DOI: 10.1111/exd.12309 www.wileyonlinelibrary.com/journal/EXD
Commentary from the Editorial Board
Alopecia areata and vitiligo – Partners in crime or a case of false alibis Desmond J. Tobin Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire, Great Britain Correspondence: Des J. Tobin, PhD, Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire BD7 1DP, Great Britain, Tel.: +44(0)1274-233585, Fax: +44(0)1274-309742, e-mail: [email protected] Abstract: It has long been appreciated in science that correlation does not imply causation. However, with any logical fallacy, simply spotting that the reasoning behind an argument is faulty does not imply that the resulting conclusion is false. Thus, I begin the tricky business of exploring the basis upon which researchers and clinicians are often tempted to conclude that two medical conditions (here alopecia areata and vitiligo), with some striking resemblances, are in fact related. This is relevant, particularly if
assumptions of shared aetiology (and to some extent shared pathomechanism) encourage a common strategy to finding a treatment or cure.
Commentary
The terrifically complex biomolecular cascades that result in and/or from immune-mediated or genuinely autoimmune events can leave a bewildering plethora of calling cards from an everexpanding list of factors. Many (if not most) of these are likely to be wholly redundant distractions [i.e. potential examples of coincident effects of a common cause, (9)]. An example may be the striking shared involvement of melanocytes as targets in both AA and vitiligo (10–13). Unfortunately, these provide, however, fertile ground for researchers to enthusiastically swop individual jig-saw pieces from the separate AA and vitiligo aetiologic/pathologic pictures, just because these pieces look like they may fit. For example, it is altogether possible that epitope spreading can occur secondarily to involve melanocytes in AA, which only then reveal the apparent association with vitiligo [note presence of common antibody targets (14,15)]. The markedly different effects of biologics in so-called autoimmune dermatoses appear to support the above interpretation. A case in point was the expectation that treatments found effective in the similarly defined ‘T-cell-mediated autoimmune’ condition psoriasis would also be effective in AA proved unfounded at least for efalizumab (16) and etanercept (17). Indeed, all studies to date including prospective, randomized placebo-controlled studies and individual case reports on biological agents, including adalimumab, alefacept, etanercept and infliximab, have shown these to be ineffective in the treatment of AA. Frustratingly, some individuals even developed AA while under treatment with biological agents for other conditions. Similarly, while it has been shown that tumor necrosis factor alpha (TNF-a) can destroy melanocytes, anti-TNF-a agents have so far not been effective in vitiligo (18). These studies should serve as a cautionary tale to avoid simplistic data interpretation. Importantly, there is no evidence to date that cytokines that are active in either AA or vitiligo can ‘cause’ the onset of the other disorder, or even to damage hair follicle or epidermis via some kind of collateral effect. This is striking. In this context, we need to take care when diagnosing general cases of leukoderma as vitiligo vulgaris, or vitiligo-associated leukotrichia as similar to the initial regrowth of white hair in AA.
While we all appreciate that correlation does not imply causation, a faulty argument in its defense does not mean the conclusion itself is false (1). In this way, both researchers and clinicians are often tempted to conclude that two medical conditions are related, when in fact they simply exhibit some striking resemblances. The fascinating viewpoint article Vitiligo and alopecia areata: Apples and oranges? by John Harris in the December 2013 issue (2) tackles one of the more interesting ‘pairings’ in dermatology and is to be commended for drawing together in one place a smorgasbord of delectable resemblances of alopecia areata (AA) (3) and vitiligo (4). For balance, John also highlights some of the differences between these two conditions. Perhaps, the most current reason for suggesting that AA and vitiligo are both ‘apples’ is the emerging view that both may have an autoimmune basis. Some experts struggle with assigning ‘immunemediated’ versus ‘autoimmune-mediated’ as the basis for particular diseases. This is in part because both similarly respond to immunosuppressive and immunomodulatory therapies to reduce the inflammation thought to drive the pathology (i.e. hair loss in AA and depigmentation in vitiligo). Regardless of the residual uncertainty about where AA and vitiligo are along this (auto)immunemediated spectrum, there remains the inescapable need to identify the primary or precipitating defect(s) in both conditions. For example, it is known that fundamental biochemical impairments, genetic or otherwise, may alter ‘antigenicity’ in targeted tissue components and that these can subsequently alert a wholly normal immune response (5). Its corollary may also be true, in that an abnormal immune response to normal tissue components may result from the desequestration of normally hidden targets (6). Insights from the flurry of progress in elucidating the genetics of both AA and vitiligo strongly support this view (7,8). It is, however, important not to overinterpret genetic data (including from large GWAS studies), especially regarding reported genetic risk factors, as these are likely to be relevant to several (auto)immune disorders. In this way, they may not show selectivity for either AA or vitiligo and may not support linkage between them.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 23, 153–154
Key words: alopecia areata – autoimmunity – comorbidity – melanocyte – vitiligo
Accepted for publication 17 December 2013
153
Commentary from the Editorial Board
Figure 1. Patchy alopecia areata anatomically colocalized with vitiligo vulgaris. Reproduced with permission from: Kumar S, Mittal J, Mahajan B. Colocalization of vitiligo and alopecia areata: coincidence or consequence? Int J Trichology. 2013 Jan; 5(1):50–2. Published by Medknow.
An important issue raised by Harris’ article is how we should interpret AA and vitiligo comorbidity and the occasionally observed anatomical co-existence of AA and vitiligo (Fig. 1) (2). AA and vitiligo (and indeed psoriasis) may share some common trigger factors (e.g. the K€ obner phenomenon). However, we must satisfy ourselves that the prevalence of one disorder in individuals with another disorder (or vice versa) falls outside the prevalence range of the population used as background; otherwise, it may reveal coexistence of the two diseases due to chance alone. So far an increase in the expected prevalence of psoriasis in individuals with vitiligo (or vice versa) has not been found (19), and some have proposed and others doubted this for AA and vitiligo
(20–23). In a recent 10-year retrospective study of comorbidities in a US vitiligo population of 2441 patients, the most frequently observed comorbidity was thyroid related (12%), and a full 50% of patients had elevated thyroid peroxidase antibodies (24). However, AA was reported as a comorbidity in the medical records of only 59 individuals in this same study (2.4%). Given that the lifetime risk of AA has been confirmed recently as approximately 2.1% (25), the association between these conditions may be very weak or only coincidental. Similarly, a recent evaluation of an 11year data set of comorbidities in AA did not report an association with vitiligo; instead high associations were reported for those with thyroid disease (14.6%,) and diabetes mellitus (11.1%) (26). However, Harris makes the valid point here that true prevalence for both AA and vitiligo is likely to be extremely difficult to estimate accurately, given that more minor forms of both conditions may never come to the attention of the physician. In my view, clues to even a weak association between AA and vitiligo are most likely to be found in the thyroid, the atopic state, and the latter’s common partner in crime – the cross-reacting cases of antigenic mimicry. There is an indisputable higher prevalence of thyroid disease in patients with AA and vitiligo (24,26,27). It is known that atopic patients may have an earlier onset or more severe form of AA and vitiligo (27,28), and one must be open to the possibility that atopic reactions can be triggered by localized ‘hypersensitivity’ to an allergen/cross-reactive antigen. There may be one ‘test’, however, where these two disorders may reveal their hidden mechanistic association(s), if present at all. This is whether redox imbalance drives pathology in AA as it clearly does in vitiligo? (29). While oxidative stress in AA may be anatomically deeper, and qualitatively/quantitatively different than for vitiligo, if evidence [and some already appears to be emerging, (30)] was found to involve some of its key features (e.g. catalase deficiency) a stronger case may indeed be revealed to suggest real association. Some are even proposing an underlying role for oxidative stress in autoimmune disease in general (31). Still, it is entirely possible that upon deeper investigations, the emergent data may reveal that oranges (or indeed apples) are not the only fruit.
Conflict of interest The author has declared no conflicting interests.
References 1 Shipley B. Cause and Correlation in Biology. Cambridge University Press, Cambridge, UK, 2002. 2 Harris J. Exp Dermatol 2013: 22: 785–789. 3 McElwee K J, Gilhar A, Tobin D J et al. Exp Dermatol 2013: 22: 609–626. 4 Laddha N C, Dwivedi M, Mansuri M S et al. Exp Dermatol 2013: 22: 245–250. 5 Marrack P, Kappler J W. Cold Spring Harb Perspect Med 2012: 2: a007765. 6 Ito T, Meyer K C, Ito N et al. Curr Dir Autoimmun 2008: 10: 27–52. 7 Spritz R A. J Invest Dermatol 2012: 132: 268–273. 8 Jabbari A, Petukhova L, Cabral R M et al. Dermatol Clin 2013: 31: 109–117. 9 Sober E. The European Philosophy of Science Association. de Regt HW, Hartmann S, Okasha S (eds) Springer, Amsterdam 2009: 362–364.
154
10 Tobin D J, Fenton D A, Kendall M D. J Invest Dermatol 1990: 94: 803–807. 11 Paus R, Slominski A, Czarnetzki B M. Yale J Biol Med 1993: 66: 541–554. 12 Gilhar A, Landau M, Assy B et al. J Invest Dermatol 2001: 117: 1357–1362. 13 Wu J, Zhou M, Wan Y et al. Mol Med Rep 2013: 7: 237–241. 14 Kim J Y, Do J E, Ahn K J et al. J Dermatol Sci 2011: 62: 202–204. 15 Rahoma S F, Sandhu H K, McDonagh A J et al. Br J Dermatol 2012: 167: 17–28. 16 Price V H, Hordinsky M K, Olsen E A et al. J Am Acad Dermatol 2008: 58: 395–402. 17 Strober B E, Siu K, Alexis A F et al. J Am Acad Dermatol 2005: 52: 1082–1084. 18 Alghamdi K M, Khurrum H, Taieb A et al. J Drugs Dermatol 2012: 11: 534–539. 19 Sawchuk M, Spano F, Loo W J et al. J Cutan Med Surg 2012: 16: 300–305. 20 Schallreuter K U, Lemke R, Brandt O et al. Dermatology 1994: 188: 269–275.
21 Kumar S, Mittal J, Mahajan B. Int J Trichology 2013: 5: 50–52. 22 Krishnaram A S, Saigal A, Adityan B. Indian J Dermatol Venereol Leprol 2013: 79: 535–537. 23 Ozcan D, Cevlik Aydoðan F. Australas J Dermatol 2012: 53: e61–63. 24 Sheth V M, Guo Y, Qureshi A A. Dermatology 2013 [Epub ahead of print]. 25 Mirzoyev S A, Schrum A G, Davis M D et al. J Invest Dermatol 2013 [Epub ahead of print]. 26 Huang K P, Mullangi S, Guo Y et al. JAMA Dermatol 2013: 149: 789–794. 27 Vrijman C, Kroon M W, Limpens J et al. Br J Dermatol 2012: 167: 1224–1235. 28 Ezzedine K, Diallo A, Leaute-Labreze C et al. Br J Dermatol 2012: 167: 490–495. 29 Schallreuter K U, Moore J, Wood J M et al. J Investig Dermatol Symp Proc 1999: 4: 91–96. 30 Bakry O A, Elshazly R M, Shoeib M A et al. Am J Clin Dermatol 2013 [Epub ahead of print]. 31 Shah A A, Sinha A A. Eur J Dermatol 2013: 23: 5–13.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 23, 153–154
Commentary from the Editorial Board
Alopecia areata and vitiligo – Partners in crime or a case of false alibis Desmond J. Tobin Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire, Great Britain Correspondence: Des J. Tobin, PhD, Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire BD7 1DP, Great Britain, Tel.: +44(0)1274-233585, Fax: +44(0)1274-309742, e-mail: [email protected] Abstract: It has long been appreciated in science that correlation does not imply causation. However, with any logical fallacy, simply spotting that the reasoning behind an argument is faulty does not imply that the resulting conclusion is false. Thus, I begin the tricky business of exploring the basis upon which researchers and clinicians are often tempted to conclude that two medical conditions (here alopecia areata and vitiligo), with some striking resemblances, are in fact related. This is relevant, particularly if
assumptions of shared aetiology (and to some extent shared pathomechanism) encourage a common strategy to finding a treatment or cure.
Commentary
The terrifically complex biomolecular cascades that result in and/or from immune-mediated or genuinely autoimmune events can leave a bewildering plethora of calling cards from an everexpanding list of factors. Many (if not most) of these are likely to be wholly redundant distractions [i.e. potential examples of coincident effects of a common cause, (9)]. An example may be the striking shared involvement of melanocytes as targets in both AA and vitiligo (10–13). Unfortunately, these provide, however, fertile ground for researchers to enthusiastically swop individual jig-saw pieces from the separate AA and vitiligo aetiologic/pathologic pictures, just because these pieces look like they may fit. For example, it is altogether possible that epitope spreading can occur secondarily to involve melanocytes in AA, which only then reveal the apparent association with vitiligo [note presence of common antibody targets (14,15)]. The markedly different effects of biologics in so-called autoimmune dermatoses appear to support the above interpretation. A case in point was the expectation that treatments found effective in the similarly defined ‘T-cell-mediated autoimmune’ condition psoriasis would also be effective in AA proved unfounded at least for efalizumab (16) and etanercept (17). Indeed, all studies to date including prospective, randomized placebo-controlled studies and individual case reports on biological agents, including adalimumab, alefacept, etanercept and infliximab, have shown these to be ineffective in the treatment of AA. Frustratingly, some individuals even developed AA while under treatment with biological agents for other conditions. Similarly, while it has been shown that tumor necrosis factor alpha (TNF-a) can destroy melanocytes, anti-TNF-a agents have so far not been effective in vitiligo (18). These studies should serve as a cautionary tale to avoid simplistic data interpretation. Importantly, there is no evidence to date that cytokines that are active in either AA or vitiligo can ‘cause’ the onset of the other disorder, or even to damage hair follicle or epidermis via some kind of collateral effect. This is striking. In this context, we need to take care when diagnosing general cases of leukoderma as vitiligo vulgaris, or vitiligo-associated leukotrichia as similar to the initial regrowth of white hair in AA.
While we all appreciate that correlation does not imply causation, a faulty argument in its defense does not mean the conclusion itself is false (1). In this way, both researchers and clinicians are often tempted to conclude that two medical conditions are related, when in fact they simply exhibit some striking resemblances. The fascinating viewpoint article Vitiligo and alopecia areata: Apples and oranges? by John Harris in the December 2013 issue (2) tackles one of the more interesting ‘pairings’ in dermatology and is to be commended for drawing together in one place a smorgasbord of delectable resemblances of alopecia areata (AA) (3) and vitiligo (4). For balance, John also highlights some of the differences between these two conditions. Perhaps, the most current reason for suggesting that AA and vitiligo are both ‘apples’ is the emerging view that both may have an autoimmune basis. Some experts struggle with assigning ‘immunemediated’ versus ‘autoimmune-mediated’ as the basis for particular diseases. This is in part because both similarly respond to immunosuppressive and immunomodulatory therapies to reduce the inflammation thought to drive the pathology (i.e. hair loss in AA and depigmentation in vitiligo). Regardless of the residual uncertainty about where AA and vitiligo are along this (auto)immunemediated spectrum, there remains the inescapable need to identify the primary or precipitating defect(s) in both conditions. For example, it is known that fundamental biochemical impairments, genetic or otherwise, may alter ‘antigenicity’ in targeted tissue components and that these can subsequently alert a wholly normal immune response (5). Its corollary may also be true, in that an abnormal immune response to normal tissue components may result from the desequestration of normally hidden targets (6). Insights from the flurry of progress in elucidating the genetics of both AA and vitiligo strongly support this view (7,8). It is, however, important not to overinterpret genetic data (including from large GWAS studies), especially regarding reported genetic risk factors, as these are likely to be relevant to several (auto)immune disorders. In this way, they may not show selectivity for either AA or vitiligo and may not support linkage between them.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 23, 153–154
Key words: alopecia areata – autoimmunity – comorbidity – melanocyte – vitiligo
Accepted for publication 17 December 2013
153
Commentary from the Editorial Board
Figure 1. Patchy alopecia areata anatomically colocalized with vitiligo vulgaris. Reproduced with permission from: Kumar S, Mittal J, Mahajan B. Colocalization of vitiligo and alopecia areata: coincidence or consequence? Int J Trichology. 2013 Jan; 5(1):50–2. Published by Medknow.
An important issue raised by Harris’ article is how we should interpret AA and vitiligo comorbidity and the occasionally observed anatomical co-existence of AA and vitiligo (Fig. 1) (2). AA and vitiligo (and indeed psoriasis) may share some common trigger factors (e.g. the K€ obner phenomenon). However, we must satisfy ourselves that the prevalence of one disorder in individuals with another disorder (or vice versa) falls outside the prevalence range of the population used as background; otherwise, it may reveal coexistence of the two diseases due to chance alone. So far an increase in the expected prevalence of psoriasis in individuals with vitiligo (or vice versa) has not been found (19), and some have proposed and others doubted this for AA and vitiligo
(20–23). In a recent 10-year retrospective study of comorbidities in a US vitiligo population of 2441 patients, the most frequently observed comorbidity was thyroid related (12%), and a full 50% of patients had elevated thyroid peroxidase antibodies (24). However, AA was reported as a comorbidity in the medical records of only 59 individuals in this same study (2.4%). Given that the lifetime risk of AA has been confirmed recently as approximately 2.1% (25), the association between these conditions may be very weak or only coincidental. Similarly, a recent evaluation of an 11year data set of comorbidities in AA did not report an association with vitiligo; instead high associations were reported for those with thyroid disease (14.6%,) and diabetes mellitus (11.1%) (26). However, Harris makes the valid point here that true prevalence for both AA and vitiligo is likely to be extremely difficult to estimate accurately, given that more minor forms of both conditions may never come to the attention of the physician. In my view, clues to even a weak association between AA and vitiligo are most likely to be found in the thyroid, the atopic state, and the latter’s common partner in crime – the cross-reacting cases of antigenic mimicry. There is an indisputable higher prevalence of thyroid disease in patients with AA and vitiligo (24,26,27). It is known that atopic patients may have an earlier onset or more severe form of AA and vitiligo (27,28), and one must be open to the possibility that atopic reactions can be triggered by localized ‘hypersensitivity’ to an allergen/cross-reactive antigen. There may be one ‘test’, however, where these two disorders may reveal their hidden mechanistic association(s), if present at all. This is whether redox imbalance drives pathology in AA as it clearly does in vitiligo? (29). While oxidative stress in AA may be anatomically deeper, and qualitatively/quantitatively different than for vitiligo, if evidence [and some already appears to be emerging, (30)] was found to involve some of its key features (e.g. catalase deficiency) a stronger case may indeed be revealed to suggest real association. Some are even proposing an underlying role for oxidative stress in autoimmune disease in general (31). Still, it is entirely possible that upon deeper investigations, the emergent data may reveal that oranges (or indeed apples) are not the only fruit.
Conflict of interest The author has declared no conflicting interests.
References 1 Shipley B. Cause and Correlation in Biology. Cambridge University Press, Cambridge, UK, 2002. 2 Harris J. Exp Dermatol 2013: 22: 785–789. 3 McElwee K J, Gilhar A, Tobin D J et al. Exp Dermatol 2013: 22: 609–626. 4 Laddha N C, Dwivedi M, Mansuri M S et al. Exp Dermatol 2013: 22: 245–250. 5 Marrack P, Kappler J W. Cold Spring Harb Perspect Med 2012: 2: a007765. 6 Ito T, Meyer K C, Ito N et al. Curr Dir Autoimmun 2008: 10: 27–52. 7 Spritz R A. J Invest Dermatol 2012: 132: 268–273. 8 Jabbari A, Petukhova L, Cabral R M et al. Dermatol Clin 2013: 31: 109–117. 9 Sober E. The European Philosophy of Science Association. de Regt HW, Hartmann S, Okasha S (eds) Springer, Amsterdam 2009: 362–364.
154
10 Tobin D J, Fenton D A, Kendall M D. J Invest Dermatol 1990: 94: 803–807. 11 Paus R, Slominski A, Czarnetzki B M. Yale J Biol Med 1993: 66: 541–554. 12 Gilhar A, Landau M, Assy B et al. J Invest Dermatol 2001: 117: 1357–1362. 13 Wu J, Zhou M, Wan Y et al. Mol Med Rep 2013: 7: 237–241. 14 Kim J Y, Do J E, Ahn K J et al. J Dermatol Sci 2011: 62: 202–204. 15 Rahoma S F, Sandhu H K, McDonagh A J et al. Br J Dermatol 2012: 167: 17–28. 16 Price V H, Hordinsky M K, Olsen E A et al. J Am Acad Dermatol 2008: 58: 395–402. 17 Strober B E, Siu K, Alexis A F et al. J Am Acad Dermatol 2005: 52: 1082–1084. 18 Alghamdi K M, Khurrum H, Taieb A et al. J Drugs Dermatol 2012: 11: 534–539. 19 Sawchuk M, Spano F, Loo W J et al. J Cutan Med Surg 2012: 16: 300–305. 20 Schallreuter K U, Lemke R, Brandt O et al. Dermatology 1994: 188: 269–275.
21 Kumar S, Mittal J, Mahajan B. Int J Trichology 2013: 5: 50–52. 22 Krishnaram A S, Saigal A, Adityan B. Indian J Dermatol Venereol Leprol 2013: 79: 535–537. 23 Ozcan D, Cevlik Aydoðan F. Australas J Dermatol 2012: 53: e61–63. 24 Sheth V M, Guo Y, Qureshi A A. Dermatology 2013 [Epub ahead of print]. 25 Mirzoyev S A, Schrum A G, Davis M D et al. J Invest Dermatol 2013 [Epub ahead of print]. 26 Huang K P, Mullangi S, Guo Y et al. JAMA Dermatol 2013: 149: 789–794. 27 Vrijman C, Kroon M W, Limpens J et al. Br J Dermatol 2012: 167: 1224–1235. 28 Ezzedine K, Diallo A, Leaute-Labreze C et al. Br J Dermatol 2012: 167: 490–495. 29 Schallreuter K U, Moore J, Wood J M et al. J Investig Dermatol Symp Proc 1999: 4: 91–96. 30 Bakry O A, Elshazly R M, Shoeib M A et al. Am J Clin Dermatol 2013 [Epub ahead of print]. 31 Shah A A, Sinha A A. Eur J Dermatol 2013: 23: 5–13.
ª 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2013, 23, 153–154
