0411) and 17.5% by SEC 150 mg (P = 0.5722); At week 52, PPPASI 75 in 41.8% with SEC 300 mg vs in 35.0% with SEC 150 mg	Most frequent AEs: nasopharyngitis, upper respiratory tract infections; no new or unexpected safety event	High
Mrowietz U, 2020^Citation70	RCT	Secukinumab initiation, 1x/4w 1) 300 mg 2) 150 mg sc 3) placebo switch secu 300 mg 4) placebo switch secu 150 mg after 16 weeks	148 weeks	94 1) 36 2) 31 3) 17 4) 10)	PPPASI	PPPASI 75: 4) 75%, 3) 77.8%, 1) 78.3% and 2) 100%	No new or unexpected AE	High
Reolid A, 2022^Citation80	Retrospective cohort study	Secukinumab (standard dose)	Mean 13.4 months	17	pppIGA, responders defined if achieving PPPIGA 0/1 or reduction of at least 2 points on scale	3 months: 47% responders, 18 and 24 months: 100% responders (52.9% in last observation carried forward analysis)	No severe adverse events	Medium
Bissonnette R, 2014^Citation72	RCT	1) Ustekinumab 45 mg −90 mg, weeks 0, 4, 16, followed by placebo at weeks 20; 2) Placebo weeks 0 and 4, Ustekinumab weeks 16 and 20	16 weeks	20	PPPASI	No statistically significant difference in achieving PPPASI-50 at week 16 (P = 1.000)	Cellulitis (1), pneumonia (1)	Medium
Hegazy S, 2018^Citation76	Retrospective cohort study	Ustekinumab 45 mg-90 mg sc, weeks 0 and 4 then every 12 weeks	6–17 months	9	Clinical response	Week 16: clearance in 5/9	1 urinary tract infection	Low
Buder V, 2016^Citation73	Case Series	Ustekinumab 45 mg-90 mg sc, weeks 0, 4, 12, and 24	24–60 months	9	PPPASI	PPPASI 100 (2/9), PPPASI 75 (4/9)	Local injection site reactions (1)	Medium
Bertelsen T, 2014^Citation75	Retrospective cohort study	Ustekinumab 45 mg sc at weeks 0 and 4 then 12-weeks intervals	1 month-5 years	11	Clinical evaluation	Complete or partial response in 45%	Flu-like symptoms, headache, fatigue (2)	Low
Morales-Múnera C, 2013^Citation74	Case series	Ustekinumab 45 mg sc, weeks 0 and 4 then every 12 weeks	11–23 months	5	PPPASI, DLQI, PASI	Response after 2–3 weeks, PPPASI 100 after 16 weeks in all patients. No relapse	No AEs	Medium
Bissonnette R, 2008^Citation77	RCT	Etanercept 50 mg sc 2x/week vs placebo (2:1)	3 months	15	PPPASI	Week 24: significant reduction of PPPASI in ETA (p = 0.038) but not control
Husson B, 2020^Citation78	Retrospective cohort study	Etanercept, Adalimumab, Infliximab, Ustekinumab	Mean 5 months (range 1–72)	82	Clinical evaluation	Complete clearance ETA (13.3%), ADA (17.6%), UST (37.9%), INX 19.0%). No significant difference in complete clearance rates between biologics	Paradoxical psoriasis (ADA, UST, ETA), injection site reaction (ADA/ETA), tuberculosis (ADA), alopecia areata (ADA), pneumonia (UST), angioedema (ETA, INX), Hypersensitivity reaction/ gain of weight/Schoenlein-Henoch purpura/ influenza-like illness/headache/nausea (INX)	High
Mrowietz U, 2021^Citation81	RCT	Spesolimab 300 mg vs 900 mg iv; weeks 0, 4, 8, 12, and 16	16 weeks treatment, 16 weeks follow-up	59 (19: 300 mg, 19: 900 mg, 21: placebo); 47 completed weeks 16	PPPASI	No significant differences between spesolimab and placebo	Comparable to placebo; 1 SAE non treatment related, 1 SAE treatment related (syncope), mild/moderate AEs: nasopharyngitis, headache, PPP, arthralgia, cough	High
Kromer C., 2018^Citation79	Retrospective cohort study	Conventional therapies, biologics, small molecules	NA	347	PPPASI	PPPASI 75 reached by CyA (51.4%; 36/70), APR (31.4%; 11/35), ALI (22.6%; 12/53), ACI (19.5%; 40/205), FAE (17.7%; 17/96), MTX (16.8%; 7/220), CER 62.5% of (5/8), GOL (41.7%; 5/12), INX (40.6%; 13/32), ADA (33.3%; 23/69), UST (31%; 13/42), SEC (29%; 9/31), and ETA (19.4%; 12/62);	AEs were the reason for discontinuation (if discontinued) in ACI 59.6%, MTX 41.1%, FAE 68.8%, CyA 46.7%, ALI28.2%, APR: 28.6%, ADA 38.3%, ETA 21.2%, INX 45.0%, GOL 16.7%, CER 100%, UST 14.3%, SEC 11.1%	Medium
Carr D, 2008^Citation13	Clinical trial	Alefacept 15 mg im/week for 8 weeks, then 30 mg im/week	16 week	15	PSI, PGA	Week 28: significant reduction of mean PSI (p<0.0001). PSI 50 (10/14)	Pneumonia, upper respiratory tract infections, sinus infection, bronchitis, cellulitis of bilateral ring fingers, an inguinal abscess, and perianal cyst	Medium
Guenther LC, 2007^Citation82	Clinical trial	Alefacept 15 mg im, 1x/week	16 weeks	15	PPPAS, PGA	PPPASI reduction of 49.6%; PPPASI 50 (53.3%) PPPASI 75 (26.7%)	Injection-site reactions, mild headaches, severe-moderate dermatitis, infections, upper respiratory tract infection	Medium
Cro S, 2021^Citation79	RCT	Anakinra, 100 mg/0.67 mL sc, 1x/d	8 weeks	64 (31 anakinra, 33 placebo)	PPPASI	No superiority of anakinra vs placebo	No severe events, injection site reactions (19)	High
Wolk, 2023^Citation83	Clinical trial	Apremilast	20 weeks	21	IL-19 level	Significant reduction in IL-19 mRNA level in skin at week 20 and IL-19 level in serum at weeks 4 and 20	NA	Medium
Wilsmann-Theis D, 2021^Citation84	Clinical trial	Apremilast	20 weeks	21	PPPASI, pustule count, DLQI	PPASI 50 (61.9%), PPPASI 75 (14.3%); median reduction 76.3%	TEAE nausea (6), diarrhea (5), headache (5), nasopharyngitis (5)	Medium
Kato N, 2021^Citation85	Retrospective cohort study	Apremilast 30 mg po, 2x/d (after induction)	2 weeks (min)	10	PPPASI	Significant decrease of PPPASI compared to baseline after 2 weeks (p=0.013)	Frequent bowel movements (8/10), diarrhea (6/10), weight loss (3/10), headache (1/10), palpitation (1/10), nausea (1/10)	Medium
Ständer S, 2020^Citation86	Case series	Apremilast 30 mg po, 2x/d	18 months	6	PGA	PGA reduction from 4 to 1 (2/6), from 3 to 1 (3/6)	Mild nausea, diarrhea	Low
Soufila KT, 2021^Citation87	Case series	Apremilast 30 mg po 2x/d (after initiation dose)	4–24 weeks	5	PPPASI	PPPASI 100 in 2/5, PPPASI 50 in 4/5	2/4 had AE (nausea, vomiting, epigastric pain, and diarrhea)	Medium

Abbreviations: RCT, randomized controlled trial; PPPASI, palmoplantar pustulosis area and severity index; PGA, physician global assessment; PPPSI, PPP severity index; GUS, guselkumab; SEC, secukinumab; UST, ustekinumab; ETA, etanercept; ADA, adalimumab; INX, infliximab; GOL, golimumab; CER, certolizumab; APR, apremilast; FAE, fumaric acid esters; ACI, acitretin; ALI, alitretinoin; CyA, ciclosporin A; MTX, methotrexate; SAE, severe adverse event.

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