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Keywords:

  • Koebner’s phenomenon;
  • isomorphic response;
  • vitiligo;
  • melanocytorrhagy;
  • review;
  • pathogenesis;
  • trauma

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

Koebner’s phenomenon (KP) has been observed in a number of skin diseases, including vitiligo. Its clinical significance in vitiligo with respect to disease activity and course is still debatable, while its relevance for surgical techniques has been demonstrated in some reports. We present a literature review on the currently known facts about KP in vitiligo, including details of clinical, experimental, and histopathological changes. The consensus view is that there are still no methods to define and assess KP in vitiligo. A new classification is proposed to allow an evaluation of KP in daily practice or in experimental studies. However, many unanswered questions still remain after redefining KP in patients with vitiligo. Active research focusing on KP in vitiligo may not only provide unexpected clues in the pathogenesis of vitiligo but also help to tailor novel therapies against this chronic and often psychologically devastating skin disease.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

Historical background

Koebner’s phenomenon (KP) is a well-known phenomenon in dermatology. The reaction is named after a German dermatologist, Heinrich Koebner (1838–1904), who observed in his patients with psoriasis the development of new lesions at sites of skin trauma (Köbner, 1877). Over the years, numerous reports have been published describing this phenomenon in a wide range of dermatological disorders after diverse environmental stimuli. The experimental induction of this reaction is termed ‘the Koebner experiment’ (Miller, 1982a). Since Koebner’s discovery, there have been several attempts to provide insight into the pathogenesis and clinical relevance of this reaction.

Definition

Koebner’s phenomenon (KP), also called ‘isomorphic response’, has been defined as ‘the development of lesions at sites of specifically traumatized uninvolved skin of patients with cutaneous diseases’ (Köbner, 1877; Miller, 1982a). These lesions are clinically and histopathologically similar to the original skin disease and can be repeatedly evoked experimentally.

Diseases that show Koebner’s phenomenon

There are many diseases in which KP has been described after skin injury. These include infectious diseases (e.g., warts), non-infectious inflammatory disorders (e.g., psoriasis, lichen planus, lichen nitidus, pityriasis rubra pilaris, lichen sclerosus…), vascular diseases (vasculitis, anaphylactoid purpura…), vesiculobullous and vesicopustular diseases (bullous pemphigoid, pemphigus vulgaris…), connective tissue disorders (e.g., lupus erythematosus), histiocytoses, genodermatoses, tumors, and metabolic disorders (Rubin and Stiller, 2002). However, as in theory all skin diseases may appear in sites of previous trauma, Boyd and Neldner (1990) suggested that the term ‘Koebner’s phenomenon’ should only be used for those diseases in which KP is reproducible in many patients, by different types of insults, and not by auto-inoculation (pseudo-Koebnerization) as seen in infections (warts, molluscum contagiosum) or allergic reactions (Boyd and Neldner, 1990; Melski et al., 1983). Lichen planus, psoriasis, and vitiligo are categorized as diseases that show the ‘true Koebner responses’.

Incidence in vitiligo

The reported incidence of KP in vitiligo varies widely and is reported to occur in 21–62% of patients (Barona et al., 1995; van Geel et al., 2010a; Hann et al., 1997; Mazereeuw-Hautier et al., 2010). This wide range probably reflects the difficulties and lack of consensus in assessment methods to evaluate KP. A history of KP (as assessed by the question: ‘does your skin remain white at sites of injury?’) was present in about 30% of 251 patients with generalized vitiligo seen at the Department of Dermatology, Ghent University Hospital (van Geel et al., 2010a), and in 30.4% of 217 patients of the Vitiligo European Task Force definition paper based on the question: ‘Is there any evidence of depigmentation on scars (Koebner’s phenomenon)?’ (Taïeb et al., 2007). It is still unknown whether or not the incidence of KP is linked to ethnicity, skin photo type, or tendency of the individual toward post-inflammatory hypo- or hyperpigmentation. KP is reported (in children and adults) to occur more frequently in generalized vitiligo compared to segmental vitiligo, although reported incidences vary because of the different assessment methods used (van Geel et al., 2010b; Mazereeuw-Hautier et al., 2010; Njoo et al., 1999). When exclusively assessed by clinical inspection, KP was a rare event in patients with segmental vitiligo, suggesting that apart from areas where there is segmental involvement the skin is ‘normal’ (van Geel et al., 2010b). However, this assumption that besides segmental involvement the skin is ‘normal’ may be challenged by recent observations in patients with mixed vitiligo, the association of a characteristic segmental involvement associated in a second step with the onset of bilateral vitiligo patches. Hence, in a recent paper to be published (Ezzedine et al., 2010), the authors found that KP was clinically present in repeated pressure or friction (elbows and knees) and/or areas of chronic friction in 6 of 19 patients (32%) of their case series of mixed vitiligo.

Koebner’s phenomenon: clinical aspects

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

Clinical presentation

In patients with vitiligo, the post-traumatic depigmented lesions (KP) are clinically and histologically indistinguishable from vitiligo. It can be present in different clinical forms. (i) The depigmented macules may exactly correspond to the traumatized areas and are easy to recognize because of their artefactual or elongated linear shape, (ii) In other cases, KP may present with a border of intermediate pigmentation (trichrome vitiligo) (Gauthier and Benzekri, 2010), (iii) In a subgroup of patients, the depigmented macules slightly exceed the dimensions of trauma while preserving the morphology of a lesion clinically still recognizable as a Koebner reaction, and (iv) However, some patients clearly state that depigmented lesions arise after trauma, while a depigmented area is clinically present in accordance with classic vitiligo. Furthermore, it has also been suggested that the location of vitiligo lesions in general is related to areas of repeated friction that may occur during washing, dressing, personal care, sports and occupational activity, or continuous pressure from clothing or other items (Gauthier, 1995 and Gauthier and Benzekri, 2010). These stimuli can be regarded as delayed or as chronic koebnerization factors. These ‘hidden’ koebnerization factors could result in the chronicity of vitiligo. This is in accordance with the theory that generalized vitiligo is triggered by a complex interplay of stressors including mechanical trauma (Cario-André et al., 2007).

Koebner’s phenomenon (KP) in patients with vitiligo is different from hypopigmentation following cutaneous trauma or inflammation (= post-inflammatory hypopigmentation). The latter is a common physiological phenomenon, which may be attributed to a partial melanocyte loss or deficient melanosome production and transfer. As melanocytes are not totally absent in the affected area, Wood’s light inspection will demonstrate a hypomelanotic skin (and not amelanotic skin as in vitiligo). Moreover, it is characterized by its temporary appearance. In the weeks or months after trauma, new melanocytes can migrate from the hair follicles leading to repigmentation of the affected area. The susceptibility to develop hypopigmented lesions varies between individuals and has been termed by Ruiz-Maldonado and Orozco-Covarrubias (1997) the individual’s ‘chromatic tendency’. This may be caused by a difference in response of each person’s melanocytes to trauma. Genetic variations in melanocytes may lead to a different susceptibility to melanocyte apoptosis after trauma and a difference in the trauma-induced production of melanin (normal, enhanced, or decreased) (Ruiz-Maldonado and Orozco-Covarrubias, 1997).

Sites of predilection

Koebner’s phenomenon (KP) can be observed not only at the classical areas of vitiligo (e.g., elbows, knees, and fingers), but also at other anatomic sites. The typical sites of involvement seem to be related to the possibility of external injury to the skin (e.g., the hands, the lower arms, the lower legs, scalp area in male pattern alopecia...). It seems likely that areas of protected or shock-absorbing skin (e.g., haired scalp, palmar side of hands) are less prone to koebnerization, although exact clinical data with respect to these areas in vitiligo are missing. In vitiligo, some of the anatomic areas susceptible to koebnerization are in accordance with the classical distribution of the KP as observed in other inflammatory dermatoses such as psoriasis (e.g., the elbows, knees) and lichen planus, while others are areas of chronic friction, pressure, or repeating movement (e.g., belt or tight underwear and narrow jeans, dorsal surface of feet, perioral, periocular), which seem predominantly affected in vitiligo.

Triggering factors, depth, degree of trauma, timing, and inhibitory factors

Triggering factors

The skin injury inducing KP in vitiligo may be of any kind: (i) physical (wounds, cuts, and scratching), (ii) mechanical (friction), (iii) chemical/thermal (burns and sun burns), (iv) allergic (contact dermatitis) or irritant reactions (vaccination and tattoos…), (v) chronic pressure, (vi) inflammatory dermatoses (psoriasis…), or (vii) therapeutics (radiotherapy, phototherapy, and topical immunotherapy with diphenylcyclopropenone in patients with alopecia areata). These are non-specific stimuli, which commonly induce inflammatory reactions. However, in some of the aforementioned examples, post-inflammatory hypopigmentation may be difficult to distinguish from koebnerization of vitiligo. However, clinical inspection under Wood’s light and re-evaluation on the long term can help to differentiate in doubtful situations.

Depth/degree of trauma

Although koebnerization can be induced by a variety of skin injuries, it has been observed in psoriasis by Kalayciyan et al. (2007) that not all types of trauma will induce KP in the same patient. In some of their patients with psoriasis, a superficial epidermal trauma did not induce new lesions, while injury to the papillary dermis results in KP. It has been suggested that epidermal rupture can initiate koebnerization, but to form psoriatic lesions secondary dermal events are required (Powles et al., 1990; Weiss et al., 2002). Moreover, it is not clear whether the same type of trauma will evoke KP at all sites of the body. This forms the basis for the ‘all or none principle’ theory as described in psoriasis by Pedace et al. (1969) assuming that once a patient reacts to one area of injury, all injured areas respond the same. However, clinical observations in vitiligo and psoriasis suggest that KP does not always occur in accordance with the ‘all or none principle’. Kalayciyan et al. (2007) suggest that other factors may additionally determine the risk for KP in psoriasis. These may include the extent and proximity of the affected skin and differences in disease activity status on different body sites (Kalayciyan et al., 2007). In vitiligo, the value of this ‘all-or-none phenomenon’ has yet to be investigated.

Timing

The time interval of KP in vitiligo is not well studied. It remains unclear whether the time interval from skin trauma to KP varies in vitiligo according to the site on the body, the type of trauma, or the individual koebnerization response. In psoriasis, the interval has been reported to be in general between 10 and 20 days, although shorter (3 days) or longer (2 yrs) time intervals are described as well (Pedace et al., 1969).

Inhibitory factors

In psoriasis, vasoconstriction may prevent the development of KP (Miller and Griffiths, 1982b). No similar investigations have been performed in the case of vitiligo. On the one hand, it is generally agreed on that chronic pressure can be a provoking factor in vitiligo (Gauthier and Benzekri, 2010). On the other hand, under experimental conditions, temporary pressure is capable of inhibiting the Koebner reaction in psoriasis, probably because of capillary occlusion (Miller and Griffiths, 1982b). Similarly, injections with adrenaline may induce a delay in KP in psoriasis (Eddy et al., 1964).

Clinical significance of Koebner’s phenomenon

In psoriasis, it has been suggested that patients are more prone to koebnerization during an active stage of the disease or in patients with an early age of onset (Eyre and Krueger, 1982). An experimentally induced Koebner phenomenon was positively correlated with the extent of psoriatic lesions (Eyre and Krueger, 1982). In vitiligo, active or stable disease is much more difficult to assess. Basak et al. (2009) found higher serum levels of IFN-γ in vitiligo patients with KP which may correlate with the activity of the disease. Njoo et al. (1999) demonstrated that an experimentally induced KP in vitiligo indicated active disease, but did not necessarily infer more extensive disease. These authors investigated the implications of experimentally induced KP (KP-e) and KP by history (KP-h) on disease activity and therapeutic responsiveness. They concluded that KP-e may function as a clinical indicator to assess present disease activity and it may predict the responsiveness to therapy with topical steroids plus UVA but not to UVB (311 nm). Their results suggested that the presence or absence of KP-h should be confirmed by inducing KP-e, because KP-e seems to occur more frequently than KP-h. Importantly, the KP-h was false negative in their study in up to 48% of cases and false positive in 10.5%. The authors concluded that some patients did not recognize or notice the appearance of white lesions after skin injury or that some patients never had skin trauma at all.

Several investigators have observed that the presence of KP in vitiligo negatively influences surgical treatment results (Boersma et al., 1995). This was also demonstrated in a double-blind placebo-controlled study of autologous non-cultured epidermal cell transplantation (van Geel et al., 2004a). However, the observations described in the literature also contain many uncertainties and discrepancies. For example, koebnerization at the donor site has been seen in combination with stable vitiligo and is even reported in some exceptional cases with repigmentation of the surgically treated recipient area (Malakar et al., 2000). The same applies to the relationship between disease activity and surgical treatment outcome. Until now, no laboratory test has been able to determine the activity of vitiligo and no consensus exists regarding clinical evaluation of disease activity. According to the literature, most authors classified vitiligo as being stable when further progression of lesions or development of new lesions has been absent for the past year (van Geel et al., 2004b). However, the absence of clinical progression may not correspond to the situation at a cellular level [e.g., production of inflammatory cytokines (TNF-α IL-1, IL-6), expression of ICAM-1], which may carry a predisposition to develop depigmentation after minor trauma (Abdallah et al., 2003; Mulekar et al., 2007). Some colleagues prefer to use a mini-grafting test before a surgical intervention, although there has been discussion about its usefulness (Falabella et al., 1995).

Experimentally induced Koebner’s phenomenon

Experimentally induced KP in vitiligo using scarification and ‘tape stripping’ was reported by Gopinathan (1965). This author observed KP on non-involved vitiligo skin in 69% (9/13) of their patients after scarification, but in none after tape stripping. They concluded that trauma to the dermis, and not only superficial (epidermal) trauma, is required to induce KP. In the study by Njoo et al. (1999), KP in vitiligo was induced experimentally by epidermo-dermal trauma using 2-mm biopsy punches (Njoo et al., 1999). KP was present in 61% of the patients with generalized vitiligo and could not be provoked in patients with segmental vitiligo.

Reverse koebnerization

The clearance of an affected skin area after injury is called the reverse Koebner phenomenon and has been mostly reported in psoriasis (Eyre and Krueger, 1982). Repigmentation of vitiligo lesions can similarly occur following injury to that lesion. A variant on this ‘reverse Koebner phenomenon’ reaction has been reported in patients with vitiligo undergoing mini-punch grafting. Spontaneous repigmentation of non-treated lesions has been observed after successful mini-punch grafting. This has been named the ‘remote reverse Koebner phenomenon’ (Malakar and Dhar, 1998). Agarwal et al. (2004) found the same phenomenon in the surrounding untreated vitiligo lesions after punch grafting and proposed the term ‘satellite repigmentation’. The pathophysiology of this phenomenon remains unknown. Malakar and Dhar (1998) hypothesized that cytokines derived from the donor skin may influence perilesional melanocytes at distant sites after local secretion.

Koebner’s phenomenon: pathogenesis

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

The pathogenesis of KP in vitiligo is intriguing, but remains unclear. Most experiments on KP have been performed in patients with psoriasis, although some research has been performed in vitiligo. Several etiological theories for KP in vitiligo (including immunologic mechanisms, deficient melanocyte adhesion, and increased oxidative stress) are considered (Westerhof and d’Ischia, 2007). The pathophysiology of KP in different skin diseases has been classified by Ueki (2005) into two steps. These steps are derived from their observations in lupus erythematosus and not from vitiligo. The first step in the development of KP they mention is the release of several common inflammatory factors (e.g., TNF-α, IL1, IL6, Hsp70, Hsp72, Hsp90, and ICAM-1), which is triggered by environmental stimuli such as skin trauma. In the second step, disease specific auto-antigens may be the target inducing a local flare of the skin disease.

Theories

Immune-mediated mechanisms

In the general view of vitiligo, most evidence supports an immune-based melanocyte elimination as being the main etiological pathway (Figure 1). This has also been ratified by genetic evidence, as nearly all the recently discovered susceptibility genes encode components of the immune system (Jin et al., 2010). Circulating melanocyte-specific CD8-cells (e.g., directed against melanocyte differentiation antigens MART1, gp100/SILV, and tyrosinase) have been detected in patients with vitiligo (van den Boorn et al., 2009; Garbelli et al., 2005). The same underlying immune-based mechanism may be implicated in the occurrence of KP. The release of inflammatory cytokines (IFN-γ, TNF-α, IL1, and IL6) after skin trauma may be an essential trigger to recruit and activate these melanocyte-specific T cells in the skin and provides access to antigen-expressing melanocytes. The inflammatory response induced after skin trauma might also expose melanocytes by upregulating their MHC and ICAM-1 expression. Increased expression of ICAM-1 has been detected more in active vitiligo lesions and in lesions with early pigment loss after autologous mini-grafting compared to stable lesions and repigmenting lesions, respectively (Abdallah et al., 2003; al Badri et al., 1993).

image

Figure 1.  Proposed model of the two-step hypothesis of the Koebner phenomenon in vitiligo integrating multiple etiological mechanisms: cytotoxic melanocyte elimination (possibly enhanced by activated pDCs sensing self-DNA and LL37), increased oxidative stress, defective melanocyte adhesion, and deficiency of melanocyte growth factors [such as stem cell factor (SCF) and basic fibroblast growth factor (bFGF)]. In the first step, common inflammatory signals are released and in the second step multiple mechanisms are involved in the specific targeting of melanocytes.

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Support for a crucial role of KP in vitiligo is provided in an animal model (Steitz et al., 2004). It was demonstrated that local inflammation at the site of self-antigen endogenous expression was required to break tolerance against a MHC class I-restricted melanocyte self-antigen (murine tyrosinase-related protein 2) in mice immunized with TYRP2/dopachrome tautomerase.

More recently, the role of plasmacytoid dendritic cells has been related to skin injury and to chronic inflammatory skin disorders such as psoriasis and lichen planus (Baker et al., 1988; Lee and Modlin, 2005). It was demonstrated in psoriasis that plasmacytoid dendritic cells can respond to self-DNA when this forms complexes with endogenous antimicrobial peptides (e.g., LL37; also known as CAMP or cathelicidin) produced in damaged skin (Conrad et al., 2009; Lande et al., 2007). This might result in IFN-driven autoimmunity by the activation of myeloid dendritic cells and subsequent induction of antigen-specific Th1 and T helper 17 cells. However, the potential pathogenic relevance of plasmacytoid dendritic cells and LL37 in vitiligo has to be shown.

Increased oxidative stress

In vitiligo, it has been suggested that physical or chemical trauma (KP) to the skin may lead to increased oxidative stress including accumulation of hydrogen peroxide (H2O2), as demonstrated by Schallreuter et al. (1999). As described by Kostyuk et al. (2010), Spencer et al. (2007) and Salem et al. (2009), redox disturbance [increased H2O2 low catalase, increased GST and peroxynitrite (ONOO−)] is a potent cytotoxic factor affecting the integrity and function of melanocytes (e.g., by damaging melanocortins) and inducing melanocyte loss (Kostyuk et al., 2010; Salem et al., 2009; Spencer et al., 2007). In response to prolonged H2O2 exposure, many proteins are affected including stress proteins such as Hsp70 which prevent premature degradation of cellular proteins (Salem et al., 2009; Schallreuter et al., 2009). Although initially protective for the cell, once released into the extracellular environment these stress proteins are very immunogenic. As mentioned by Noessner et al. (2002), stress proteins elicit autoimmune responses by serving as auto-antigens, facilitating the presentation of other antigens to DCs and enhancing phagocytosis. Moreover, increased oxidative stress may trigger the process of haptenation by increasing the levels of surrogate substrates of tyrosinase resulting in the formation of highly immunogenic neoantigens in vitiligo (Westerhof and d’Ischia, 2007; Westerhof et al., 2011).

Defective melanocyte adhesion (melanocytorrhagy)

It is tempting to speculate that KP in vitiligo may appear only when melanocyte loss reaches a certain threshold value which could vary between patients. Mottaz et al. (1971) reported that minor skin trauma, such as removal of the stratum corneum by tape stripping can induces a machinery of cytokines (including TNF-α), stimulates tyrosinase activity in basal melanocytes, inhibits the transfer melanin to keratinocytes, and can induce detachment of some melanocytes. It has been suggested that in vitiligo defective adhesion could be involved in melanocyte detachment and loss. Kroll et al. (2005) hypothesize that extracellular matrix molecules that inhibit the adhesion of melanocytes to fibronectin may contribute to the loss of pigment cells in vitiligo. This hypothesis was supported by an in vivo observation in which repeated friction to perilesional skin in non-segmental vitiligo induces detachment and death of melanocytes (Gauthier et al., 2003a). The investigators proposed that defective adhesion of melanocytes, termed ‘melanocytorrhagy’, could be the major and possibly the primary predisposing factor in KP (Gauthier et al., 2003a,b).

Melanocyte growth factors

Stem cell factor (SCF), released by keratinocytes, is essential for the survival of melanocytes and binds to the KIT receptor on melanocytes. As suggested by Lee et al. (2005), in response to trauma, UV exposure or increased levels of H2O2, the keratinocyte-dependent production of SCF and other melanocyte growth factors such as basic fibroblast growth factor (bFGF/FGF2) can decrease, which may lead to apoptosis of melanocytes (Lee et al., 2005).

Integrated theory

Similar to the convergent hypothesis for the etiopathogenesis of vitiligo, we propose to integrate for KP in vitiligo, the autoimmune, defective melanocyte adhesion, impaired redox status, and melanocyte growth factor pathomechanisms (Le Poole et al., 1993; Ongenae et al., 2003). However, we suggest as well to take various koebnerization factors into account (including mechanical trauma, UV irradiation, chemical stress…) as important initial triggering factor for the different pathophysiological pathways (Figure 1).

In vitro models of Koebner’s phenomenon

Human skin is repeatedly exposed to mechanical stretching in vivo. Mechanical modulations of the cell shape are believed to cause different responses. A culture technique to mimic this physical stretching was developed by Kippenberger et al. (1999), who showed that enhanced growth of melanocytes exposed to cyclic stretch was closely associated with an increased level of protein Hsp 90 (Kippenberger et al., 1999).

Catecholamines, H2O2, and sera from patients with very extensive vitiligo have been tested on reconstructed epidermis derived from cells of ‘healthy’ skin donors and non-lesional skin of patients with generalized vitiligo. Epinephrine and H2O2 were able to trigger the transepidermal loss of normal and vitiligo melanocytes. Some sera induced melanocyte detachment but without any clear correlation with vitiligo disease activity in the donors (Cario-André et al., 2007). This is the first step toward obtaining a reproducible melanocytorrhagic in vitro model using some documented stressors.

Koebner’s phenomenon: how to assess it ?

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

Proposed methods of clinical assessment

We suggest three different methods, corresponding to levels of increasing evidence to assess KP: by patient’s history (type 1), by clinical examination (type 2), and in the context of experimentally induced KP (type 3, Figure 2).

image

Figure 2.  Proposed classification of Koebner’s phenomenon.

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  • Type 1
    We propose to ask the following question: ‘Did your skin remain white (depigmented) after skin injury during the last year?’ (injury by any of the following provoking factors: physical injury (= wounds, cuts, and scratching), mechanical injury (friction), chemical/thermal (= burns, sun exposure), allergic skin reactions or irritant reactions (vaccination and tattoos...), chronic pressure (e.g., compressive bandage, tape, and brace), inflammatory dermatoses (e.g., eczema and skin infection), or therapeutics (e.g., radiotherapy and phototherapy...).
  • Type 2
    Clinical differentiation can be made between type 2A and type 2B. In type 2A, leukoderma is present on any of the following areas corresponding either to areas of repeated pressure or friction (e.g., elbows and knees) or areas of chronic friction related to cloths/accessory: e.g., waistband (‘underwear print’) hips (jeans), dorsal site of feet (‘shoe-print’), wrist site of a watch, necklace or bra. In type 2B examination shows the presence of linear (Figure S1), punctiform, or crenate depigmentation suggestive of previous injury.
  • Type 3
    Experimentally induced KP can be divided according to the eliciting trauma: level 1 includes superficial irritation (tape stripping, pressure, and friction); in level 2, the KP is caused by superficial epidermal trauma, diamond fraise, Stiefel curette, and laser abrasion (e.g., CO2 laser and Erbium Yag); level 3 includes deeper dermo-epidermal trauma (e.g., scarification, mini-punch, 755 nm Alexandrite laser, and cryotherapy).

Proposed classification

To assess the probability of a real KP based on history and clinical examination, we propose the following classification:

  • Grade 0 = no evidence of Koebner.

  • Grade I = presence of Koebner response type 1.

  • Grade II = presence of Koebner response type 2A.

  • Grade III = presence of Koebner response type 2B.

  • Grade IV = presence of Koebner response types 1 and 2B.

Redefining Koebner’s phenomenon in vitiligo

The proposed consensus from the VETF group forms a basis to distinguish three different types of KP : type 1, 2 (A + B) and 3 (Table 1 and Figure 2).

Table 1.   Definition subtypes Koebner’s phenomenon
Koebner subtypeIs considered to be positive….
Type 1If the answer of the patient is ‘yes’ or ‘sometimes’ to the suggested question: ‘Did your skin remain white (depigmented) after skin injury during the last year?’
Type 2AIf at clinical inspection depigmentations are present at sites of chronic pressure or repeated friction
Type 2BIf at clinical examination and Wood’s light inspection, depigmentations are present and clearly induced by trauma (linear, punctiform, crenate)
Type 3If at least 1 experimentally induced injury (level 1–3) to the skin induces a clear depigmentation, that remains for several months.

Need for future investigations

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

Unanswered questions

The proposed redefinition of KP in vitiligo as outlined here is a consensus of the VETF group. However, many clinically related questions still remain unanswered (Table 2). Furthermore, these questions should be addressed through an epidemiological study with the aim to define a dynamic scoring for KP in vitiligo. This dynamic score may reflect the ‘real-life’ experience in which KP seems to be fluctuant over time. This scoring may predict the disease ability to spread over a short period and thus, help in better defining accurate therapeutics.

Table 2.   Open questions about Koebner’s phenomenon
Why does only a subgroup of vitiligo patients develop KP, do they have particular characteristics and can they be identified in advance?
Is the presence of KP associated with disease activity? Is koebnerization less likely during a period of treatment response?
Is KP associated with more extensive disease?
Do patients with KP have a different prognosis to patients without KP?
What topical or systemic medication can inhibit koebnerization? Can the vasoconstrictor action of adrenaline inhibit KP?
Is ‘temporary’ Koebner only because of post-inflammatory hypopigmentation?
Is KP more prevalent in familial vitiligo than in the sporadic form, are the genetic factors playing a role in its occurrence?

Research agenda toward experimentally induced Koebner’s phenomenon in vitiligo

Design of an in vivo Koebner model

Design of a suitable in vivo model to investigate the pathogenetic events of the experimentally induced KP in patients with vitiligo could be most informative to investigate the inflammatory/immune response. Major challenges are the development of effective and reproducible protocols to induce KP and perform an adequate imaging and analysis. In analogy to other cutaneous procedures (e.g., patch testing…), a standardization of the test location is needed. As controls, normal individuals and patients with psoriasis vulgaris may be used for such an in vivo model.

Monitoring of the cutaneous stress response

Even before any invasive procedure (skin biopsies), it will be worthwhile to monitor in vivo the cutaneous stress response (including the generation of H2O2) in experimentally induced KP lesions from patients with vitiligo compared to controls. Here, state-of-the-art novel imaging techniques including 5-dimensional multi-photon microscopy, complementing standard infrared and Raman spectroscopy as well as high lateral resolution techniques like tip-enhanced Raman spectroscopy are yet to be applied techniques to investigate experimentally induced KP in a non-invasive fashion in vivo.

Microscopic investigation and (semi)-quantitative analyses of skin biopsies

After performing skin biopsies, the histomorphological and ultrastructural changes can be examined by light and electron microscopy. These studies may disclose the fate of melanocytes (apoptosis?), the response of neighboring keratinocytes (deposition of extracellular granular material?), and the inflammatory response after a given stressor. The skin samples can be further processed for a panel of semi-quantitative and quantitative methodologies including immunohistochemistry, in situ-RT-PCR, ex vivo real-time RT-PCR, and ex vivo western immunoblotting. For example, it would be highly interesting to check the induction of the mitogen- and stress-activated protein kinase cascades, key signal transducers (e.g., p38 kinase), and heat shock proteins (HSPs).

Cytokines and growth factors

The in vivo induction of proinflammatory and apoptogenic cytokines (e.g., IL1β and TNF-α) on the one hand and the expression of various melanocyte growth factors (e.g., MGF/SCF) on the other hand may be imperative to investigate by the aforementioned techniques. These experiments will allow to test whether experimentally induced KP in patients with vitiligo is associated with an imbalance of these homeostatic factors.

Neurohormones and neuromediators

It will also be interesting to examine in an vivo KP model the relation between neuropeptides such as neuropeptide Y and immune responses, as controversies still exist regarding its relevance in the etiopathogenesis of vitiligo (Al’abadie et al., 1994). Furthermore, this model could be used to evaluate the role of neurohormones/neuromediators involved in limiting the cutaneous stress response. Here, pro-opiomelanocortin-derived peptides such as α-melanocyte-stimulating hormone (both anti-inflammatory and cytoprotective) (Brzoska et al., 2008), upstream hormonal players of the cutaneous hypothalamic-pituitary-adrenal-like axis (Slominski et al., 2000), and related substances (e.g., acetylcholine) are attractive candidates to be explored in this context.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

Koebner’s phenomenon (KP) was originally described in psoriasis and has subsequently been observed in vitiligo and other skin diseases. It has become one of the basic principles in dermatology. Nonetheless, clear evidence regarding the pathophysiology and clinical consequences of KP in vitiligo remains scarce. Multiple mechanisms including immunologic, deficiency of melanocyte growth factors, and increased oxidative stress ultimately leading to depigmentation may play a role. As suggested by Gauthier et al. (2003b), another possible explanation is based on a mechanical detachment of melanocytes followed by transepidermal elimination because of a defective melanocyte adhesion.

Summarizing the literature, we can state that there is no clear definition and no golden rule yet for the assessment of KP in vitiligo. However, to unravel this phenomenon, the first requirement is to reach a consensus concerning the evaluation of the Koebner phenomenon. Therefore, the proposed consensus aims to unravel this phenomenon. Clearly, more active research into this quite unexplored field can lead to advance of our current knowledge on vitiligo not only with regard to the clinical relevance of KP but also to foster novel ideas about the pathogenesis of this disease with the possibility to find novel therapies.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Koebner’s phenomenon: clinical aspects
  5. Koebner’s phenomenon: pathogenesis
  6. Koebner’s phenomenon: how to assess it ?
  7. Need for future investigations
  8. Conclusion
  9. References
  10. Supporting Information

Figure S1. Depigmentations suggestive for previous injury (Koebner phenomenon type 2B).

FilenameFormatSizeDescription
PCMR_838_sm_FigS1.png135KSupporting info item

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