Keratosis Pilaris and its Subtypes

Associations, New Molecular and Pharmacologic Etiologies, and Therapeutic Options

Jason F. Wang; Seth J. Orlow

Am J Clin Dermatol. 2018;19(5):733-757.

Medications Causing KP-like Lesions

Cyclosporine

KP may arise in patients receiving cyclosporine (Table 6).^[219] Graft-versus-host disease (GVHD) is a common complication in transplant recipients, and cutaneous manifestations, including KP, are frequently the presenting symptoms. A retrospective study of 100 patients with chronic GVHD after hematopoietic stem cell transplantation found KP in 1% (1/100) of the cohort; however, many of these patients were receiving cyclosporine, a known cause of KP.^[220]

B-Raf Inhibitors

Generalized eruptions of diffuse follicular keratotic papules are common in patients treated with inhibitors of the serine/threonine kinase B-Raf (Table 6).^[221–223] In patients treated with the B-Raf inhibitor dabrafenib, KP is more likely to develop in younger patients (p = 0.02), and it seems to be protective against developing seborrheic keratoses (p = 0.05).^[223] Although combined treatment with mitogen-activated protein kinase (MAPK) inhibitors prevents some skin toxicities, it does not prevent KP. Vemurafenib may also cause KP,^[224–228] potentially because of activation of downstream protein kinase R-like endoplasmic reticulum kinase (pERK) in follicular epithelial cells.^[229] Paradoxical activation of the MAPK pathway by vemurafenib is another possible mechanism, affecting both keratinocyte differentiation and melanocyte proliferation, as shown by a case report of KP, eruptive melanocytic nevi, and hidradenitis suppurativa in a patient receiving vemurafenib.^[230] B-Raf inhibitors are thought to induce aberrant signaling in the MAPK pathway, another plausible mechanism for the development of KP.^[231]

Tyrosine Kinase Inhibitors

Nilotinib is a second-generation selective inhibitor of the Bcr-Abl tyrosine kinase that has been known to induce both KP and KPA (Table 6).^[232–237] The pathogenesis of this reaction is unclear; nilotinib may affect the tyrosine kinase receptors of hair follicles, affect the c-Kit receptor in basal skin cells, or have off-target effects against Raf, which could explain its shared toxicity with B-Raf inhibitors.^{[232,234,238]} Dasatinib, another second-generation Bcr-Abl tyrosine kinase inhibitor (TKI), can also induce KP.^[235] In a case series of nine patients receiving single or combination TKI therapy, six receiving nilotinib, three receiving dasatinib, and two receiving ponatinib, all developed KP-like lesions, which resolved with dose reduction, cessation, or TKI switching.^[238]

Erlotinib is a TKI that inhibits epidermal growth factor receptor (EGFR) and may induce KP, perhaps due to the role of EGFR in the skin and hair follicle signaling.^[239] Sorafenib is a TKI with several targets, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and several Raf kinases, the latter of which most likely explains why a number of patients receiving sorafenib in one study developed generalized KP.^[240]

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Next Section

Abstract and Introduction
Clinical Overview, Pathophysiology, and Histopathology of Keratosis Pilaris (KP) and its Subtypes
Cellular and Biochemical Characterization
Genomics
Disease Associations
Hereditary and Syndromic Associations
Medications Causing KP-like Lesions
Environmental Exposures
Therapeutic Options and new Procedures
Conclusion
References
Sidebar

Table 1. Publications providing evidence on the epidemiology of keratosis pilaris in the pediatric population
Study	Study design	Nationality or ethnicity	Subject age range, years	Subjects (N)	Percentage of subjects with KP (N)
Brown et al. [4] 2009	Cross-sectional	British	7–9	792	34.4 (273)
Anand et al. [5] 2012	Cross-sectional	India	5–15	988	20 (198)
Dogra and Kumar [6] 2003	Cross-sectional	India	6–14	12,586	1.3 (160)
Yosipovitch et al. [7] 2000	Cross-sectional	Jewish	17–18	202	16 (33)
Tay et al. [8] 2002	Cross-sectional	Singapore	7–16	12,323	13 (1602)
Inanir et al. [9] 2002	Cross-sectional	Turkey	6–14	785	12.5 (98)
Popescu et al. [10] 1999	Cross-sectional	Romania	6–12	1114	4 (45)
Del Pozzo-Magana et al. [11] 2012	Retrospective	Mexico	0–18	5250	3.7 (192)
Al-Saeed et al. [12] 2006	Cross-sectional	Saudi Arabia	6–17	2239	2.2 (50)
Figueroa et al. [13] 1996	Cross-sectional	Ethiopia	5–16	112	1.8 (2)
Fung and Lo [14] 2000	Cross-sectional	Hong Kong	6–21	1006	1.3 (13)
Bechelli et al. [15] 1981	Cross-sectional	Brazil	6–16	9955	0.75 (75)

KP keratosis pilaris

Table 2. Clinical and histopathologic descriptions of keratosis pilaris and its subtypes
Condition	Description	Onset	Clinical findings	Natural history	Histopathologic findings
KP	Common follicular skin disorder [1]	Typically during childhood and adolescence; may also appear in infants and adults [21]	Spiny keratotic papules, approximately 1 mm in size, mostly distributed on the extensor surfaces of the proximal extremities [22]. Involvement of the distal extremities, face, trunk, and buttocks may also occur [23]. Papules can be scattered or grouped together, sometimes with subtle perifollicular erythema [1]. Dermoscopic findings: follicular hyperkeratosis, dermal vascular ectasia, widened follicular orifices, hyperpigmentation, perifollicular erythema, scaling, and thin and short hair shafts in lesional skin [24, 27–29]. Mild KP may have coiled or twisted vellus hairs, either singular or in groups of two or three, encircled by peripilar casts [24, 28]. The vellus hairs in more severe KP appear coiled and are impacted in the horny layer [24, 28]. KP is usually asymptomatic but may be pruritic and cosmetically undesirable [1]	Improves in 35% of patients by the late teens but remains unchanged in 43% of patients and worsens in 22% [22]. In a survey of 49 British patients with KP aged 2–40 years, incidence was most common during the first decade of life and decreased with age [22]. KP improved in the summer and worsened in the winter for approximately half the patients; however, of the patients with worsening KP in the summer, only 60% improved during the winter [22]. In one case of biopsyproven KP, a 25-year-old man had profuse alopecia on KP-affected sites, but after 3 months, his KP spontaneously cleared with complete hair regrowth without scarring or atrophy [26]	Orthokeratotic keratin plugs in follicular orifices, which may contain twisted hairs, dilate the infundibulum, creating the papules of KP [1]. While the epidermis exhibits mild hyperkeratosis, hypogranulosis, and follicular plugging, the upper dermis and perifollicular areas contain mild perivascular lymphohistiocytic infiltrates [24, 25]. There may be focal parakeratosis within the SC [25]. Sebaceous glands are strikingly absent from KP lesions but are present in unaffected skin from the same patient [24]
KPA	A rare, scarring subtype of KP that includes a spectrum of clinical variants [32]	Childhood [32]	In addition to the finding of KP mostly on the extensor extremities, KPA and its subtypes present with perifollicular keratosis and variable inflammation that result in atrophic scarring, usually starting on the face in childhood and potentially involving the scalp after puberty [32–34]	Progressive scarring and destruction of the follicles, which over time manifest as alopecia from the follicular papules [34]. With scalp involvement, there is expanding fibrosing alopecia [34]	Hyperkeratosis in the follicular ostia and hypergranulosis of the infundibulum and isthmus, causing chronic inflammation and deposition of cellular debris, disintegrating the follicle [34]
KPAF	Variant of KPA also known as ulerythema ophryogenes [32]	First months of life [33]	Small, follicular, keratotic papules and erythema on the lateral third of the eyebrows, potentially extending to the forehead and cheeks and eventually leading to scarring alopecia [3, 32, 33]. KP is often present on extensor surfaces [3]. Follicular atrophy may also occur in advanced EFFC, suggesting overlap between the two diseases [35]. Overlap has also been reported with KFSD [36, 37]	Disease course typically ends after puberty, but permanent alopecia and atrophy may have already manifested [32]	Keratosis of the pilosebaceous infundibulum with sebaceous gland and hair follicle atrophy, surrounded by an inflammatory infiltrate [38]
AV	Variant of KPA also known as honeycomb atrophy [32]	Usually between 5 and 12 years [38]. Rarely presents in late adolescence [39]	Begins with follicular, keratotic papules, erythema, and milia on the cheeks and heals with reticular, atrophic pitting of the cheeks, creating a worm-eaten or honeycomb appearance [32, 38]. Usually spares the scalp and eyebrows but may extend to the ears, upper lip, neck, and extremities [3, 32, 40]	Like KPAF, perifollicular inflammation tends to stop after puberty, but progression is also possible [32]. The erythema and reticulated atrophy tend to improve spontaneously and gradually [42]	There is epidermal atrophy, capillary dilation, and dermal collagen sclerosis [41]. The pilosebaceous unit is abnormal, and sebaceous glands are atrophic or absent [42]. There are fewer elastic fibers in the dermis [43]
KFSD	Variant of KPA [32]	Typically begins in infancy [31]	Malar, follicular, keratotic, sometimes erythematous papules that can progress to involve the eyebrows, eyelashes, neck, extremities, scalp, and even axillae and pubic areas with scarring, patchy alopecia [3, 32, 38, 44, 45]. Other cutaneous findings include widespread KP, palmoplantar keratoderma, prominent cuticles, and hyperkeratosis of the calcaneal heels and knees [3, 45]. Extracutaneous manifestations may include blepharitis, keratitis, corneal dystrophy, photophobia, and enamel hypoplasia [45, 46]	X-linked dominant KFSD tends to remit after puberty [32]	There is variable acanthosis and papillomatosis, hair follicles are dilated and contain keratin plugs and trapped hair shafts, and there is periadnexal inflammatory infiltrate in the dermis comprising lymphocytes, diffusely scattered plasma cells, and multinucleated giant cells [47–49]
FSD	Variant of KFSD [32]	Childhood to adolescence [44]	Desquamation and pustular inflammation of the scalp [32, 44]. KP can also be present [50]	Exacerbates after puberty with recurrent flares [32]	Follicular plugging, follicular and interfollicular hyperkeratosis, mild inflammation, and focal scarring [50]
EFFC	Rare subtype of KP [54]	Usually between ages 8 and 12 years [54]	Bilateral hyperpigmentation, follicular papules, and erythema on the cheeks and temples, potentially progressing to the submandibular neck and preauricular areas [54, 56]. Affected skin is rough with fewer vellus hairs, but there is neither scarring nor atrophy [54]. Associated KP can be seen in 88% (22/25) of patients, often exhibits perifollicular erythema, and most commonly affects the arms and upper back and sometimes lower or entire body [54–56]. Typically asymptomatic, although photosensitivity is possible [54]	Disease duration varies from 2 to 14 years after onset [54]	Follicular plugging, hyperkeratosis, increased basal membrane pigmentation, periadnexal and perivascular inflammatory infiltrate, and vascular dilation in the upper dermis [54, 57]. The degree of basal membrane pigmentation and the percent area of blood vessels in the upper dermis correlate with disease severity [57]
KPR	Common variant of KP [23]	Conflicting data [23, 58]	KP with more overt erythema and a larger distribution of skin involvement, most often the lateral cheeks and proximal extremities [23]	Erythema persists during puberty and can even worsen [23]	Follicular infundibular plugging and mild perifollicular inflammation and fibrosis [23]

AV atrophoderma vermiculatum, EFFC erythromelanosis follicularis faciei et colli, FSD folliculitis spinulosa decalvans, KFSD keratosis follicularis spinulosa decalvans, KP keratosis pilaris, KPA keratosis pilaris atrophicans, KPAF keratosis pilaris atrophicans faciei, KPR keratosis pilaris rubra, SC stratum corneum

Table 3. Publications providing evidence for the association of keratosis pilaris with atopic dermatitis and ichthyoses
Study	Study design	Nationality or ethnicity	Subject age, years^a	Subjects (N)	Conclusions
Cheng et al. [95] 2016	Questionnaire and cross-sectional with genomic analysis	Han Chinese	AD cases: 5.4±7.7 Controls:27.5±12.6	4321 total: 2205 AD cases, 2116 controls	KP was present in 13.1% (289/2205) of AD pts. The A allele of rs6780220 on chromosome 3p21.33 is potentially less frequent in AD pts with KP than those without KP (p<0.024, not significant after Bonferroni correction)
Chen et al. [96] 2011	Cross-sectional with genomic analysis	Singaporean Chinese	IV cases: NR AD cases without IV: "adult" AD cohort: 1–21 Controls: 1–80	92 total in the filaggrin mutation discovery cohort: 69 IV cases, 23 AD cases without IV. 865 total in the AD cohort: 425 AD cases, 440 controls	KP was present in 7.1% (30/425) of AD pts. KP was present in 10% (7/69) of IV pts, but this was similar to the 13% (3/23) prevalence of KP in the AD without IV cohort. KP is associated with filaggrin mutations (p=0.001). AD pts without KP are unlikely to carry filaggrin-null mutations, as the positive and negative predictive values of KP for such mutations were 31.6% and 79.3%, respectively
Mevorah et al. [20] 1985	Cross-sectional	Switzerland	AD cohort: 0.5–59 IV cohort: 35–70 Controls: 1–74	343 total: 61 AD cases without IV, 35 IV cases without AD, 247 controls without AD or IV of which 155 were examined for scaling (40 with scaling, 115 without scaling)	KP was present in 42.6% (26/61) of AD pts without IV, which was lower than the 74.3% (26/35) prevalence of KP in IV pts (p<0.001) but similar to the 41.7% (103/247) prevalence of KP in controls. KP is associated with scaling among controls without AD or IV, present in 62.5% (25/40) of controls with scaling and 38.3% (44/115) of controls without scaling (p<0.01). KP is not helpful to the diagnosis of AD but is part of the phenotype of dominant IV
Tay et al. [8] 2002	Questionnaire and cross-sectional	Singapore (Chinese, Malays, Indians, and others)	7, 12, or 16	12,323 total students: 2563 with AD	KP was present in 13.4% (343/2563) of AD pts, but this was similar to the 13% (1602/12323) prevalence of KP in the study population. KP is not more common in AD pts
Wahab et al. [97] 2011	Descriptive	Bangladesh	1–12	210 with AD	KP was present in 14.8% (31/210) of AD pts
Macharia et al. [98] 1993	Cross-sectional with consecutive sampling	Kenya	0.25–10.25	54 with AD	KP was present in 72% (39/54) of AD pts
Kwon et al. [99] 2004	Survey and cross-sectional	South Korea	12–40	48 with AD	KP was present in 43% (21/48) of AD pts
Bremmer et al. [103] 2008	Cross-sectional	USA	0–33	898 with valid data points for hyperlinear palms/KP and IV: 278 IV cases, 620 without IV	KP was present in 52.9% (147/278) of IV pts, which was more common than in those without IV (28.4%, 176/620; p<0.001). KP supports a diagnosis of IV but is nonessential to the diagnosis
Mevorah et al. [104] 1991	Cross-sectional	Switzerland	3–70	85 total: 33 with X-linked, 52 with autosomal dominant ichthyosis	KP was more likely to occur in pts with autosomal dominant ichthyosis (proportion NR) than pts with X-linked ichthyosis (21%, 7/33; p<0.0001). However, presence of KP does not rule out a diagnosis of X-linked ichthyosis
Ghosh et al. [105] 2017	Cross-sectional	India	0.25–75	79 with IV	KP was present in 6.3% (5/79) of IV pts
Al-Akloby [106] 2004	Retrospective	Saudi	NR	61 total: 25 with IV, 11 with X-linked recessive ichthyosis, two with epidermolytic hyperkeratosis, 23 with autosomal recessive ichthyosis	KP was present in 24.6% (15/61) of pts with primary hereditary ichthyoses, including 52% (13/25) in pts with IV, 9.1% (1/11) in pts with X-linked ichthyosis, and 4.3% (1/23) in pts with autosomal recessive ichthyosis. KP was not present in either of the two pts with epidermolytic hyperkeratosis

AD atopic dermatitis, IV ichthyosis vulgaris, KP keratosis pilaris, NR not reported, pts patients
^aAge given as mean ± standard deviation or as range

Table 4. Publications providing evidence for the association of keratosis pilaris with high body mass index and type 1 diabetes mellitus
Study	Study design	Nationality or ethnicity	Subject age, years^a	Subjects (N)	Conclusions
Yosipovitch et al. [7] 2000	Questionnaire and cross-sectional	Jewish	17–18	202 students: 33 with KP, 169 without KP	BMI was higher in those with KP (mean BMI 24.8) vs. without KP (mean BMI 21.7; p<0.001). KP was present in 39% (14/36) of subjects with BMI>25, which was higher than those with BMI≤25 (11%, 19/166; p<0.001), OR 4.9
Boza et al. [115] 2012	Cross-sectional	Brazil	Obese cases: 49.7±15.6 Controls:49.1±14.5	148 total: 76 obese pts, 72 normal-weight controls	After controlling for atopy, KP still had a higher prevalence in obese individuals (23.7%, 18/76) vs. controls (5.5%, 4/72) with an adjusted prevalence ratio of 11.15 (p=0.006)
Nazik et al. [116] 2016	Cross-sectional	Turkey	Obese cases: 29.8±16.4 Overweight cases: 44.9±13.4 Controls: 32.1±10.9	510 volunteers: 230 obese (BMI>30.0), 130 overweight (25.0≤BMI≤29.9), 150 controls (BMI<25.0)	KP was present in 21.2% (108/510) of overweight and obese subjects
Garcia-Hidalgo et al. [117] 1999	Cross-sectional	Mexico	16–89	156 obese patients: 28 grade I (10–25% excess weight), 34 grade II (26–50% excess weight), 29 grade III (51–75% excess weight), 30 grade IV (76–100% excess weight), 35 grade V (>100% excess weight)	KP was present in 21.2% (33/156) of obese pts and was more common in those with obesity grades IV and V (32.3%, 31/65) than those with obesity grades I, II, and III (13.2%, 12/91; p<0.007), OR 3.14
Plascencia Gomez et al. [118] 2014	Cross-sectional	Mexico	8–69	109 overweight patients	KP was present in 42.2% (46/109) of overweight pts but was not associated with grade of obesity
Guida et al. [119] 2010	Cross-sectional	Italy	Obese cases: 37.1±13.1 Controls: 41.0±12.3	80 total: 60 obese (36 class I [30<BMI<35], 14 class II [35<BMI<40], 10 class III [BMI≥40]), 20 normal weight	KP was present in 13.3% (8/60) of obese subjects and none of the controls. KP was associated with grade of obesity and was present in 6% (2/36) of class I, 14% (2/14) of class II, and 40% (4/10) of class III (p=0.01)
Pavlovic et al. [121] 2007	Cross-sectional	Serbia	2–22	408 total: 212 T1DM pts, 196 age-and sex-matched controls	KP was more common in pts with T1DM (11.7%, 27/212) than controls (1.5%, 3/196; p<0.01) and was more common in patients aged>10 years (21/27). Ichthyosiform skin changes were associated with KP in T1DM pts (p<0.001), OR 1.53
Yosipovitch et al. [122] 1998	Cross-sectional	Israel	T1DM pts: 12–44 Controls: 16–36	360 total: 238 T1DM pts, 122 healthy controls	KP was more prevalent in T1DM pts (21%, 50/238) than controls (9%, 11/122). T1DM pts also had more extensive KP mostly on the extensor limbs, and the presence of KP was associated with higher BMI (p<0.0001)

BMI body mass index, KP keratosis pilaris, OR odds ratio, pts patients, T1DM type 1 diabetes mellitus
^aAge given as mean ± standard deviation or as range

Table 5. Syndromic and hereditary associations with keratosis pilaris and its subtypes
Association	Evidence
Neurodevelopmental disorders
DS and KP	KP was found in 46% (51/110) of males with DS, mostly between the ages of 20 and 40 years, but was relatively rare in females [145]. In a couple of other studies, KP was found in 14% (8/57) and 11.8% (24/203) of DS pts [146, 147]. However, the rate of KP was only 4% (4/100) in a cross-sectional study of 100 DS pts aged 3–20 years [148]. In addition, a couple of studies have found similarly low rates of KP in DS pts, such as 3.2% (7/213) and 2.8% (2/71) [149, 150]
DS and KFSD	DS occurring with KFSD has been reported [151]
Cabezas syndrome and KP	A case series of three brothers with Cabezas syndrome found KP in one [152]
SMS and KP	In a cross-sectional study of 20 pts with SMS, extensive KP was present in 65% (13/20) of pts, mostly adults [153]
Cornelia de Lange syndrome and KPAF	KPAF has been reported in Cornelia de Lange syndrome [154]
RTS and KPAF	There has been a case report of KPAF in a pt with RTS [155]
Neuro-cardio-facial-cutaneous syndromes
CFCS and KP	In addition to several case reports [158–162], KP was present in 80% (49/61) of pts in a survey of 61 CFCS pts aged 16 months–31 years with MEK1, MEK2, BRAF, and KRAS mutations [163] and 73% (19/26) of pts in a survey of 38 CFCS pts aged 1–23 years [164]
CFCS and KPAF	KPAF was present in 90% (55/61) of CFCS pts in a survey of 61 pts [163]. This association has also been documented in several case reports [168]
CS and KP	In a cross-sectional study of 46 pts with CS, the frequency of KP was 32.6% (15/46), which is less frequent than in CFCS (80.3%, 49/61; p = 0.001) [167]. No CS pts had KPAF [167]
NS and KP	There have been reports of KP occurring in pts with NS [169, 170]. A cross-sectional study of 129 pts with NS found facial KP in 50% (8/16) of pts with an SOC1 mutation [171]
NS and KPAF	There have been several cases of NS occurring with KPAF, two of which were proven to be caused by an SOC1 mutation [38, 170, 172–175]
EDs
PKCAS and KPAF	Both type 1 and type 2 include widespread, severe KP [178, 179]
HMD and KP	The frequency of KP among published cases of HMD is 77% (23/30) [180]
PC and KP	PC is often associated with KP in case reports [182, 183]
Monilethrix and KP	There are several reports of KP occurring in pts with monilethrix [184–187]
IFAPS and KP	There are reports of IFAPS presenting with KP [79, 188]
Skin appendage disorders
WH and KP	A few reports have associated WH with KP [170, 193–196]
WH and KPAF	KPAF and WH have also been reported in association within a few families [195, 196]
Hypotrichosis and KP	There has been a case of a 19-year-old Japanese male with this disorder [197]
HK and KP	KP has been reported in association with HK [198, 199]
LT and KP	In two cases, a brother and sister presented with LT, KP, and hyperhidrosis [200]. In three different cases, a mother and her two daughters have been reported to have an unnamed syndrome characterized by LT, KP, palmoplantar keratoderma, and hypotrichosis [201]
Other syndromes
ZS, KP, and KPAF	There have been very few reported cases of ZS [202–207]
Collagen VI-related myopathies and KP	In a case series, KP was reported in eight children with Ullrich congenital muscular dystrophy with mutations in COL6A1, COL6A2, or COL6A3 and one adult with Bethlem myopathy with a mutation in COL6A3 [210]
Peeling skin syndromes and KP	An association with KP was found by a retrospective study of 21 pts with a peeling skin syndrome [211]
Olmsted syndrome and KP	Olmsted syndrome sometimes presents with widespread KP [84]
Dyschromatosis universalis hereditarian and KP	A case of KP associated with dyschromatosis universalis hereditaria was reported in a 16-year-old Indian boy [213]
Rombo syndrome and AV	A couple of cases of Rombo syndrome occurring with AV have been reported [216]
LDS and AV	AV has been reported in three cases of TGFBR2-related LDS [217, 218]
Steatocytoma multiplex and AV	A case of AV was reported in association with steatocytoma multiplex [32]

AV atrophoderma vermiculatum, CFCS cardio-facial-cutaneous syndrome, CS Costello syndrome, DS Down syndrome, ED ectodermal dysplasia, HK hereditary koilonychia, HMD hereditary mucoepithelial dysplasia, IFAPS ichthyosis follicularis alopecia and photophobia syndrome, KFSD keratosis follicularis spinulosa decalvans, KP keratosis pilaris, KPAF keratosis pilaris atrophicans faciei, LDS Loeys–Dietz syndrome, LT leukonychia totalis, NS Noonan syndrome, PC pachyonychia congenita, PKCAS palmoplantar keratoderma-congenital alopecia syndrome, pts patients, RTS Rubinstein–Taybi syndrome, SMS Smith–Magenis syndrome, WH woolly hair, ZS Zouboulis syndrome

Table 6. Medications causing keratosis pilaris-like eruptions
Medication	Evidence
Cyclosporine and KP	In a cross-sectional study of 67 renal transplant recipients receiving cyclosporine and methylprednisolone, 21% (14/67) developed KP [219]
Dabrafenib and KP	In a prospective study of 59 pts treated with vemurafenib, dabrafenib, or a combination of dabrafenib and trametinib, 32.2% (19/59) pts, all of whom were receiving dabrafenib, developed KP no earlier than 27 days after starting therapy [223]
Vemurafenib and KP	There have been several reported cases of KP-like lesions occurring with vemurafenib therapy, along with a study of 28 pts with metastatic melanoma receiving vemurafenib, which found KP in 43% (12/28) pts [224–228, 230]. When vemurafenib was undergoing phase II trials, three of seven enrolled pts developed KP [229]
Nilotinib and KP	There have been several case reports of pts with CML developing KP-like eruptions after treatment with nilotinib, one of which resolved after switching to dasatinib [232–236, 238]
Nilotinib and KPA	In one case, a 46-year-old with CML developed KPA 2 months after initiating nilotinib therapy [237]
Dasatinib and KP	There are several reports of KP-like lesions developing in pts treated with dasatinib [235, 238]
Ponatinib and KP	There are two cases of ponatinib causing KP-like lesions [238]
Erlotinib and KP	In a 60-year-old woman with stage IV lung cancer, scattered KP developed 5 months after discontinuing erlotinib therapy [239]
Sorafenib and KP	In one study examining two cohorts of pts receiving sorafenib, generalized KP developed in 21% (5/24) of pts in the prospective cohort and in 41% (17/41) of the cohort of pts consulted after developing a dermatologic adverse event to sorafenib [240]

CML chronic myeloid leukemia, KP keratosis pilaris, KPA keratosis pilaris atrophicans, pts patients

Table 7. Publications providing evidence for the treatment of keratosis pilaris and its subtypes
Treatment	Study	Study design	Subject age	Subjects (N)	Conclusions
Topical and systemic therapies
LA vs. SA	Kootiratrakarn et al. [243] 2015	Prospective, randomized, clinical	NR	50	10% LA or 5% SA BID for 12 weeks: reduction of KP lesions in 66% of LA group and 52% of SA group (p<0.05 for each). Conductance improved with both, but no effect on transepidermal water loss. Adverse effects: mild local irritation
LA, SA, tretinoin, topical corticosteroids, systemic antibiotics, and/or isotretinoin	Baden and Byers [34] 1994	Prospective cohort	12–48 years	21	KPA: SA and LA smoothened skin without complete clearing. 14 used topical corticosteroids, with/without tretinoin: helped partially. Five used systemic antibiotics: minimal, transient improvement. Three received isotretinoin: minimal responses, one flared
SA and urea	Novick [244] 1984	Treatment recommendation	NR	30	Combined with short showers and topical corticosteroids for inflammation, SA and urea QD are effective for widespread, atypical KP. 75–100% clearance achieved in 2–3 weeks
Aquaphor vs. tacrolimus	Breithaupt et al. [248] 2011	Double-blind, bilateral paired comparison	2–16 years	30	27 pts completed study, Aquaphor to one limb and tacrolimus to the other BID for 4 weeks: improved investigator's global assessment score was 81% for tacrolimus and 78% for Aquaphor, both improved vs. baseline (tacrolimus: p<0.001, Aquaphor: p<0.005). Tacrolimus more likely to have marked effect. Adverse events: mild and transient
Tazarotene	Gerbig [247] 2002	Open with consecutive recruitment	NR	20	KP improved with QD application as early as 2 weeks, gradually fading from 4–8 weeks
Tretinoin	Patel et al. [238] 2016	Case series	55–56 years	3	Three cases of KP induced by nilotinib, dasatinib, or ponatinib: slight improvement
LA, urea, propylene glycol, emollients, surgras soap, topical corticosteroids, oral corticosteroids, and antihistamines	Castela et al. [21] 2012	Prospective cohort	10 months–3 years	11	Not effective: emollients, topical corticosteroids, oral corticosteroids, antihistamines, surgras soap. Partially effective: propylene glycol, LA, urea
Calcipotriol	Kragballe et al. [252] 1995	Randomized, double-blind, vehicle-controlled, right/left comparative	16–45 years	9	KP appears unresponsive to calcipotriol
Combination peel with incorporated fractional prickle coral calcium	Park et al. [249] 2014	Pilot	12–41 years	16	Five treatments of KP on upper arms at 2-week intervals: improvement in erythema (p=0.011) and melanin (p=0.006) index of mexameter relative to baseline, maintained at 2-month follow-up. Adverse events: mild and transient, including erythema, pruritus, stinging
Ammonia-oxidizing bacteria (Nitrosomonas eutropha) spray-on mist	Lee et al. [250] 2018	Double-blinded, placebo-controlled, split-arm	18–65 years	24	4 weeks of BID treatment for KP: larger % reduction in height of follicular papules by quantitative digital topographic analysis in the treatment group (18% vs. 15.2%;p=0.007)
Chlorine dioxide complex cleanser	Zirwas and Fichtel [251] 2018	Case series	11–28 years	5	90–100% of KP papules resolved from 2 days to 1 month with QD treatment
Energy-based therapies
Photopneumatic therapy	Ciliberto et al. [254] 2013	Pilot	13–45 years	10	One treatment: erythema and skin texture of KP improved for at least 1 month (skin types I–III). Adverse events: transient hypopigmentation, purpura
Intense pulsed light	Rodríguez-Lojo et al. [255] 2010	Case series	14–20 years	4	5–9 sessions for KPA: reduced erythema 75–100%, reduced skin roughness with no adverse effects, no recurrence after 10 months
<600 nm: KTPL and PDL	Schoch et al. [256] 2016	Case series	14–16 years	8	1–4 treatments with PDL: all pts reported improved erythema in KPR. Six pts sustained results up to 19 months
	Alcántara González et al. [257] 2010	Case series	8–35 years	10	2–7 sessions of PDL: all pts with KPR (8/10) or KPAF (2/10) had marked reduction in erythema, low incidence of adverse events
	Clark et al. [258] 2000	Prospective cohort	5–23 years	12	2–8 treatments: PDL reduced KPA-associated erythema (p<0.05) and may improve skin roughness, minimal adverse events
	Kaune et al. [259] 2009	Case report	17 years	1	Erythema and follicular hyperkeratosis of severe KPR and KPAF: marked improvement with PDL every 6 weeks, remained stable for 9 months
	Dawn et al. [59] 2002	Case report	15 years	1	Topical clobetasone butyrate: minimal effect, but seven treatments of KTPL at 6-to 8-week intervals reduced erythema, cleared keratotic papules of KPR
Combination of 595-nm PDL, long-pulsed 755-nm alexandrite laser, and microdermabrasion	Lee et al. [261] 2013	Retrospective	19–45 years	26	51.7% of KP pts, all type IV skin: marked improvement or total clearance in erythema, skin texture, brownish dyschromias without significant side effects, except scaling with microdermabrasion
	Lee et al. [260] 2012	Case series	23 and 28 years	2	4 months after final treatment: marked improvement in KP, satisfied with results
810 nm: long-pulsed diode laser	Ibrahim et al. [262] 2015	Split-body, rater-blinded, parallel-group, balanced (1:1), placebo-controlled RCT	18–65 years	23	18 KP pts with skin types I–III completed study: three treatments induced improvement in overall severity (p=0.005), skin texture (p=0.004), but erythema did not improve (p=0.11)
1064 nm: Q-switched Nd:YAG laser	Saelim et al. [263] 2013	Split-body RCT	15–42 years	18	Three treatments at 4-week intervals: 17 KP pts completed trial, improvement in erythema (p=0.009), global assessment (p=0.007), quantity of keratotic papules (p=0.009). All reported improvement, satisfaction
	Park et al. [264] 2011	Pilot	18–35 years	12	Ten treatments once every 2 weeks for KP: skin texture, dyspigmentation improved>25% in 11/12 pts, texture improved>50% in 6/12 pts, dyspigmentation improved>50% in 5/12 pts. 11/12 pts satisfied. No significant adverse events
Combination of 1064 nm: Q-switched Nd:YAG laser and topical urea	Kim [245] 2011	Pilot	19–29 years	10	Five weekly laser treatments, urea emollient application BID: all pts (skin types IV–V) improved in postinflammatory hyperpigmentation associated with KP (p<0.05). Minimal adverse events
10,600 nm: fractional carbon dioxide laser	Vachiramon et al. [265] 2016	Prospective, randomized, single-blinded, intraindividual comparative	19–32 years	24	All pts reported improvement in KP after one treatment. 30% of 20 pts completed study: moderate–good improvement by physician's assessment at 12 weeks. Hyperpigmentation, keratotic papules responded better than erythema. Darker skin types may develop transient pigment changes

BID twice a day, KP keratosis pilaris, KPA keratosis pilaris atrophicans, KPAF keratosis pilaris atrophicans faciei, KPR keratosis pilaris rubra, KTPL potassium titanyl phosphate laser, LA lactic
acid, Nd:YAG neodymium-doped yttrium aluminum garnet, NR not reported, PDL pulsed dye laser, pts patients, QD once a day, RCT randomized controlled trial, SA salicylic acid