Hair and Scalp Changes in Cutaneous and Systemic Lupus Erythematosus

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1 Am J Clin Dermatol REVIEW ARTICLE Hair and Scalp Changes in Cutaneous and Systemic Lupus Erythematosus Siriorn Udompanich 1 Kumutnart Chanprapaph 1 Poonkiat Suchonwanit 1 Ó Springer International Publishing AG, part of Springer Nature 2018 Abstract Cutaneous and systemic lupus erythematosus (SLE) commonly involves the hair and scalp. Alopecia can result from direct activity of disease on the scalp or from the state of physical stress in the form of telogen effluvium. Discoid lupus erythematosus and lupus panniculitis/profundus are known to cause scarring alopecia, while accumulation of recent studies has shown that non-scarring alopecia in SLE may have different subtypes, comprising lupus erythematosus-specific and lupus erythematosusnonspecific changes on histology. This review aims to summarize the clinical pattern, trichoscopic, histopathological, and direct immunofluorescence features of different types of alopecia in cutaneous and systemic lupus erythematosus, as well as exploring their relationship with SLE disease activity. Key Points Alopecia is among one of the most common cutaneous involvements in systemic lupus erythematosus (SLE). Alopecia in SLE comprises different subtypes. Recent studies have introduced new terms such as diffuse and patchy alopecia in SLE. These conditions have lupus erythematosus-specific changes on histology and are reversible after SLE treatment. Physicians who encounter patients should always spare some time to examine the hair and scalp as they can provide valuable clues for the diagnosis and monitoring of SLE. 1 Introduction & Poonkiat Suchonwanit poonkiat@hotmail.com 1 Division of Dermatology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchathewi, Bangkok 10400, Thailand Systemic lupus erythematosus (SLE) affects various organs in the body, with cutaneous involvement being the second most common clinical manifestation after joint inflammation [1]. The active role of dermatologists in detecting, monitoring, and managing skin lesions can be challenging given the heterogeneous nature of the disease. Nevertheless, details on clinical, trichoscopic, histopathological, and direct immunofluorescence (DIF) features of different forms of cutaneous lupus erythematosus (LE), along with their risks of systemic involvement, have been collectively studied and implemented daily in clinical practice. On the contrary, hair and scalp involvement in cutaneous and systemic LE may have been overlooked, despite the fact that the prevalence of alopecia ranges from 17.3 to

2 S. Udompanich et al. 85.2% of SLE patients [2 4]. Furthermore, the impact on their quality of life can be overwhelming, as evidenced by the statistically significant lower Dermatology Life Quality Index (DLQI) score [5]. In this review, we aim to provide a comprehensive summary of different types of hair and scalp manifestations in cutaneous and systemic LE in the hope of improving our understanding and, consequently, patient management. Current diagnostic criteria, classification, and scoring systems for cutaneous and systemic LE, especially regarding the incorporation of alopecia, are discussed, followed by details of the clinical presentation, differential diagnosis, relationship with SLE, and treatment and prognosis of each type of scarring and non-scarring condition. Finally, miscellaneous conditions that are linked to SLE are discussed, thus providing thorough information on all pathologies that can occur on the scalp. 2 Diagnostic Criteria, Classifications, Scoring Systems, and the Incorporation of Alopecia Alopecia is a common, well-recognized sign of LE, as evidenced by its integration into the most widely accepted classification and scoring systems for cutaneous and systemic LE. For SLE, the original diagnostic criteria, by the American College of Rheumatology (ACR), were created in 1982 and revised in 1997 [6, 7]. In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) proposed a new criteria that proved to be more sensitive in clinical practice [8]. For cutaneous involvement, the SLICC has incorporated acute cutaneous lupus, chronic cutaneous lupus, and oral or nasal ulcers into the criteria, as well as a separate section entitled non-scarring alopecia that defines as diffuse, thinning or hair fragility with visible broken hairs, in the absence of other causes such as alopecia areata (AA), drugs, iron deficiency, and androgenic alopecia. Cutaneous manifestation of LE can occur as part of SLE or as an isolated disease confined to the skin. From the dermatologists perspective, cutaneous LE can be divided into histopathology-specific and non-specific lesions [9]. Despite not possessing features of LE on histology, the risk of systemic disease for non-specific LE is relatively high [10]. Following this review, we classified hair involvement in the same manner by considering a condition as LEspecific when LE and interphase changes have been detected on histology, or when the condition has been described exclusively in LE patients. Table 1 shows our proposed classification for alopecia in SLE, while Table 2 provides a summarized comparison. Various scoring systems for monitoring disease activity include alopecia as one of the indicators of SLE exacerbations, although they are primarily used in research studies. An example is the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), which gives alopecia a score of 2 and describes the condition as abnormal, patchy, or diffuse loss of hair [11]. The British Isles Lupus Activity Group (BILAG) index also mentions alopecia in their severity score, dividing alopecia into mild and severe [12]. Nevertheless, the association between alopecia and SLE activity has not been fully validated, given the wide range of abnormal clinical and laboratory data in SLE. It is possible that different types and extent of alopecia have different degrees of correlation, with several studies attempting to prove this relationship in the past. In a large cross-sectional study of 122 SLE patients, no correlation was found between alopecia and SLEDAI [4]. In contrast, a study evaluating 74 SLE patients found a statistically significant association between alopecia and other LE cutaneous manifestations, conjunctivitis, and Raynaud s phenomenon. However, there was no association with systemic disease manifestations such as arthritis or renal involvement, or with laboratory variables such as antideoxyribonucleic acid antibodies, complement component 3 (C3), or erythrocyte sedimentation rate (ESR) [13]. These findings were derived from cross-sectional studies and should be interpreted with caution as timing between onset of alopecia and disease severity assessment was obscure. Future prospective cohort studies may help justify the relationship. Meanwhile, studies on specific types of alopecia have provided information on the status of patients included in the study, giving an approximate estimation of whether or not the pattern correlates with disease exacerbation. 3 Scarring Alopecia in Systemic Lupus Erythematosus (SLE) Scarring or cicatricial alopecia refers to hair loss conditions in which the destruction of follicular stem cells leads to permanent alopecia. In patients with SLE, discoid lupus erythematosus (DLE) and lupus panniculitis/profundus are well known to cause scarring alopecia. 3.1 Discoid Lupus Erythematosus Clinical Presentation, Trichoscopic, Histopathological, and Direct Immunofluorescence (DIF) Features DLE is classified as chronic cutaneous LE. The most common locations are on the face, ears and scalp. Up to 60% of patients with DLE have scalp involvement, onethird of whom suffer from scarring alopecia, which can

3 Hair and scalp changes in cutaneous and systemic LE Table 1 Proposed classification for alopecia in SLE LE-specific (alopecia as a direct result of LE activity on the scalp) Scarring: Discoid lupus erythematosus Classic lupus panniculitis/profundus Non-scarring: Diffuse non-scarring alopecia in SLE Patchy, non-scarring alopecia in SLE Lupus hair Linear and annular lupus panniculitis of the scalp LE nonspecific Telogen effluvium Anagen effluvium Alopecia areata Secondary cutaneous lesions related to SLE: Alopecia mucinosa Basaloid follicular hamartoma Dystrophic calcinosis cutis on the scalp Hair shaft abnormalities related to SLE LE lupus erythematosus, SLE systemic lupus erythematosus greatly impact their quality of life [10]. Classically, DLE is a well-demarcated erythematous scaly plaque with epidermal atrophy, follicular plugging, central hypopigmentation and peripheral hyperpigmentation in dark-skinned individuals. The lesion progressively develops, starting from an early non-scarring to late scarring alopecic patch, and may be pruritic, tender, or asymptomatic (Fig. 1a). Follicular red dots are the most characteristic sign on trichoscopy. Additional trichoscopic findings are large yellow dots, thick arborizing vessels, scattered dark-brown discoloration, and blue-gray dots forming a speckled pattern (Fig. 1b) [14 16]. On histopathology, basal vacuolization of the epidermis and follicular epithelium (Fig. 1c), perieccrine and perivascular lymphocytic infiltration, and increased dermal mucin are typically seen. These findings are specific to LE. On DIF, granular deposits of mainly immunoglobulin (Ig) G and C3 along the dermoepidermal junction (DEJ) and follicular epithelium are noted (Fig. 1d). However, even in clear-cut DLE cases, DIF can be negative [17] Differential Diagnosis DLE on the scalp must be differentiated from other conditions that can cause scarring alopecia. Lichen planopilaris (LPP), a form of lichen planus on the scalp, also occurs more often in women and presents with perifollicular erythema, scale, and scarring. Variants of LPP include frontal fibrosing alopecia, a condition that affects the anterior hairline of postmenopausal women, and Graham Little syndrome, in which scarring alopecia of the scalp is accompanied by non-scarring alopecia of the axillary and pubic regions and spinous follicular papules on the body [18, 19]. Trichoscopic examination reveals discrete white dots, a distinguishing sign of LPP that signifies the loss of melanin over perifollicular fibrotic tracts. The process of fibrosis is relatively more diffuse in DLE, resulting in an appearance of milky red or white areas between the follicles [20]. Blue-gray dots in a target pattern are found in LPP, while a speckled pattern suggests DLE [16]. Nevertheless, the diagnosis of LPP can sometimes be made on clinical grounds alone, however confirmatory histology sections showing lichenoid infiltration along the follicular epithelium or colloid bodies may be required in case of doubt. Other differential diagnoses in the scarring alopecia group are central centrifugal cicatricial alopecia, Brocq s alopecia, and alopecic patches from morphea. At times, early DLE may share similar clinical features with AA as both conditions are localized and well-defined. Patchy, non-scarring alopecia in SLE, a form of hair loss classified as LE-specific and providing similar histopathological and DIF features as DLE, should also be included in the differential diagnosis Relationship with SLE/Correlation with Disease Activity The risk of SLE in patients with DLE is relatively small (approximately 5 15%) [21 24], but may be higher when the lesions are below the head and neck, or when periungual telangiectasias, arthritis, or abnormal laboratory results are noted, including high titer antinuclear antibodies (ANA), leukopenia, anemia, and persistently elevated ESR rate [25]. Conversely, among SLE patients, % developed DLE [26, 27]. The presence of DLE has been inconclusively linked with a more benign systemic disease, having been associated with a significantly decreased risk of arthritis and pleuritis in one cohort and a lower risk of end-stage renal disease in the other [26, 27] Treatment and Prognosis With DLE, prompt diagnosis and treatment are the key, and physicians should bear in mind that once the scarring process has fully involved the hair follicles, hair loss is permanent. Photoprotection with sunscreens, and smoking cessation, may play a role in the prevention of new lesions [28, 29]. When detected early, DLE lesions respond well to oral antimalarial medication and potent topical, oral, and intralesional corticosteroids. Topical calcineurin inhibitors are also considered first-line treatment, especially on the area of thinned skin or where skin atrophy from the disease is already evident, although longer treatment duration may

4 S. Udompanich et al. Table 2 Clinical presentation, investigation, treatment, and prognosis of alopecia in SLE Discoid lupus erythematosus [19 21] Classic lupus panniculitis/lupus profundus [33, 34] Diffuse non-scarring alopecia in SLE [2] Clinical features Erythematous plaque with epidermal atrophy, plugged follicular ostia, central hypopigmentation, and peripheral hyperpigmentation Tender indurated plaques of scarring alopecia with erythema Diffuse hair loss, can be severe ([50% of the scalp surface area), positive hair-pull test Trichoscopic features Follicular red dots, large yellow dots, thick arborizing vessels, scattered dark-brown discoloration, blue-gray dots forming a speckled pattern, milky red or white areas between the follicles Pathology Basal vacuolization of the epidermis and follicular epithelium, perieccrine and perivascular infiltration, increased dermal mucin Large yellow dots, black dots, short vellus hairs, thick arborizing vessels, diffuse erythema between the follicles Same as DLE for lupus profundus Lobular panniculitis with hyaline necrosis and predominantly lymphoplasmacytic infiltration Scaling, perifollicular telangiectasia, hair shaft hypopigmentation, increased number of vellus hair, focal atrichia Epidermal atrophy with focal liquefaction degeneration of basal cells, thickening of the basement membrane, pigment incontinence, increased catagen/ telogen to anagen ratios and mild focal perivascular and perifollicular lymphocytic infiltrates Direct immunofluorescence Granular deposition of IgG, IgM and C3 at the DEJ and/or the junction of the follicular epithelium and dermis Granular deposition of IgG and C3 at the DEJ and/or the junction of the follicular epithelium and dermis IgG, C3, C1q, Fg, IgA, IgM along the epidermal basal membrane Patchy, non-scarring alopecia in SLE [47, 48] Alopecic patches, oval or irregular in shape, mostly with incomplete hair loss, and erythema, and sometimes with scales Hair can be thin and hypopigmented Telangiectasia (mostly polymorphous interfollicular), hair shaft hypopigmentation, hair shaft thinning, honeycomb pigment pattern Atrophy of the epidermis, hyperkeratosis, focal liquefaction degeneration of epidermal basal cells, incontinence of pigment in the dermis, dermal mucin, perivascular/perieccrine inflammation, peribulbar mononuclear cell infiltration (denser than AA), decreased anagen-to-telogen ratio Epidermal nuclear staining and homogenous granular deposition of IgG, IgM and C3 along the DEJ and follicular epithelium Lupus hair [54, 55] Linear and annular lupus panniculitis of the scalp [57 59] Short, coarse, dry, and lustreless hair along the anterior hairline; disheveled appearance Linear/annular/arcuate non-scarring alopecia along Blaschko s line Thin erythematous plaques and mild tenderness Hair shaft thinning, hair shaft hypopigmentation, interfollicular telangiectasia Numerous thick arborizing vessels, patchy erythematous areas, large yellow dots, black dots, perifollicular white scales Focal basal vacuolization, melanophages, sparse superficial vascular lymphocytic infiltration Granular deposition of IgG along the follicular epithelium Epidermis: often unremarkable, some basal vacuolar degeneration and epidermal atrophy Dermis: dense perifollicular lymphocytic infiltration, especially peribulbar area, superficial and deep perivascular and perieccrine lymphocytic infiltration Subcutaneous tissue: hyaline degeneration of fat, fat necrosis, abundant mucin deposition Granular deposition of IgM, IgG, C3 along the basement membrane or follicular epithelium DIF can also be negative

5 Hair and scalp changes in cutaneous and systemic LE Table 2 continued Lupus hair [54, 55] Linear and annular lupus panniculitis of the scalp [57 59] Patchy, non-scarring alopecia in SLE [47, 48] Diffuse non-scarring alopecia in SLE [2] Classic lupus panniculitis/lupus profundus [33, 34] Discoid lupus erythematosus [19 21] Can be found in SLE patients or healthy individuals Found exclusively in SLE, mostly in active disease Found exclusively in SLE, mostly in active disease Positive ANA titer is common (85 95%), but risk of SLE is 10 50% Can be found in SLE or healthy individuals Association with SLE/ SLE disease activity 5 15% risk of SLE Lower risk of developing SLE than typical lupus panniculitis/profundus Found exclusively in SLE, mostly in active disease, and persists for longer after SLE remission Higher risk with generalized DLE AA, morphea (en coup de sabre), lipedematous alopecia, SPTL Hair abnormalities found in hypothyroidism AA, syphilitic alopecia, psoriatic alopecia Telogen effluvium, anagen affluvium, androgenetic alopecia, diffuse AA Morphea, traumatic panniculitis, SPTL Differential diagnosis AA, lichen planopilaris, morphea, central centrifugal cicatricial alopecia, Brocq s alopecia Treatment for SLE Treatment for SLE Treatment for SLE Hydroxychloroquine, prednisolone, intralesional corticosteroids Oral antimalarials, topical/oral/ intralesional corticosteroids Treatment Oral antimalarials, topical/oral/ intralesional corticosteroids Often complete remission without recurrence Persists even after SLE treatment Reversible, resolved after improvement of SLE Reversible, resolved after improvement of SLE Prognosis Hair loss permanent Chronic, relapsing nature ANA antinuclear antibodies, C1q complement component 1q, C3 complement component 3, DEJ dermoepidermal junction, DIF direct immunofluorescence, DLE discoid lupus erythematosus, Fg fibrinogen, Ig immunoglobulin, SLE systemic lupus erythematosus, SPTL subcutaneous panniculitis-like T-cell lymphoma be required when compared with topical corticosteroids [30]. Other treatment modalities with limited supporting evidence include methotrexate, topical and systemic retinoids, dapsone, thalidomide, and mycophenolate mofetil. Severe cases may benefit from rituximab, ustekinumab, and intravenous IG (IVIG). Potential novel therapies, including various biologics, are currently under investigation [30]. 3.2 Lupus Panniculitis/Lupus Profundus Clinical Presentation, Trichoscopic, Histopathological, and DIF Features Lupus panniculitis is chronic inflammation of subcutaneous tissue caused by LE. This rare type of chronic cutaneous LE only features in 2 3% of the group of patients with lupus panniculitis. Overlying DLE is found in approximately one-third of patients, and together the lesion is termed lupus profundus [31]. Lupus panniculitis/profundus occurs predominantly in young women. The tender indurated erythematous subcutaneous nodules or plaques appear most frequently on the face, arms, hips, and trunks (Fig. 2a). Trichoscopic features have not been reported in previous publications. Regarding our experience, large yellow dots, black dots, short vellus hairs, thick arborizing vessels, and diffuse erythema on the interfollicular areas can be observed under trichoscopy. Without proper management, the lesion can progressively become atrophic and disfiguring. Scalp involvement was reported in up to 16.4% of cases, typically resulting in scarring alopecia [32, 33]. An unusual presentation was reported in the form of sclerodermic linear lupus panniculitis [34]. As opposed to classic lupus panniculitis lesions, the invasion of subcutaneous tissue of the scalp by LE may manifest as linear, arcuate, or annular patches along the suspected Blaschko s lines of the scalp. This condition is termed linear lupus panniculitis of the scalp (LLPS) or linear and annular lupus panniculitis of the scalp (LALPS). In contrast to classic lupus panniculitis, the alopecia is non-scarring and reversible. Further information on this condition is discussed later in this review. Pathology section of lupus panniculitis shows lobular panniculitis with hyaline necrosis and predominant lymphoplasmacytic infiltration, occasionally forming lymphocytic aggregation and lymphoid follicles (Fig. 2b) [35]. Furthermore, the presence of overlying skin changes resembling DLE can aid the diagnosis. In a retrospective review of biopsy specimens, thickening of the basement membrane, basal vacuolization, and pigment incontinence were evident, even in cases that displayed no epithelial changes clinically [32]. A majority of lesions stain positive on DIF, with granular deposition of IgM and C3 at the DEJ

6 S. Udompanich et al. Fig. 1 Discoid lupus erythematosus. a Two focal areas of round plaques, the right showing adherent scale with follicular plugging, and the left showing central atrophy. b Trichoscopic features of discoid lupus erythematosus: follicular red dots, thick arborizing vessels, scattered dark-brown discoloration, and milky red or white areas between the follicles (original magnification 920). c Histological section showing thickened basement membrane, focal basal vacuolization along the dermoepidermal junction and follicular epithelium; perifollicular lymphocytic infiltration is seen (hematoxylin and eosin stain; original magnification 940). d Direct immunofluorescence staining of immunoglobulin M showing thick homogenous granular deposition along the basement membrane and follicular epithelium or around blood vessels [35]. Additional investigations for lupus panniculitis include immunophenotyping, molecular analysis, and polymerase chain reaction analysis of the T-cell receptor-c gene rearrangement [36] Differential Diagnosis Fig. 2 Lupus panniculitis/profundus on the scalp. a Localized, welldefined erythematous indurated plaque behind the left ear, with extension to the left posterior hairline, causing scarring alopecia. b Lobular panniculitis with predominantly lymphohistiocytic infiltration and hyaline necrosis (hematoxylin and eosin stain; original magnification 910) Once lupus panniculitis is suspected, the most important condition to rule out is subcutaneous panniculitis-like T-cell lymphoma (SPTL) as the condition associates with a higher risk of morbidity and mortality. In a study comparing 13 SPTL patients with 7 lupus panniculitis patients, SPTL more frequently involved the lower extremities, buttocks, and scalp [37]. A common perception in the past was that atypical lymphocytes, rimming of fat lobules, and abnormal T-cell receptor gene rearrangement were sufficient differentiating factors; however, recent studies have reported overlapping features between the two conditions [32]. Recently, Ki-67 hot spots were detected in SPTL only, but never in lupus panniculitis, thus providing a

7 Hair and scalp changes in cutaneous and systemic LE useful differentiating tool [37]. Other forms of panniculitis such as traumatic panniculitis or panniculitis associated with morphea and dermatomyositis can affect the scalp Relationship with SLE/Correlation with Disease Activity In a review of 44 cases of lupus profundus, abnormal positive ANA titers were detected in up to 95.2% of patients; however, these positive ANA results were of varying strength and even the lowest ANA titers were considered positive [32]. Other possible abnormal laboratory findings are leukopenia, hypocomplementemia, circulating rheumatoid factors, and increased ESR. The final diagnosis of SLE with fulfilled criteria is only made in 10 50% of cases [32, 33, 38 40] Treatment and Prognosis Due to its rarity, studies focusing on treatment and their outcome are lacking. In clinical practice, the mainstay treatment for lupus panniculitis/profundus is antimalarials. Systemic corticosteroids, methotrexate, and dapsone are added when the disease cannot be controlled by antimalarials alone, or when there is association with SLE. Intralesional corticosteroids could be considered as a treatment option in selected cases due to the risk of skin atrophy [40]. Most patients respond well to treatment but are likely to suffer from relapse after treatment discontinuation [36]. 4 Non-Scarring Alopecia in SLE The description of non-scarring alopecia in SLE in the SLICC criteria is rather unspecific and refers mainly to diffuse hair loss [41]. However, the accumulation of research studies has pointed out that non-scarring alopecia in SLE can in fact manifest as different clinical patterns, with variable risk of systemic disease. Figure 3 offers approach considerations for non-scarring alopecia in SLE. 4.1 Diffuse Non-Scarring Alopecia in SLE Clinical Presentation, Trichoscopic, Histopathological, and DIF Features Diffuse non-scarring hair loss is the most frequently observed type of alopecia in SLE, potentially reflecting a patient s disease activity [4, 42]. While altered immune status, ongoing physical stress, and a vigorous medication regimen can indirectly result in diffuse hair loss (in the form of telogen effluvium or anagen effluvium), recent research has suggested that the diffuse hair loss may be a direct result of SLE activity on the scalp. Gong et al. reported on four SLE patients with severe diffuse nonscarring alopecia, involving more than 50% of the scalp surface area [2]. All four patients were women with active SLE flare-up, and, on physical examination, all had scalp erythema, scaling, and a positive gentle hair pull test. Trichoscopic examination revealed scalp changes, including scaling, telangiectasia, and focal atrichia. The hair shafts were segmentally hypopigmented with uneven diameter. These heterogeneous findings have led to speculation that damage to the hair matrix and dermal papillae in SLE may be a selective process. Histopathological findings in all four cases revealed epidermal atrophy with focal basal vacuolization, thickening of the basement membrane, pigment incontinence, increased catagen/telogen-to-anagen ratio, and mild perifollicular and perivascular lymphocytic infiltration. DIF revealed IgG and C3 in three cases, and IgM and IgA in one case. All four patients received treatment according to their disease severity, and all achieved complete hair regrowth without recurrence [2]. From our experience, the extent of hair loss varies tremendously from patient to patient, and even in the same patient at different points in time. During the follow-up period when the disease is quiescent, most patients still complain of some degree of hair loss, and physical examination indeed revealed diffuse thinning (Fig. 4a), with sparse to abundant interfollicular telangiectasia on trichoscopy (Fig. 4b). It is possible that some background SLE activity is always present on the scalp, and gradual accumulation of inflammation along certain hair follicles is enough to shorten the anagen phase or induce anagen arrest. However, the correlation with SLE exacerbation seems to exist only when the alopecia is severe, often involving more than 50% of the scalp surface area. This may represent a vigorous and synchronized attack on the hair follicles. Histopathological findings demonstrate specific LE changes (Fig. 4c). In addition, there is usually an increased percentage of the catagen/telogen-to-anagen ratio, suggesting that SLE has a predilection for anagen hair, in a similar manner to AA, which is also an autoimmune condition. DIF further supports the diagnosis of cutaneous LE, with homogenous or focal granular deposition of mainly IgG and C3 along the DEJ and follicular epithelium (Fig. 4d). Other important forms of non-scarring alopecia in SLE are telogen effluvium and anagen effluvium. Both conditions appear simultaneously with SLE exacerbation, and its vigorous management occurs simultaneously. As these conditions relate to SLE, but do not exhibit specific LE changes on histopathology, we propose they are classified as LE non-specific alopecia. Telogen effluvium is an increase in normal telogen hair shedding, occurring

8 S. Udompanich et al. Fig. 3 Approach considerations for non-scarring alopecia in SLE. SLE systemic lupus erythematosus, AA alopecia areata approximately 3 6 months after a precipitating event. In SLE, it is likely that telogen effluvium results from severe catabolic effects and elevated levels of circulating proinflammatory cytokines around the hair follicles [42]. Drugs used in SLE have been reported to cause telogen effluvium, including chloroquine, hydroxychloroquine, acitretin, azathioprine, cyclosporine and dexamethasone [43]. On examination, diffuse non-scarring alopecia is mild but may be accompanied by some short regrowing hairs. The severity of hair loss can be a convenient discriminating factor as when there is more than 50% hair loss, telogen effluvium is unlikely. On trichoscopy, empty hair follicles and numerous short regrowing hairs are the most common findings [44], while histopathology reveals normal total hair count, normal number of terminal hairs, and increased telogen count to more than 20% in the absence of any inflammation or scarring [20]. Anagen effluvium is caused by the direct insult of chemotherapy on the rapidly dividing hair follicle cells in the anagen phase, leading to sudden arrest of mitotic activity [45]. Hair shedding begins 1 3 weeks after initiation of chemotherapy, and, since 90% of scalp hair is in the anagen phase, patients can experience extensive hair loss [46]. However, the process is reversible and hair tends to grow back in 3 6 months after chemotherapy cessation. Cyclophosphamide, an alkylating agent frequently used during SLE flare-ups, can cause anagen effluvium in more than 60% of patients [46]. Another possible mechanism in SLE patients is that severe disease exacerbations can trigger a temporary shutdown of the follicular stem cells and hair matrix cells [42] Differential Diagnosis Other forms of non-scarring alopecia must be considered, namely androgenic alopecia and diffuse AA. History and physical examination are usually sufficient; for example, the chronic onset and specific pattern of hair loss in androgenic alopecia are familiar to dermatologists. Diffuse AA is sometimes difficult to diagnose clinically or trichoscopically. Scalp biopsy for horizontal and vertical sections can help to establish the diagnosis Relationship with SLE/Correlation with Disease Activity This type of non-scarring alopecia was initially observed and recognized in patients with SLE and therefore is exclusive to the disease. In severe cases with more than 50% hair loss, the correlation with disease activity is almost definite [2]. However, as the condition may be underrecognized, studies on its true relation with SLE disease activity are lacking. Patients from previous studies have complained of malar rash, oral ulcers, photosensitivity, and other extracutaneous symptoms of SLE [2]. In addition to these manifestations, our patients with severe diffuse hair loss were admitted with class V lupus nephritis and neuropsychiatric symptoms.

9 Hair and scalp changes in cutaneous and systemic LE Fig. 4 Diffuse non-scarring alopecia in systemic lupus erythematosus. a Mild diffuse non-scarring alopecia and severe diffuse nonscarring alopecia. b Trichoscopic examination showing hair shaft thinning and numerous interfollicular arborizing telangiectasia (original magnification 920). c Epidermal atrophy, basal vacuolization along the basement membrane and follicular epithelium with Treatment and Prognosis Treatment of SLE itself is usually sufficient and no progression of hair loss is noted after 2 3 weeks of treatment. Prominent hair regrowth was observed after 7 8 weeks and all patients eventually achieved complete hair regrowth without any recurrence [2]. 4.2 Patchy, Non-Scarring Alopecia in SLE Clinical Presentation, Trichoscopic, Histopathological, and DIF Features During the initial presentation of SLE or at the time of disease exacerbations, localized, well-defined patches of partial or total hair loss may appear on the scalp. Closer inspection of the lesion reveals no evidence of scarring, only mild erythema and yellow scale [47]. The hair shafts themselves are thin and hypopigmented, suggesting a direct insult to the hair follicles (Fig. 5a). This form of alopecia is melanophages and superficial perivascular lymphohistiocytic infiltration (hematoxylin and eosin stain; original magnification 940). d Direct immunofluorescence showing homogenous granular deposition of immunoglobulin M along the basement membrane, and homogenous granular deposition of complement 3 along the follicular epithelium fairly common, contributing up to 15% of alopecia in SLE, but has so far received little attention in the literature [4]. Trichoscopic examination of the hair loss region not only confirms hair shaft thinning and hypopigmentation but also exhibits unique scalp changes such as polymorphous telangiectasia located in the interfollicular area (Fig. 5b) [48]. It was speculated that the visible angiotelectasis is caused by local vasculitis, and that the pathology may result in local inflammation of hair follicles and consequent hair loss. Similar to the diffuse form, histological examination of patchy alopecia in SLE shows epidermal atrophy, focal basal vacuolar degeneration in the epidermis and follicular infundibula (Fig. 5c), perieccrine and perivascular lymphoplasmacytic inflammation, and increased dermal mucin. Deep perifollicular inflammation and an increased catagen/telogen percentage in the affected areas was also documented. In our opinion, the pathophysiology of patchy, non-scarring alopecia in SLE may be similar to those of severe diffuse type, and that a synchronized and intense attack on the hair follicles is involved, but in this case the

10 S. Udompanich et al. Fig. 5 Patchy, non-scarring alopecia in systemic lupus erythematosus. a Solitary, welldefined non-scarring alopecia on the left vertex. b Trichoscopic features showing hair shaft thinning and hypopigmentation, along with multiple interfollicular telangiectasia on the scalp (original magnification 920). c Lymphocytic infiltration and basal vacuolization of the follicular epithelium (hematoxylin and eosin stain; original magnification 960). d Direct immunofluorescence staining of immunoglobulin M showing thick homogenous granular deposition along the basement membrane and follicular epithelium inflammation is concentrated in one region. To date, no data have been reported on the DIF findings of this condition. From our experience, DIF from the non-scarring alopecic patch resembles those of acute cutaneous LE. Epidermal nuclear staining and homogenous granular deposition of IgG, IgM, and C3 along the DEJ and follicular epithelium were observed (Fig. 5d) Differential Diagnosis In clinical practice, when localized non-scarring alopecia is encountered, the main differential diagnosis is AA. Werth et al. examined a cohort of 39 patients with DLE and mild SLE, and found the incidence of AA to be higher than general dermatologic patients (10 and 0.42%, respectively) [49]. Biopsies taken from the alopecic patches were concluded to be consistent with AA, with an increased number of catagen hairs and lymphocytic infiltration along fibrous tracts and hair follicles. However, DIF studies showed homogenous granular deposition of IgG or IgM along the DEJ, which was absent on normal scalp specimens taken from the same patient. This finding strongly suggests LE activity on the alopecic patch. Subsequent publications believe that the coexistence between SLE and AA was merely an incidental finding and that clinicians may have misdiagnosed patchy alopecia in SLE as AA [50]. The pathophysiological process of patchy, non-scarring alopecia in SLE is still controversial, whether the condition is one of the hair loss presentations from SLE or coexistent AA. Due to this inconclusive relationship, we propose that AA falls into the group of non-specific LE. Moreover, the pathological discriminating features for both conditions are unclear. Sperling et al. believed that the peribulbar mononuclear cell infiltrate found adjacent to the anagen hair bulb is denser in SLE, when compared with AA [47]. The percentage of catagen and telogen hairs is greatly increased [51]. On the contrary, a recent comparative study of 21 patients with non-patchy alopecia in SLE and 21 AA patients concluded that while AA lesions were characterized by the usual swarm of bee-like lymphocytic inflammations around the hair follicles, this feature is absent in SLE patients. The study reported specific trichoscopic features, including exclamation mark hairs, black dots, and broken hairs, which were only found in AA lesions. The study also reported peripilar signs and perifollicular red dots as specific trichoscopic features of patchy, non-scarring alopecia in SLE, thus providing useful clues for the differential diagnosis [48]. In general, further studies are required to draw definite conclusions on their histological differences, but clinicians should always rule out the possibility of AA whenever diagnosing patchy alopecia in SLE. Both clinical and histological features of patchy alopecia in SLE may also resemble hair loss found in secondary syphilis. Syphilitic alopecia can be diffuse or localized, but the most common pattern has been described as motheaten, with multiple small areas of non-scarring alopecia with an irregular, poorly defined border [52]. Trichoscopy

11 Hair and scalp changes in cutaneous and systemic LE shows yellow dots, black dots, a reduced number of terminal hairs, and intense red-brown pigmentation [52, 53]. On histology, lymphohistiocytic inflammatory infiltrate with abundant plasma cells surrounds the fibrous streamer and the bulb [54]. Distinguishing features between syphilitic alopecia and AA have long been a subject of debate as some believe the presence of plasma cells and the absence of eosinophils are highly suggestive of syphilitic alopecia [54]. Some histological features may help to distinguish SLE from its histological mimics, such as increased dermal mucin, perieccrine lymphocytic infiltration, and focal basal vacuolization of the hair follicles [51]. Now that patchy alopecia in SLE has been increasingly recognized, it should also be added into the frame. Finally, an early form of DLE may present as localized, non-scarring alopecic patches on the scalp in which, without any treatment, epithelial changes and scarring alopecia will inevitably pursue. Whether non-scarring, patchy alopecia in SLE is the same entity as early DLE is questionable, especially when DLE is regarded as biphasic, causing non-scarring alopecia in the beginning and irreversible scarring alopecia later on. However, the fact that patchy, non-scarring alopecia in SLE occurs abruptly and most predominantly in severe uncontrolled SLE cases has marked resemblance with AA, and acute LE changes on pathology/dif indicates that the condition may be more comparable to acute cutaneous LE, rather than DLE Relationship with SLE/Correlation with Disease Activity The condition is exclusive to SLE. There is currently no documentation on non-scarring alopecic patches, with LE features on histopathology, occurring outside the context of SLE. The correlation with disease activity is not confirmed, but most literature regards the condition as a marker for severe, uncontrolled disease [47] Treatment and Prognosis Similar to the diffuse form, patchy, non-scarring alopecia is reversible after treatment of SLE. An increase in vellus hair is the earliest sign that emerges, while hair shaft hypopigmentation is the earliest feature to disappear, followed by the disappearance of telangiectasia [48]. 4.3 Lupus Hair Clinical Presentation, Trichoscopic, Histopathological, and DIF Features Originally proposed by Armas-Cruz et al. in 1958, lupus hair is used to describe a distinct pattern of non-scarring alopecia in chronically active SLE patients [55]. Lupus hair can be detected most frequently along the anterior hairline, the hair appears short, fragile, coarse and dry, and sometimes mild erythema is present in the background (Fig. 6a). Hair growth is speculated to be retarded, producing a disheveled appearance. Other peripheral scalp regions can also be affected but may be less obvious. Hair abnormalities described in lupus hair do not always demonstrate hair loss; however, in most cases, this change of hair structure associates with non-scarring alopecia. The incidence ranges from 10.7 to 30% of all SLE patients. Although lupus hair manifests in a number of patients with active SLE, this condition is still not definitively defined. Trichoscopic, histopathologic, and DIF features of lupus hair are still unknown. Only microscopic examination of lupus hair from the front hairline has been reported, revealing a pointed end, which suggested hair growth retardation [56]. In our SLE clinics, we have come across numerous patients with short, brittle hair along their frontal hairline. Hair shaft thinning, hair shaft hypopigmentation, broken hairs, and interfollicular telangiectasia were apparent on trichoscopic examination (Fig. 6b). These findings are consistent with other forms of non-scarring alopecia in SLE. A biopsy taken from our patient revealed focal basal vacuolization along the DEJ, and sparse superficial perivascular lymphocytic infiltration (Fig. 6c). On DIF, granular deposition of IgG along the follicular epithelium was observed (Fig. 6d) Differential Diagnosis The coarse, dry, and dull appearance of lupus hair can resemble hair abnormalities found in patients with hypothyroidism [55]. The receding hairline may need to be differentiated with androgenetic alopecia, as well as frontal fibrosing alopecia. Both conditions do not present brittle hairs, which can be examined by performing a tug test. Scalp biopsy for horizontal and vertical sections should be performed, especially in controversial cases. A recent report of two cases of histopathologically proven frontal fibrosing alopecia-like cutaneous LE stressed the importance of skin biopsy [57]. Other differential diagnoses belong in the group of acquired hair shaft disorders associated with increased hair fragility, such as trichorrhexis nodosa or bubble hair, a condition that is caused by hair weathering Relationship with SLE/Correlation with Disease Activity Lupus hair is a distinct finding of SLE that correlates with severe and chronic disease [42]. A previous study found that in all patients, the development of lupus hair coincided with clinical and laboratory evidence of disease activity;

12 S. Udompanich et al. Fig. 6 Lupus hair. a Frontal hairline recession with short, coarse, dry, and lustreless hair. b Trichoscopic examination of the frontal hairline showing hair shaft thinning and hypopigmentation; mild scalp erythema is seen in the background (original magnification 920). c Thickened basement membrane with a few scattered necrotic keratinocytes in the epithelium; mild focal basal vacuolization along the dermoepidermal junction with melanophages below; and mild superficial perivascular lymphocytic infiltration (hematoxylin and eosin stain; original magnification 940). d Direct immunofluorescence staining of immunoglobulin G showing homogenous granular deposition along the follicular epithelium however, the details of this clinical and laboratory evidence, as well as the statistical evaluation for this correlation, were omitted [56] Treatment and Prognosis After adequate treatment of SLE flare-up, patients hair and scalp may return to normal. Nonetheless, lupus hair tends to persist for longer and can be present even when alopecia has resolved [56]. 4.4 Linear and Annular Lupus Panniculitis of the Scalp Clinical Presentation, Trichoscopic, Histopathological, and DIF Features LALPS was first reported by Nagai et al. in 2003 [58]. The condition represents a unique type of alopecia which, despite affecting the subcutaneous tissue, is non-scarring and always reversible. This rare entity exists in only 10 cases reported from different parts of the world, predominantly from East Asia, hence its true incidence is unknown. Patients present with long-standing peculiar linear, annular, or arc-shaped patches of non-scarring alopecia along the suspected Blaschko s line of the scalp. At times, the patch may evolve into erythematous plaque with mild tenderness, but signs of DLE such as skin atrophy and sclerotic changes are usually absent (Fig. 7a). Reported trichoscopic features include yellow dots, perifollicular white scales, and some patchy erythematous areas [59]. In addition to these features, we observed numerous thick arborizing vessels, large yellow dots, and black dots in our patients. On histology, the abnormality is confined to the subcutaneous tissue. The epidermis is often unremarkable, although basal vacuolar degeneration and epidermal atrophy can still be present. The dermis shows dense perifollicular, perivascular, and perieccrine lymphocytic infiltration, while the subcutaneous tissue resembles that of lupus panniculitis, showing lobular lymphocytic infiltration (Fig. 7b), hyaline fat degeneration, fat necrosis, and abundant mucin deposition. DIF from previous cases showed granular deposition of IgG or IgM along the basement membrane and at the peribulbar area. In some cases, DIF was negative for all IGs and C3 [60]. A plausible explanation for its non-scarring nature could be that the pathology is concentrated deep down the hair follicles, well below the stem cells reservoir. Alternatively, it is possible that we regard the condition as non-scarring because it has always been detected and treated early, as alopecia is an alerting early sign that typically results in patients seeking prompt consultation. A report of sclerodermic linear lupus panniculitis in two cases, both with long-standing clinical course, supports the relationship between disease duration and the scarring process [34]. It is unclear why these lesions follow the lines of Blaschko, in which the exact pattern on the head and neck is unknown. Nevertheless, it has been hypothesized that linear

13 Hair and scalp changes in cutaneous and systemic LE patients had recurrence on the same or different parts of the scalp. 5 Miscellaneous Findings Fig. 7 Linear and annular lupus panniculitis of the scalp. a Linear non-scarring alopecic patch in a bizarre configuration. b Lobular panniculitis with lymphocytes and deep lymphocytic infiltration surrounding a hair follicle (hematoxylin and eosin stain; original magnification 910) cutaneous eruptions occur as a result of a genetically programmed cloning of cells along Blaschko s lines during early embryogenesis [34] Differential Diagnosis LALPS should be differentiated from morphea en coup de sabre, although the latter typically presents with scarring sclerotic plaques. AA and trichotillomania may produce non-scarring alopecia with bizarre configurations. In addition, whenever there is lymphocytic involvement of subcutaneous tissue, SPTL must be ruled out. As mentioned above, the classic form of lupus panniculitis on the scalp is usually scarring, and does not follow the lines of Blaschko. In comparison to the classic form, LALPS occurs in a younger age group, and has a higher frequency of male patients and lower rate of association with SLE [60] Relationship with SLE/Correlation with Disease Activity LALPS most likely occurs as an isolated cutaneous lesion, and development of SLE is probably the rarest among all types of alopecia. Approximately 50% of patients had a positive ANA test, but a final diagnosis of SLE has not been reported Treatment and Prognosis Oral hydroxychloroquine and oral and intralestional corticosteroids were the treatment of choice. A majority of patients achieved complete recovery within 1 year. Few Secondary cutaneous lesions related to SLE can involve the scalp. For example, accumulation of mucin around hair follicles and sebaceous glands can lead to papulonodular mucinosis. Up to 79% of the disease associates with SLE [61]. When these lesions appear on the scalp, diffuse nonscarring alopecia can follow and, if left untreated, can result in scarring and irreversible hair loss [62]. This condition is termed alopecia mucinosa, or follicular mucinosis. Basaloid follicular hamartoma is a form of follicular alteration that has been reported to associate with SLE and can also present on the scalp [63 65]. Clinically, patients present with multiple follicular papular lesions, along with diffuse non-scarring alopecia. Aggregation of basaloid cells can be seen on histology, similar to those found in trichoepitheliomas [63, 65]. In a case report by Smith and Skelton, oral and topical retinoids proved to be beneficial [63]. Other miscellaneous findings include diffuse dystrophic calcinosis cutis on the scalp following the development of DLE, and scarring alopecia in a patient with long-standing SLE [66]. This is a rather rare phenomenon as dystrophic calcinosis cutis normally occurs in systemic sclerosis and juvenile dermatomyositis. Morphea and cutaneous LE developing in the same lesion has been reported in previous literature [34, 67 74]. Possible mechanisms are that both diseases coexisted or that one evolved into the other; however, there are no reports of such combinations on the scalp. Finally, it is important to bear in mind that SLE can alter hair quality without any hair loss. Seyahi et al. quantitatively compared the hair thickness of SLE patients with that of patients with rheumatoid arthritis, as well as healthy controls [75]. The mean hair diameter in SLE patients was significantly lower than that of healthy controls, even after age-adjusted analysis. Among the SLE group, no differences in hair diameter were seen in patients using azathioprine/cyclophosphamide and corticosteroids when compared with patients who were not using those agents. This finding eliminates the effect of a drug as a confounder. However, no difference was seen between SLE and rheumatoid arthritis, suggesting that the apparent reduction in hair diameter could have reflected the state of being ill. Hair shaft hypopigmentation is not uncommon in our SLE clinics. A valid explanation could be the effect of chloroquine. However, a majority of our patients are taking hydroxychloroquine, for which reports of hair hypopigmentation are exceedingly rare. Hair lightening after