¹Harvard Medical School, Harvard University, Boston, MA, USA
²Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA
³King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
⁴King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
⁵Division of Dermatology, Department of Medicine, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia
⁶Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
⁷Farwaniya Hospital, Kuwait City, Kuwait
⁸Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest:
The authors have no conflicts to disclose.

Abstract:
Acne vulgaris is a troubling skin disease known to have both physiologic and psychological effects on patients. Acne scars, a frequent complication, can further impact patients’ quality of life. Scars result from an impairment in the healing process. Acne scars can be categorized as follows: atrophic scars (including ice pick, rolling, boxcar subtypes) and trophic (including hypertrophic and keloid scars), the latter being less common. Though various treatment approaches have been suggested, there is a lack of high‐quality evidence on effective, type-specific acne scar approaches. Herein, we aim to review the current evidence for treating various acne scars.

Key Words:
acne scars, atrophic, ice pick, rolling, boxcar, hypertrophic, keloid

Introduction

Acne vulgaris is the most common skin disease affecting adolescents and adults.¹ Studies have demonstrated that about 99% of the population has had acne at some point in their lives, varying in degree of severity, duration, and age of onset.¹

The psychological impact of acne is well known. Acne can have social and psychological consequences beyond the apparent visual deformity. This common condition has been linked to stress, anxiety, depression, and suicidal ideation.² Singam et al. reported that severe acne is associated with comorbid mental health disorders in 25% of acne patients, including anxiety, adjustment, personality, and substance use disorders.³ Acne has also been associated with reduced academic achievement and social difficulties.¹

Acne scars are a frequent complication that results from damage to the skin during the healing process of lesions, with studies indicating that 50% of those suffering from acne may develop scars.⁴ Increased risk of scarring is associated with severe disease, time between acne onset and first effective treatment, relapsing acne, and males.4 Herein, we discuss different types of acne scars and present an updated review on type-specific management approaches.

Discussion

Acne scars can be classified as atrophic, hypertrophic, or keloidal. The morphology of these scars is summarized in Figure 1. Atrophic acne scars are further subdivided into three subtypes: ice pick, rolling, and boxcar.

The management approach for treating acne scars should be type-specific given the differences in underlying pathophysiology. Treatment options for each type of scar are summarized in Table 1.

Table 1. Clinical presentation and treatment options of acne scars

Ice Pick Scars

Ice pick scars extend vertically into the deep dermis or subcutaneous tissue. They are narrow (<2 mm) at the surface and taper as they extend into the deep dermis. Conventional skin resurfacing treatment options may not be adequate due to their depth. Punch excision can be used to treat ice pick scars. Though this method forms a new scar, it is generally less visible than the original ice pick scar.⁵ The punch excision can be followed by a resurfacing procedure after 4 to 6 weeks, which can further improve the scar’s appearance. Notably, laser skin resurfacing can be safely and effectively performed on the same day that the punch scar is created.⁶

Another treatment option for ice pick scars is chemical reconstruction of skin scars (CROSS) using high concentrations of trichloroacetic acid (TCA) to induce skin regeneration. TCA is strictly applied to localized areas; the controlled application results in a shorter recovery time compared to medium or deep chemical peels. The degree of clinical improvement is dependent on the total number of treatments.⁷

TCA CROSS can also be used in darker skin types. In a study evaluating the efficacy and safety of CROSS technique, researchers used 100% TCA to treat ice pick scars in patients with Fitzpatrick phototypes IV and V. Nearly 75% of participants experienced excellent improvement in the appearance of their scars after 4 sessions at 2-week intervals.⁸

Radiofrequency (RF) is another option for treating ice pick scars. RF devices use electromagnetic radiation to produce an electric current that delivers heat to the dermis, which in turn causes neocollagenesis and skin contraction. This technique is considered both safe and efficacious, offering minimal downtime and adverse events.9 Additionally, RF is a safe procedure in skin of color (SOC) as it does not directly target pigment.

Several studies have demonstrated the effectiveness of RF in the management of ice pick scars. Ramesh et al. reported that fractional bipolar RF (FRF) achieved good results in 73% patients after 4 sessions. Patients with ice pick scars exhibited a better response than those with rolling and boxcar scars.¹⁰

Conversely, Peterson et al. found that 15 patients diagnosed with rolling and boxcar scars responded better to 5 sessions of a combination of RF and FRF than patients with ice pick scars.¹¹

Another mode of therapy for ice pick scars is resurfacing lasers. This treatment modality has yielded only mild-to-moderate efficacy for ice pick scars, compared to other subtypes. Sardana et al. reported that treatment with a 1,540 nm fractional nonablative laser improved scar appearance for only 25.9% of patients with ice pick scars, compared with 52.9% and 43.1% improvement in boxcar and rolling scars, respectively.¹²

Combining ablative fractional carbon dioxide (CO2) laser with platelet-rich plasma (PRP) injections represents an innovative approach. PRP involves preparing and administering the patient’s own concentrated platelets in plasma containing variable growth factors and cytokines that promote wound healing. A recent meta-analysis investigated the efficacy and safety of combining fractional CO2 laser with PRP for managing atrophic acne scars. It was concluded that the dual approach led to enhanced outcomes compared to using ablative fractional CO2 laser alone. Specifically, the combination resulted in clinical improvement, increased patient satisfaction, and accelerated recovery after laser damage. However, further research is needed to evaluate the efficacy of PRP for acne scars.¹³ PRP can also be combined with microneedling to treat any atrophic acne scars.

Rolling Scars

Rolling scars result from dermal tethering of abnormal fibrous bands that produce skin indentation. The scars are 4-5 mm wide and are sloped, with shallow borders.

Rolling scars can be best managed surgically with subcision, which involves the use of a tri-beveled hypodermic needle to free the tethering subdermal fibrous bands. Al-Dhalimi et. al showed
that subcision downgraded the severity of rolling acne scars from moderate-to-severe grade to mild grade in 53% of patients, with minimal side effects.¹⁴ The subcision was done once and repeated every 6 weeks, as required.

Subcision has been combined with the application of soft tissue fillers and non-ablative laser to improve the appearance of rolling scars. Hyaluronic acid fillers can expand the volume of tissue in these scars and encourage collagen production. Sapra et al. assessed the management of rolling scars with poly-L-lactic acid (PLLA) in 22 patients and demonstrated that after 3 to 4 treatments at 4-week intervals with PLLA, 54.4% of patients exhibited excellent results.¹⁵ A controlled and blinded study was performed on 147 patients with rolling acne scars to evaluate the effectiveness of 1 injection of polymethylmethacrylate (PMMA) filler. Neary 65% of patients demonstrated good improvement, compared to 33% of control subjects.¹⁶

Microdermabrasion and dermabrasion are physical ablating modalities used to manage rolling scars. Microdermabrasion is more superficial whereas dermabrasion reaches the deeper papillary dermis layer. The procedures promote a wound healing response and new collagen formation. Eventually, dermabrasion treatment results in smoother and uniform appearance of the scar.¹⁷ Microdermabrasion received at weekly intervals appears to be safe in SOC.¹⁸

Microneedling is another beneficial option for managing rolling scars. Microneedling involves creating small wounds in the dermis to activate a cascade of growth factors and eventually stimulate collagen production.¹⁹ Microneedling can be effective in managing rolling scars for darker-skinned patients due to the low risk of hyperpigmentation compared to fractional nonablative laser therapy.⁷

RF can also be used safely and effectively to manage rolling acne scars with minimum adverse effects and limited downtime.⁷

Non-ablative lasers can also be used to manage rolling scars. Their mechanism of action involves targeting tissues in the dermis for selective photothermolysis to encourage collagen and
dermal remodeling, thereby improving the appearance of scars.²⁰

Boxcar Scars

Boxcar scars are broad, round-to-oval or rectangular box-like depressions with sharply defined edges. Punch excision and punch elevation are two excellent techniques for the treatment of boxcar scars, but there is still a paucity in literature evaluating their effectiveness for improving acne scarring.⁷ For punch elevation, the punch biopsy tool is used to fragment the deeper aspect of the scar without removing any epidermis or dermis.

Dermabrasion can be an effective option for managing boxcar scars, but it is a painful procedure that requires local or general anesthesia and the healing time may extend to several weeks, with significant postoperative discomfort.²¹ Microneedling RF is another useful technique that can be employed to manage atrophic boxcar scars.¹¹ RF does not directly target melanin and can thus be safely used in SOC.

Subcision is moderately effective for managing boxcar scars, but it can be combined with other resurfacing procedures such as cosmetic fillers and non-ablative lasers to achieve better results.²⁰ Chemical peeling with TCA can be used to manage hard-to-treat boxcar scars.²² Finally, laser skin resurfacing can deliver excellent results for managing acne scars. One study demonstrated that use of a high-energy pulsed CO2 laser provided 75% improvement in atrophic facial scars, including boxcar scars.²³ Ablative lasers, such as CO2 and erbium-doped yttrium aluminum garnet (Er:YAG), should be used with caution when treating atrophic scars in SOC. The risk of postinflammatory hyperpigmentation (PIH) appears to be decreased with Er:YAG. Post ablative laser PIH may last for 5 weeks and can be treated with a topical depigmenting agent such as hydroquinone 4% or combination topicals (retinoid, hydroquinone and corticosteroid).^24,25

Hypertrophic Scars and Keloids

Hypertrophic scars and keloids are more severe types of acne scars. They are less common compared to atrophic acne scars, but can be difficult to treat. Typically, hypertrophic scars appear as pink, raised lesions that persist within the borders of the original site of injury.²⁶ Keloids present as reddish-purple scars that frequently extend beyond the borders of the original site of injury.²⁷ From a pathophysiological perspective, hypertrophic and keloidal scars demonstrate excessive expression of collagen with reduced collagenase activity.²⁸

Intralesional corticosteroid injections represent the mainstay of treatment for hypertrophic and keloid scars. However, multiple treatment approaches can be used simultaneously to maximize the potential for success and minimize adverse effects.²⁹ For example, intralesional corticosteroid injections can be accompanied by 5-fluorouracil (5-FU) to reduce the risk for hypopigmentation, skin atrophy, telangiectasias, rebound scars, ineffectiveness, and injection site pain.²⁸

Laser resurfacing can be considered for managing hypertrophic and keloid acne scars. Specifically, pulsed dye laser is an excellent option to consider.³⁰ Thick keloid or hypertrophic scars can benefit from using a combination of pulsed dye laser and intralesional corticosteroid injections along with 5-FU.³¹ In fact, this combination seems to be the most promising, currently available therapy for keloids.³²

Another effective non-surgical method for managing small hypertrophic acne scars is cryotherapy, which can also be combined with intralesional triamcinolone to maximize effectiveness.³³

Surgical excision can be used in combination with other approaches including radiotherapy, interferon, bleomycin, cryotherapy, or corticoids to optimize the efficacy of the management protocol.³⁴ Surgical excision may be needed when acne scars are disabling, but in some cases laser and light-based therapies may be preferential.³⁵

Large keloid scars have been effectively managed with surgical excision followed by radiation using brachytherapy. This is better tolerated and enables delivery of high radiation doses to a focused area, with decreased side effects, in comparison to traditional external beam radiation.³⁶ Intralesional injection of interferon and bleomycin are additional options for managing keloid and hypertrophic scars. These treatments work to increase collagen breakdown and inhibit collagen synthesis, respectively. Both therapies can enhance the scar’s appearance.^37,38

The post-excision recurrence of keloids has shown to decrease with daily application of topical imiquimod 5% cream for 8 weeks.^39,40

Conclusion

The management of acne scars often requires a combination of different treatment options. An understanding of each scar type and formulating a case-specific approach are required to achieve optimal outcomes.

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¹Division of Dermatology, McGill University Health Centre, Montréal, QC, Canada
²Division of Allergy and Immunology, McGill University Health Centre, Montréal, QC, Canada
³Division of Infectious Diseases, McGill University Health Centre, Montréal, QC, Canada
⁴Division of Hematology, McGill University Health Centre, Montréal, QC, Canada

Authorship statement:
N. Merati: reviewed literature, prepared the manuscript;
S. Sivachandran: addressed reviewer comments, reviewed literature and co-wrote the paper;
A. Jfri: contributed to the review of literature and preparation of the manuscript;
M. Ben-Shoshan: contributed to the review of literature and preparation of the manuscript;
D. C. Vinh: contributed to the review of literature and preparation of the manuscript;
G. Popradi: contributed to the review of literature and preparation of the manuscript;
I. V. Litvinov: supervised the study, reviewed literature and co-wrote the paper.

Conflict of interest:
The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: None.

Abstract:
Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. Patients with WHIM syndrome are more susceptible to human papillomavirus (HPV) infections and commonly present to a dermatologist with recalcitrant to treatment warts. Other cardinal features of WHIM syndrome include recurrent sinopulmonary bacterial infections, neutropenia/lymphopenia, low levels of immunoglobulins (IgG, IgA, IgM) and myelokathexis. Research demonstrated that truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) are responsible for this disease. Plerixafor, a specific small molecule antagonist of CXCR4, is currently used for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. It has recently shown promise for the treatment of WHIM syndrome in phase I/II clinical trials. In this paper we review the emerging patient clinical data for this medication and highlight the role of CXCR4 in other important skin diseases including keratinocyte carcinomas, psoriasis and cutaneous T-cell lymphoma.

Key Words:
plerixafor, warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome, C-X-C chemokine receptor type 4 (CXCR4), stromal cell-derived factor-1 (SDF-1), CXCL12, recalcitrant warts

Introduction

Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. As the name suggests, patients with WHIM syndrome are more susceptible to human papillomavirus (HPV),¹ which can cause warts and potentially lead to squamous cell carcinomas; hypogammaglobulinemia; recurrent bacterial infections, such as otitis media, cellulitis, pneumonia and sinusitis; and bone marrow myelokathexis, characterized by a retention and apoptosis of mature neutrophils resulting neutropenia. The laboratory manifestations include severe neutropenia, significant lymphopenia, leukopenia, and monocytopenia.

WHIM syndrome is a rare disease with ~70 cases reported in the medical literature to date.^2,3 In 2003, the cause of WHIM syndrome was traced to a heterozygous, truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) on chromosome 2 (2q22.1), resulting in a hyperactive signalling of this G-protein coupled receptor. While not yet fully deciphered, it is postulated that increased CXCR4 receptor activity upon binding of its cognate stromal cell-derived factor-1 (SDF-1; also known as CXCL12) ligand, prevents the release of mature neutrophils and promotes their apoptosis in the marrow (Figure 1A-B). This cellular mechanism drives myelokathexis that is observed clinically in affected patients. The CXCR4 mutations are inherited in autosomal dominant manner. Some patients with WHIM syndrome, however, do not have a detectable CXCR4 gene mutation, suggesting that mutations in other genes may be involved.

The diagnosis of WHIM syndrome relies on identifying the clinical features, a detailed patient medical history, family history, and genetic testing. In particular, patients with recalcitrant HPV warts and recurrent sinopulmonary bacterial infections should be further evaluated with a complete blood count and differential (to detect neutropenia and lymphopenia), and immunoglobulins (IgG, IgA, IgM) to detect hypogammaglobulinemia. Family history may reveal vertical transmission in autosomal dominant fashion, if more than one generation is affected. A bone marrow biopsy may be performed to detect myelokathexis.

While potential molecular mechanisms have been elucidated, the effectiveness of standard WHIM syndrome therapies is variable and more targeted therapies are urgently needed. Until recently most patients were managed using a combination of granulocyte colony stimulating factor (G-CSF), skin-directed treatments of warts, prophylactic antibiotics, and intravenous gamma globulin (IVIG) therapy.

In 2009, a group of researchers sought to therapeutically target the CXCR4 receptor. Plerixafor, a specific small molecule antagonist of CXCR4 (Figure 1C), was originally licensed by the United States Food and Drug Administration for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. Plerixafor (Mozobil^®) has been used in Canada and in the United States since 2012.⁴ Notably, a novel application for this medication has been defined, where McDermott and colleagues conducted a phase I clinical trial (NCT00967785) using plerixafor as a treatment for 20 patients with WHIM syndrome.^3,5-7 They found that 9 patients who received low-dose plerixafor safely mobilized neutrophils and had an improvement in all other leukocyte subsets.^3,5-7 A follow-up study in 3 of the participants demonstrated sustained responses for at least 6 months using a dosage of 0.02-0.04 mg/kg/day subcutaneously with no new warts developing and regression of old warts. In 2014, these promising results led the investigators to conduct a phase III randomized, double-blinded, crossover trial (NCT02231879) to establish safety and efficacy of plerixafor compared to standard G-CSF treatment in patients aged 10-75 years with WHIM syndrome. Nineteen patients were randomized to 1 year of G-CSF and 1 year of plerixafor using a crossover design, allowing direct comparison of infection severity during treatment with both agents. Doses were personalized to each patient’s neutrophil response. Study participants had a clinical diagnosis of WHIM syndrome and were proven to have a heterozygous mutation in the CXRC4 gene.⁸ While the trial is currently ongoing, some early data is beginning to emerge from this group.

During recruitment, McDermott and colleagues identified 3 patients who were ineligible to participate in the larger study as they could not receive G-CSF. The researchers began a concomitant study with these patients, treating them with plerixafor (according to their phase 1 protocol) for 20-50 months. These findings have been published in the New England Journal of Medicine. McDermott et al. reported improvement in all 3 patients’ white cells counts, platelet counts and hemoglobin levels.⁹ In 2 out of 3 patients these results were observed after discontinuing G-CSF, which was deemed ineffective. Bone marrow biopsies revealed marked amelioration of severe pre-treatment myelofibrosis and myelokathexis in 2 of the patients after using plerixafor for 24 and 52 months.⁹ With the adjunct use of imiquimod in 2 of the patients and double HPV vaccination in 1 of the patients, HPV-associated wart burden improved noticeably on the hands, feet and genitals. Mixed results though were obtained with HPV-associated tumors, which were managed with debulking and surgery. Susceptibility to infections and inflammation also differed amongst the patients; however, 1 patient was noted to have a marked reduction in infection frequency compared to his pre-treatment baseline, and a significantly higher quality of life, where he was able to exercise, enjoy the outdoors and work without being fearful of recurrent infections and hospitalizations.

The results of these case studies are exciting and suggest that clinicians and patients with WHIM syndrome might expect favorable clinical outcomes with plerixafor. However, as with any new therapeutic indication, we must await the efficacy and safety results of the phase III trial, especially considering that chronic leukocyte mobilization from bone marrow with plerixafor could result in as of yet undescribed cumulative toxicities.^10,11 It will also be crucial to determine the effect of plerixafor on immune cell function including mitogen induced T-cell proliferation and T-cell dependent humoral immunity.

Also, another phase II/III clinical trial (NCT03005327) is being conducted by researchers in Florida, investigating the use of mavorixafor (X4P-001), a different small molecule targeting hyperactive CXCR4 receptor.¹² Funded by X4 Pharmaceuticals, researchers have demonstrated positive preliminary clinical findings using mavorixafor in a group of 6 WHIM patients, showing increased white cell counts and improved clinical outcomes. Unlike plerixafor, mavorixafor is administered orally.¹³ Additional phase II results published on 8 patients in Blood demonstrated that this medication was well tolerated by patients (with no treatment-related serious adverse events) using a dose of 400 mg daily and led to neutrophil mobilization, reduced infection rates and reduction in the number of warts.¹⁴

Conclusion

Emerging molecular experimental and clinical data suggests that CXCR4 may play an important role in other skin and systemic diseases including mycosis fungoides/Sézary syndrome, neurofibromatosis type 1 tumors, allergic reactions, Waldenström macroglobulinemia, melanoma, non-melanoma skin cancers and other solid tumors (Table 1). Hence, ability to target the CXCR4 may improve our abilities to treat a number of these diseases in the not-too-distant future. In fact, a number of trials using mavorixafor are underway evaluating efficacy in the treatment of Waldenström macroglobulinemia, renal cell carcinoma and other cancers, where CXCR4 inhibitors are actively being evaluated as cancer immunotherapy treatments.^15,16

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