**1. Introduction**

140 Psoriasis

[122] Chel VG, Ooms ME, Popp-Snijders C, Pavel S, Schothorst AA, Meulemans CC, et al.

[124] Gottlieb AB, Chao C, Dann F. Psoriasis comorbidities. J Dermatolog Treat. 2008;19(1):5-21. [125] Christophers E. Comorbidities in psoriasis. Clin Dermatol. 2007 Nov-Dec;25(6):529-34. [126] Girolomoni G, Gisondi P. Psoriasis and metabolic comorbidities: the importance of well-designed prospective studies. Commentary. Dermatology. 2008;217(3):222-4. [127] Gottlieb AB, Dann F, Menter A. Psoriasis and the metabolic syndrome. J Drugs

[128] Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal M. Increased

[129] Palomer X, Gonzalez-Clemente JM, Blanco-Vaca F, Mauricio D. Role of vitamin D in

[130] Tai K, Need AG, Horowitz M, Chapman IM. Vitamin D, glucose, insulin, and insulin

[131] Procopio M, Magro G, Cesario F, Piovesan A, Pia A, Molineri N, et al. The oral glucose

[132] Taylor WH, Khaleeli AA. Prevalence of primary hyperparathyroidism in patients with

[133] Luong K, Nguyen LT, Nguyen DN. The role of vitamin D in protecting type 1 diabetes

[134] Mauricio D, Mandrup-Poulsen T, Nerup J. Vitamin D analogues in insulin-dependent

[135] Lemire JM. Immunomodulatory actions of 1,25-dihydroxyvitamin D3. J Steroid

[136] Ucak S, Ekmekci TR, Basat O, Koslu A, Altuntas Y. Comparison of various insulin

[137] Akhyani M, Ehsani AH, Robati RM, Robati AM. The lipid profile in psoriasis: a controlled study. J Eur Acad Dermatol Venereol. 2007 Nov;21(10):1330-2. [138] Mallbris L, Granath F, Hamsten A, Stahle M. Psoriasis is associated with lipid abnormalities at the onset of skin disease. J Am Acad Dermatol. 2006 Apr;54(4):614-21. [139] Carbone LD, Rosenberg EW, Tolley EA, Holick MF, Hughes TA, Watsky MA, et al. 25-

[140] Azfar RS, Gelfand JM. Psoriasis and metabolic disease: epidemiology and

[141] Libby P. Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr. 2006

pathophysiology. Curr Opin Rheumatol. 2008 Jul;20(4):416-22.

Apr 25;44(4):299-305.

Mar;10(3):185-97.

Jun;57(6):741-8.

Feb;83(2):456S-60S.

Dermatol. 2008 Jun;7(6):563-72.

Med. 2002 Nov;19(11):958-61.

psoriasis. Arch Dermatol Res. 2006 Dec;298(7):321-8.

diabetes mellitus. Diabet Med. 1997 May;14(5):386-9.

J Eur Acad Dermatol Venereol. 2006 May;20(5):517-22.

mellitus. Diabetes Metab Res Rev. 2005 Jul-Aug;21(4):338-46.

sensitivity. Nutrition. 2008 Mar;24(3):279-85.

Diabetes Metab Rev. 1996 Apr;12(1):57-68.

Biochem Mol Biol. 1995 Jun;53(1-6):599-602.

Ultraviolet irradiation corrects vitamin D deficiency and suppresses secondary hyperparathyroidism in the elderly. J Bone Miner Res. 1998 Aug;13(8):1238-42. [123] Lilliu H, Pamphile R, Chapuy MC, Schulten J, Arlot M, Meunier PJ. Calcium-vitamin

D3 supplementation is cost-effective in hip fractures prevention. Maturitas. 2003

prevalence of the metabolic syndrome in patients with moderate to severe

the pathogenesis of type 2 diabetes mellitus. Diabetes Obes Metab. 2008

tolerance test reveals a high frequency of both impaired glucose tolerance and undiagnosed Type 2 diabetes mellitus in primary hyperparathyroidism. Diabet

diabetes mellitus and other autoimmune diseases: a therapeutic perspective.

sensitivity indices in psoriatic patients and their relationship with type of psoriasis.

Hydroxyvitamin D, cholesterol, and ultraviolet irradiation. Metabolism. 2008

During the 8th gestational week, a condensation of cells develops on the distal dorsal aspect of the digital tip. At week 9, this migrates proximally to form a flat groove, the nail field. At week 11, an invagination develops from the proximal groove, which later forms the nail pocket or cul-de-sac, with the matrix at its bottom. Nail production starts around week 13. At the age of 20 weeks, the nail production is similar to that of an adult. From week 32 on, all nail components can be recognized (Lewis, 1954, Zaias, 1963).

The nail apparatus consists of epithelial and connective tissue components and covers the tip of the fingers and toes (Figure 1) (Lewin, 1965, Morgan et al, 2001, Zook et al, 1980). Its functions are support, protection and maintenance of the digital tips as well as enhancement of the sensory functions of the digital pulps, and the nail is a tool for scratching, defense, fine manual work, etc. The cosmetic-aesthetic and social functions of the nail have attained a lot of attention in recent years.

The nail has four epithelial components:

 The matrix epithelium is the sole structure to produce the nail plate. It is commonly divided into the proximal, medial and distal matrix (Figure 2). The existence of a socalled dorsal matrix is controversial. Most of the matrix is covered by the proximal nail fold. Under normal circumstances, its distal portion, the whitish lunula, is only seen in the thumb, index and middle finger as well as the great toe; however, manicure with pushing the free margin of the proximal nail fold back makes more of the matrix visible through the nail and lets the nail plate appear longer.

The matrix epithelium consists of a basal compartment seen as cuboid basophilic cells that migrate up to form the more eosinophilic superficial compartment (Perrin et al, 2004). Whenever a nail is avulsed the superficial compartment remains attached to it. During onychotisation, the superficial cells undergo nuclear fragmentation. Under normal circumstances, there is no granular layer.

Nail Psoriasis 143

 The hyponychium is localized at the distal end of the nail bed and forms a particular structure allowing the plate to get detached from the bed without injury. It seals the virtual space between the nail and the nail bed. The normal hyponychium shows a broad granular layer (Hanno et al, 1986, Perrin, 2008). Distal to it, digital pulp skin is

 The eponychium is a thin layer of keratin produced by the undersurface of the proximal nail fold (PNF). Approximately halfway it divides into the true eponychium remaining firmly attached to the dorsal surface of the nail plate and the false eponychium attached to the epidermis of the PNF's ventral surface. It forms the bulk of the cuticle, the

Proximally and laterally, the nail is ensheathed by the proximal and two lateral nail folds, which form a frame leaving the distal margin of the nail plate free. This allows the nail plate to grow out and not up. The proximal nail fold is a continuation of the dorsal aspect of the skin of the tip of the digit, which folds on itself thereby producing a cover for most of the matrix. Its free margin forms an acute angle, which bears the cuticle. This is the most distal portion of the false eponychium. When the distal free margin of the proximal nail fold rounds up it loses its ability to form a cuticle, and within usually a relatively short period of time the undersurface of the proximal nailfold detaches from the underlying nail plate.

The lateral nail folds are rolls of connective tissue covered with normal epithelium. Their border to the nail bed is the lateral nail groove. This is firmly attached to the nail plate preventing foreign substances from getting under the nail plate. The lateral grooves are

The nail plate – commonly called "the nail" - is the product of the matrix. It is made up of keratin which is a sulfur-rich fibrous keratin embedded in a sulfur-rich amorphous matrix. The fibrous protein structure is seen clearly under polarized light. In contrast to hair, which is made up of exactly the same material, it has no special outer structure like a cuticle of scales and the nail grows continuously from birth to death without a cyclical pattern. The plate exhibits a slight longitudinal and a more pronounced transverse curvature, the degree of which varies between different fingers and toes, during age and some diseases, and has a concave border proximally and a convex free margin. The lunula border reflects the shape of the matrix as it runs parallel to the proximal border of the nail. Usually three layers of the nail plate are distinguished (Figure 2): dorsal (superficial), middle, and deep (ventral). The dorsal nail plate layer is produced by the proximal matrix. Its cells are considerably flatter and thus, despite its lesser thickness, it has approximately as many cell layers as the considerably thicker middle nail plate layer with its higher cells. The dorsal nail plate is

function of which is to seal the cul-de-sac or nail pocket.

important to guide the nails during their forward growth.

present.

and Angus, 1996, Nishi et al, 1996, Zaias and Alvarez, 1968) although this is also controversial (Johnson et al, 1991). A normal nail bed does not form a granular layer. The nail bed epithelium-connective tissue interface is characterized by unique longitudinal rete ridges, in which 3 to 6 layers of longitudinally running capillaries are arranged one above the other. Trauma to these capillaries may produce the characteristic splinter haemorrhages, which in nail psoriasis are equivalent to Auspitz' phenomenon of the skin. The connective tissue of the nail bed is a firm layer directly attached to the bone without any subdermal fat. This and the abundance of nervous structures in the nail bed and matrix are probably the reason for the extraordinary pain elicited by trauma to the nail apparatus.

Fig. 1. Anatomy of the nail apparatus. Oblique view (A) and sagittal section (B) through the distal phalanx.

The matrix contains melanocytes most of which are located suprabasally. In light-skinned individuals, they remain functionally inactive. Independent from the skin type, the distal matrix contains more melanocytes than the proximal one (Tosti et al, 1994, Perrin et al, 1997).

The matrix connective tissue is relatively loose containing blood vessels and a considerable number of glomus bodies. Recent studies have found that matrix fibroblasts are CD 10+ similar to perifollicular fibroblasts (Lee et al, 2007- 2010). The matrix dermis has an important morphogenetic capacity allowing it to reproduce matrix epithelium when enough of it is left after trauma or superficial surgical removal. The distance from the most proximal matrix epithelium to the bone of the terminal phalanx is about 0.8 – 1 mm (Haneke, 2006, Kim et al, 2011).

 The nail bed epithelium is a relatively thin layer of keratinocytes structurally similar to tricholemmal cells. It firmly attaches the nail to the underlying distal phalanx and produces a tiny amount of nail bed keratin, which allows the nail plate to virtually slide over the nail bed without being detached from it. The nail bed keratin is structurally different from the nail plate keratin. The nail bed does not produce nail plate (de Berker

b) Fig. 1. Anatomy of the nail apparatus. Oblique view (A) and sagittal section (B) through the

The matrix contains melanocytes most of which are located suprabasally. In light-skinned individuals, they remain functionally inactive. Independent from the skin type, the distal matrix contains more melanocytes than the proximal one (Tosti et al, 1994, Perrin et al,

The matrix connective tissue is relatively loose containing blood vessels and a considerable number of glomus bodies. Recent studies have found that matrix fibroblasts are CD 10+ similar to perifollicular fibroblasts (Lee et al, 2007- 2010). The matrix dermis has an important morphogenetic capacity allowing it to reproduce matrix epithelium when enough of it is left after trauma or superficial surgical removal. The distance from the most proximal matrix epithelium to the bone of the terminal phalanx is about 0.8 – 1 mm (Haneke, 2006,

 The nail bed epithelium is a relatively thin layer of keratinocytes structurally similar to tricholemmal cells. It firmly attaches the nail to the underlying distal phalanx and produces a tiny amount of nail bed keratin, which allows the nail plate to virtually slide over the nail bed without being detached from it. The nail bed keratin is structurally different from the nail plate keratin. The nail bed does not produce nail plate (de Berker

distal phalanx.

Kim et al, 2011).

1997).

a)

and Angus, 1996, Nishi et al, 1996, Zaias and Alvarez, 1968) although this is also controversial (Johnson et al, 1991). A normal nail bed does not form a granular layer.

The nail bed epithelium-connective tissue interface is characterized by unique longitudinal rete ridges, in which 3 to 6 layers of longitudinally running capillaries are arranged one above the other. Trauma to these capillaries may produce the characteristic splinter haemorrhages, which in nail psoriasis are equivalent to Auspitz' phenomenon of the skin. The connective tissue of the nail bed is a firm layer directly attached to the bone without any subdermal fat. This and the abundance of nervous structures in the nail bed and matrix are probably the reason for the extraordinary pain elicited by trauma to the nail apparatus.


Proximally and laterally, the nail is ensheathed by the proximal and two lateral nail folds, which form a frame leaving the distal margin of the nail plate free. This allows the nail plate to grow out and not up. The proximal nail fold is a continuation of the dorsal aspect of the skin of the tip of the digit, which folds on itself thereby producing a cover for most of the matrix. Its free margin forms an acute angle, which bears the cuticle. This is the most distal portion of the false eponychium. When the distal free margin of the proximal nail fold rounds up it loses its ability to form a cuticle, and within usually a relatively short period of time the undersurface of the proximal nailfold detaches from the underlying nail plate.

The lateral nail folds are rolls of connective tissue covered with normal epithelium. Their border to the nail bed is the lateral nail groove. This is firmly attached to the nail plate preventing foreign substances from getting under the nail plate. The lateral grooves are important to guide the nails during their forward growth.

The nail plate – commonly called "the nail" - is the product of the matrix. It is made up of keratin which is a sulfur-rich fibrous keratin embedded in a sulfur-rich amorphous matrix. The fibrous protein structure is seen clearly under polarized light. In contrast to hair, which is made up of exactly the same material, it has no special outer structure like a cuticle of scales and the nail grows continuously from birth to death without a cyclical pattern. The plate exhibits a slight longitudinal and a more pronounced transverse curvature, the degree of which varies between different fingers and toes, during age and some diseases, and has a concave border proximally and a convex free margin. The lunula border reflects the shape of the matrix as it runs parallel to the proximal border of the nail. Usually three layers of the nail plate are distinguished (Figure 2): dorsal (superficial), middle, and deep (ventral). The dorsal nail plate layer is produced by the proximal matrix. Its cells are considerably flatter and thus, despite its lesser thickness, it has approximately as many cell layers as the considerably thicker middle nail plate layer with its higher cells. The dorsal nail plate is

Nail Psoriasis 145

In contrast to skin, the nail demonstrates a variety of specific reactions that are sometimes opposite to the rest of the skin. Whereas irritation and a number of inflammatory reactions cause parakeratosis in skin they may induce a granular layer in the nail, some psoriatic reactions included. Several dermatoses that are not characterized by spongiosis, may exhibit marked intercellular oedema of matrix and nail bed epithelium, e.g. in ungual lichen planus

As the dorsal layer of the nail plate is produced by the most proximal portion of the matrix any alterations of the proximal matrix will translate into changes of the nail surface and uppermost layers. The bulk of the nail is produced by the middle matrix portion; alterations here will modify the nail plate both in its thickness as well as optical coherence. When the distal matrix is involved the resulting nail alterations will appear at the undersurface of the nail (Figure 2). All matrix-derived alterations will grow out with the nail. In contrast, nail bed alterations will be seen through the nail, but will not be integrated into the nail. As the nail bed keratin moves slower than the nail plate nail bed alterations remain longer or may

Psoriasis of the nails induces characteristic histopathological changes that are pathognomonic in the vast majority of cases; however, in the beginning and with less pronounced changes it may mimic a spongiotic dermatitis or may be indistinguishable from

Whereas the main criteria for psoriasis of the skin also apply for ungual psoriasis there are

Pits are the most frequent lesions in nail psoriasis (Figs. 3, 4) with roughly 70% of the patients presenting at least some of these characteristic tiny depressions (Zaias, 1969, Tham et al, 1988). Histologically, their appearance varies slightly. In the distal nail plate, they are seen as a depression in the nail plate surface that may be lined by some parakeratotic nail cells. The more proximal the biopsy is taken, the more parakeratosis is left. Under the proximal nail fold there are not yet pits but saucer-shaped small areas of parakeratosis. When these do not break out as it most commonly happens tiny white spots remain visible giving rise to spotted nails. Usually the rest of the nail organ appears normal and only in rare circumstances is a tiny inflammatory psoriatic lesion seen at the proximal tip of the matrix. Whether or not the pits may also originate from the most proximal portion of the ventral surface of the proximal nail fold (Zaias, 1990) remains a matter of dispute. Anyhow, it is surprising how rarely the original inflammatory matrix lesions giving rise to spots and

Nail bed changes are the second most common ungual sign of psoriasis. They may present as salmon or oil spots, which represent a small psoriatic plaque of the nailbed entirely covered by the nail plate, as onycholysis when the psoriatic plaque extends to the hyponychium, or as subungual hyperkeratosis representing a hyperkeratotic psoriatic plaque. A typical salmon spot shows slight acanthosis of the nail bed epithelium, an inflammatory infiltrate mainly made up of lymphocytes that tend to migrate into the epithelium and cause spongiosis, as well as parakeratosis on top of the epithelium, which

some differences and, above all, there are signs not seen in the rest of the skin.

**2. Histopathologic nail reactions** 

and psoriasis.

even appear non-migratory.

onychomycosis if there is no proof of fungal invasion.

**3. Histopathology of nail psoriasis** 

pits are seen in histopathological slides.

responsible for the nail shine. The ventral layer is not true nail but keratin derived from the nail bed. Histologically, it is easily distinguished from nail plate.

Fig. 2. Origin of the nail plate layers: The dorsal layer is produced by the proximal matrix (pink), the main intermediate and deep nail layer by the intermediate matrix (yellow) and the so-called ventral nail layer is the keratin produced by the nail bed (orange).

The nail organ is an integral part of the functional and sensory finger tip unit (Morgan et al, 2001). This is formed by the nail apparatus itself, all constituents of the finger tip, the distal interphalangeal joints with their capsule, tendons and ligaments. The entheses, insertion structures of bone with ligaments and tendons, play an important role for the functional and aesthetic integrity of the nail and have recently been found to be of utmost importance in psoriatic arthritis and nail psoriasis (McGonagle et al, 2010, 2011). The proximal tip of the matrix is just 0.8 to 1 mm from the bone of the terminal phalanx and also very close to the distal interphalangeal joint (Haneke, 2006). The joint capsule is enforced by the flexor and extensor tendons which form the dorsal and volar aponeuroses. They insert mostly at the base of the distal phalanx, but there are also fibers radiating to the more distal dorsal surface of the bone and into the connective tissue of the proximal nail fold (Frentz et al, 2000). This led some authors to call the nail a musculo-skeletal appendage (McGonagle et al, 2009a, b). Thus not only do the complex blood supply of the distal joint and nail, but also the anatomic vicinity of matrix and joint give a possible explanation why nail involvement is so frequent in psoriatic arthritis patients.

Nails grow continuously, finger nails about 3 times faster than those of the toes. The middle finger of the dominant hand has the fastest growing nail, growing between 3 to 5 mm per month. A big toenail grows about 1 mm per month. In summer and at daytime, the nails grow faster, during winter, at night, in high altitude slower. In psoriatic subjects, the nail growth rate is slightly increased. Some drugs also enhance nail growth, such as high-dose itraconazole and fluconazole, possibly also cyclosporine. Most cytostatic drugs including methotrexate, which is often used as a systemic drug for psoriasis treatment, slow down the nail growth rate. Fast growing nails are more prone to develop psoriatic pits.

responsible for the nail shine. The ventral layer is not true nail but keratin derived from the

Fig. 2. Origin of the nail plate layers: The dorsal layer is produced by the proximal matrix (pink), the main intermediate and deep nail layer by the intermediate matrix (yellow) and

The nail organ is an integral part of the functional and sensory finger tip unit (Morgan et al, 2001). This is formed by the nail apparatus itself, all constituents of the finger tip, the distal interphalangeal joints with their capsule, tendons and ligaments. The entheses, insertion structures of bone with ligaments and tendons, play an important role for the functional and aesthetic integrity of the nail and have recently been found to be of utmost importance in psoriatic arthritis and nail psoriasis (McGonagle et al, 2010, 2011). The proximal tip of the matrix is just 0.8 to 1 mm from the bone of the terminal phalanx and also very close to the distal interphalangeal joint (Haneke, 2006). The joint capsule is enforced by the flexor and extensor tendons which form the dorsal and volar aponeuroses. They insert mostly at the base of the distal phalanx, but there are also fibers radiating to the more distal dorsal surface of the bone and into the connective tissue of the proximal nail fold (Frentz et al, 2000). This led some authors to call the nail a musculo-skeletal appendage (McGonagle et al, 2009a, b). Thus not only do the complex blood supply of the distal joint and nail, but also the anatomic vicinity of matrix and joint give a possible explanation why nail involvement is so frequent

Nails grow continuously, finger nails about 3 times faster than those of the toes. The middle finger of the dominant hand has the fastest growing nail, growing between 3 to 5 mm per month. A big toenail grows about 1 mm per month. In summer and at daytime, the nails grow faster, during winter, at night, in high altitude slower. In psoriatic subjects, the nail growth rate is slightly increased. Some drugs also enhance nail growth, such as high-dose itraconazole and fluconazole, possibly also cyclosporine. Most cytostatic drugs including methotrexate, which is often used as a systemic drug for psoriasis treatment, slow down the nail growth rate. Fast growing nails are more prone

the so-called ventral nail layer is the keratin produced by the nail bed (orange).

in psoriatic arthritis patients.

to develop psoriatic pits.

nail bed. Histologically, it is easily distinguished from nail plate.
