Papulo-Nodular Reactions in Black Tattoos as Markers of Sarcoidosis: Study of 92 Tattoo Reactions from a Hospital Material

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1 Tattoo and Body Art Original Paper Received: June 27, 216 Accepted after revision: November 8, 216 Published online: February 7, 217 Papulo-Nodular Reactions in Black Tattoos as Markers of Sarcoidosis: Study of 92 Tattoo Reactions from a Hospital Material Mitra Sepehri a Katrina Hutton Carlsen b Jørgen Serup b a Wound Healing Centre, and b The Tattoo Clinic at the Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark Keywords Tattoo complication Granuloma Papulo-nodular reaction Sarcoidosis Rush phenomenon Pigment overload Black Ink Abstract Background/Aims: Sarcoidosis is, from historical data, suggested to be more prevalent among patients with tattoo reactions. We aimed to evaluate this association in a systematic study. Methods: This is a consecutive study of patients with tattoo complications, diagnosed in the Tattoo Clinic at Bispebjerg University Hospital in Copenhagen, Denmark, from 28 to 215, based on clinical assessment and histology. From the overall group of 494 tattoo complications in 46 patients, 92 reactions in 72 patients showed a papulonodular pattern studied for local and systemic sarcoidosis, since sarcoidosis is expected to be nodular. Results: Of the 92 reactions with a papulo-nodular pattern, 27 (29%) reactions in 19 patients were diagnosed as cutaneous or systemic sarcoidosis, supported by histology; 65 (71%) were diagnosed as non-sarcoidosis due to histology and no clinical sarcoid manifestations. Rush phenomenon with concomitant reaction in many other black tattoos, triggered by a recent tattoo with a papulo-nodular reaction, was observed in 7% in the sarcoidosis group and 28% in the non-sarcoidosis group, indicating a predisposing factor which may be autoimmune and linked with sarcoidosis. Agglomerates of black pigment forming foreign bodies may in the predisposed individual trigger widespread reaction in the skin and internal organs. Conclusion: Black tattoos with papulo-nodular reactions should be seen as markers of sarcoidosis. Papulo-nodular reactions may, as triggers, induce widespread reactions in other black tattoos a rush phenomenon depending on individual predisposition. Sarcoidosis is estimated to be 5-fold increased in papulo-nodular reactions compared to the prevalence in the general population, and the association with black tattoos is strong. 217 S. Karger AG, Basel Introduction In this study, we present a large retrospective material of consecutively collected cases of tattoo reactions with cutaneous or systemic sarcoidosis, diagnosed in the Tattoo Clinic at Bispebjerg University Hospital, Denmark. Patients had been remitted from practising dermatologists, other specialists, and their general practitioners. karger@karger.com S. Karger AG, Basel /17/ $39.5/ Mitra Sepehri, MD Wound Healing Centre, Bispebjerg University Hospital Bispebjerg Bakke 23 DK 24 Copenhagen NV (Denmark) hotmail.com

2 Table 1. Papulo-nodular reactions, in a total of 46 patients with 494 tattoo reactions Papulo-nodular reaction, n = 92 (19%) sarcoidosis reaction, n = 27 (29%) cuta neous, tattoo cutaneous and other cutaneous and systemic Reaction 7 (26%) 3 (11%) 17 (63%) Biopsy Inflammation Granulomatous inflammation Sarcoid granuloma 7 7 a 3 3 b 17 1 c 16 d non-sarcoidosis reaction, n = 65 (71%) a One case was verified as sarcoid granuloma in a tattoo on the left hand. On the right hand clinical sarcoid manifestation was also seen and therefore was concluded sarcoid as well. b All 3 cases had erythema nodosum. One punch biopsy also verified sarcoid granuloma in a scar. c One case with known systemic sarcoidosis manifested in lungs and joints. d One punch biopsy verified sarcoid granuloma in a scar on the chin, another biopsy verified sarcoid granuloma on the arm, both in patients with known systemic sarcoidosis. The other cases were verified from tattoo biopsies. Sarcoidosis in a tattoo was reported for the first time in 1939 [1]. From 1939 to 211, Kluger [2] reviewed 61 publications totalling 75 patients with tattoos complicated with sarcoidosis. Manifestations of sarcoidosis were observed in tattoos, scars, and non-tattooed skin, as well as in the eyes and lungs. Sarcoid reactions appeared to be more prevalent in black and red tattoos, but other colours were also involved (e.g. blue, green, and brown). Moreover, sarcoidosis was predominantly observed in males. Autoimmunity was suggested [2]. However, case reports depicted from a broad range of clinics and over many years are obviously subject to variability in the diagnostic evaluation. The hallmark of sarcoidosis is non-caseating epithelioid cell granulomas by histology, but interpretation by pathologists varies [2 4]. Not all tissues affected by sarcoidosis, as exemplified by eye and joint affections, show a pattern of sarcoid granulomas, supporting the hypothesis that autoimmunity is involved. It should be noted that since 1939, colourants, pigments, and tattoo ink stock products underwent a major change away from inorganic pigments to organic pigments such as azo and phthalocyanine chemicals [5, 6]. Modern black pigments are alleged to be produced under more standardised conditions and are different from the old and crude pigments made by simple combustion. Old and newer tattoo inks may easily carry a different risk of sarcoidosis. Difference of ink characteristics may influence their ability to aggregate, agglomerate, and form foreign bodies in tattooed skin. Modern black pigments are essentially nanoparticles [7]. Less dispersible black inks, making visible aggregation in water, were shown to be associated with increased induction of reactive oxygen species (ROS), which may elicit an inflammatory tissue response resulting in sun sensitivity, itching, and minor complaints [8, 9]. It is known that foreign bodies in the skin may stimulate the development of granulomas and even sarcoidosis [1]. From these studies and observations, it is our hypothesis that black pigment, foreign body formation, tissue responses, and sarcoidosis are associated, and this may rely on a general predisposition of the individual to develop sarcoid granulomas and manifestations in various tissues expressing autoimmunity. In our initial publication, Classification of Tattoo Complications in a Hospital Material of 493 Adverse Events, we observed that black pigment and a papulonodular type of tattoo reaction by clinical examination are associated [11]. Sarcoid granulomas are clinically and by shape nodular. In the present study, we address black tattoos and the papulo-nodular type of tattoo reaction assessed versus any potential manifestation of sarcoidosis. Materials and Methods For further details, see the supplementary materials (for all online suppl. material, see [11, 12] (Table 1 ; Fig. 1 ). 68 Sepehri/Hutton Carlsen/Serup

3 Tattoo Clinic raw data collection Consecutive patient intake Patient history (46 with systematic records) Clinical examination (494 tattoo reactions) Biopsy, clinically indicated (26 biopsies) Rush phenomenon* Retrospective assessment of tattoo reactions Based on a published study Classification of Tattoo Complications in a Hospital Material of 493 Adverse Events [11] Consecutive study with focus on papulo-nodular reactions and sarcoidosis Papulo-nodular reactions: 92 reactions (19%) in 72 patients Clinical pattern: Papules or nodules or both, variably distributed in the tattoo, and typically confined to the problem colour, that is typically black. Histological pattern: plain inflammation, granulomatous inflammation or sarcoid granulomas, the latter pattern also associated with inflammation. Sarcoidosis: 27 reactions (29%) in 19 patients Rush: 19 (7%) Non-sarcoidosis: 65 reactions (71%) in 53 patients Rush: 18 (28%) Fig. 1. Flowchart of Materials and Methods. Study flowchart. *Rush phenomenon: a special clinical observation when a newer black tattoo, the trigger, with papulo-nodular reaction preceded the development of similar reactions in any part of the skin affecting other black tattoos. Major rush phenomenon is defined as a rush affecting many other black tattoos, minor rush phenomenon as a rush affecting only a few other tattoos and to a more limited extent. Histology: Sarcoid granuloma, epithelioid cell granulomas, typically without necrosis but with giant cells and epithelioid cells, and with inflammation. Sarcoidosis: cutaneous, tattoo only: 7 reactions (26%) in 6 patients Rush: 3 Sarcoidosis: cutaneous, tattoo, other: 3 reactions (11%) in 2 patients Rush: 2 Sarcoidosis: systemic, tattoo and organ: 17 reactions (63%) in 14 patients Rush: 14 Results In the material of 494 reactions observed in 46 patients, 92 (19%) reactions in 72 patients showed the papulo-nodular pattern. The total group of papulo-nodular reactions was differentiated into the subgroups sarcoidosis and non-sarcoidosis, depending on histopathological findings ( Figure 1 ; Table 1 ). Clinical examples are presented in Figures 2 and 3. Sarcoidosis Of 92 reactions with papulo-nodular pattern, 27 reactions (29%) were diagnosed as sarcoidosis (cutaneous or systemic) in 19 patients. All 27 sarcoid reactions had been verified by punch biopsies and were distributed in 3 subtypes according to clinical findings: 1 Sarcoidosis, cutaneous tattoo only manifested in the tattoo; 7 reactions (26%) in 6 patients. 2 Sarcoidosis, cutaneous, tattoo and other with sarcoidosis in the tattoo associated with other cutaneous manifestations of sarcoidosis but without systemic manifestations; 3 reactions (11%) in 2 patients. 3 Sarcoidosis, systemic tattoo and organ with sarcoidosis in the tattoo associated with major organ affection (i.e., systemic sarcoidosis); 17 reactions (63%) in 11 patients. Papulo-Nodular Reactions in Black Tattoos as Markers of Sarcoidosis 681

4 Fig. 2. Case of papulo-nodular reaction with pigment overload. Fig. 3. Case of papulo-nodular reaction; a well-defined nodule is seen. Fig. 4. Punch biopsy from a papulo-nodular reaction verified by histology; sarcoid reaction with sarcoid granulomas seen as a bunch of grapes. Fig. 5. Case of sarcoidosis, rush phenomenon. None of the patients with sarcoidosis, cutaneous, tattoo or sarcoidosis, cutaneous and other were diagnosed or suspected to suffer from sarcoidosis by the referring doctor. In contrast, 9/17 reactions (53%) in 7 patients in the group sarcoidosis, cutaneous and systemic were already diagnosed as systemic sarcoidosis, typically with pulmonary affection. Figure 4 shows large agglomerates of pigment seen directly by the naked eye and a bunch of grapes surface of the raw punch biopsy, indicating granulomas. Non-Sarcoidosis A total of 65 of 92 (71%) papulo-nodular reactions were clinically diagnosed as non-sarcoidosis ; 27 of these 682 Sepehri/Hutton Carlsen/Serup

5 Table 2. Rush phenomenon observed in the differentiated subtypes of sarcoidosis compared to the non-sarcoidosis group Papulo-nodular group, reaction n = 92 sarcoidosis reaction, n = 27 cuta neous, tattoo cutaneous and other cutaneous and systemic non-sarcoidosis reaction, n= 65 Rush phenomenon, total 3 (11%) 2 (7%) 14 (52%) 18 (28%) Rush phenomenon minor 1 (14%) 2 (67%) 6 (35%) 7 (11%) Rush phenomenon major 2 (29%) (%) 8 (47%) 11 (17%) Table 3. Demographic details, tattoo size, number, type, and colour relative to subgroups: sarcoidosis (n = 19 patients) and non-sarcoidosis (n = 53 patients) Papulo-nodular reaction, n = 92 sarc oidosis reaction, n = 27 non-sarcoidosis reaction, n = 65 Age (range), years 36 (22 52) 3 (19 63) Gender (F/M) F: 7 (37%) M: 12 (63%) F: 31 (58%) M: 22 (42%) Tattoo size Small (<1 cm 2 ) Medium (1 2 cm 2 ) Large (>2 cm 2 ) 2 (29%) 5 (71%) (%) 2 (16%) 5 (42%) 5 (42%) 1 (32%) 14 (45%) 7 (23%) 4 (18%) 14 (64%) 4 (18%) Multiple tattoos 2 tattoos 4/7 (57%) 9/12 (75%) 17/31 (55%) 13/22 (59%) Tattoo by type Professional 24 (89%) 57 (88%) Amateur 2 (7%) 6 (9%) Professional + amateur 1 (4%) Cosmetic Tattoo by colour 2 (3%) Black 2 (74%) 57 (88%) Red 2 (7%) 1 (2%) Other 5 (19%) 7 (11%) non-sarcoid reactions were definitely without sarcoid involvement concerning patient history and had no clinical manifestations. Of the 65 (58%) non-sarcoid reactions, 38 were apprehensive, and therefore punch biopsies were performed. All biopsies showed no evidence of sarcoid granulomas; 17 cases of granulomatous inflammation were seen (see Table 1 ). Pigment Overload In the total material of papulo-nodular reactions, pigment overload was noted in 39/92 (42%) according to clinical assessment, often associated with large-sized granulomas according to histology. Rush phenomenon was seen in all 3 subtypes of sarcoidosis, in total 19/27 (7%). Rush phenomenon was especially common in the cutaneous and systemic subtype and found in 14 of 17 reactions (82%), often manifested as major rush phenomenon ( Figure 5 ). However, rush phenomenon was also observed in non-sarcoid reactions, in total 18/65 (28%) (see Table 2 a, b). Demography, size of tattoo, and number of tattoos ( 2 tattoos) in the group of papulo-nodular reactions are presented in Table 3. The group with sarcoidosis was dominated by males (12/19, 63%). In both subgroups ( sarcoidosis and non-sarcoidosis ), the dominating colour was black (74 and 88%, respectively). There was no strong as- Papulo-Nodular Reactions in Black Tattoos as Markers of Sarcoidosis 683

6 sociation between gender and tattoo size except in the sarcoidosis group, where 42% of males had a large tattoo (compared to % among females) and males often had multiple tattoos ( 2 tattoos, 75%). Anatomical predilection sites, debut, and type of symptoms are presented as data in online supplementary Table 4. Discussion The study confirmed that sarcoidosis is remarkably common in chronic non-allergic tattoo reactions. Sarcoidosis was manifested in 5% (27/494) of all tattoo reactions observed in the Tattoo Clinic and in as many as 29% (27/92) tattoo reactions in 72 patients with a papulonodular pattern by clinical examination. Systemic sarcoidosis was diagnosed for the first time in 47% (8/17) of tattoo reactions in 4 patients examined in the Tattoo Clinic. Thus, sarcoid reaction in a tattoo is an important marker of sarcoidosis as a generalised disease showing other organ manifestations as well. A high prevalence of sarcoidosis is found in the Scandinavian population and is reported to be 5 6 cases/1, population [13] compared to 1 4 cases/1, population in the USA [14, 15], while in North European countries, sarcoidosis is estimated to affect approximately 5 4/1. population [16]. Thus, sarcoidosis is by magnitude of order and, referenced to Scandinavian estimates, about 1 times more frequent in tattoo reactions independent of type of complication and about 5 times more frequent in tattoos showing a papulo-nodular pattern. Kluger [2], in his review of tattoos and sarcoidosis with cases collected over decades and from various reports, found an association between the male gender and sarcoidosis, and the colours black and red. We found that black was the dominating colour in the papulo-nodular reactions, and the size of black tattoos was larger in males and included fields densely tattooed with pigment overload, which may explain the higher prevalence of sarcoidosis in males compared to females. Black tattoos, papulo-nodular reactions, sarcoidosis, and sarcoid reactions of tattoos are associated and a clinical panorama and entity. However, sarcoidosis is not exclusively associated with black tattoos (see Table 3 ). Punch biopsy showing sarcoid granulomas is an important tool in the distinction of sarcoidosis versus non-sarcoid papulo-nodular reactions. Granuloma formation is likely to be dependent on individual predisposition, which may determine whether a case becomes manifested as sarcoidosis or not. Histopathological assessment may be difficult and blurred by intra- and inter-observer variation among pathologists in the distinction of sarcoid granulomas versus alternative patterns, including granulomatous inflammation. The relatively high number of granulomatous inflammation in the non-sarcoidosis group presented in Table 1 may be subclinical cases of sarcoidosis and cases predisposed to sarcoidosis later in life. We may have underestimated the prevalence of sarcoidosis for several reasons. Firstly, best practice would have been to take biopsies from every papulo-nodular tattoo reaction. Furthermore, a follow-up on all patients with granulomatous inflammation or sarcoid granulomas diagnosed by biopsy should be performed in the future, since patients with granulomatous inflammation may develop sarcoidosis later in life and patients with sarcoid granulomas in the tattoo may develop systemic sarcoid manifestations. The clinician, in the interpretation of biopsies, should balance histology against clinical presentation and history. Thus, the final diagnosis of sarcoidosis depends on a synopsis of histology and objective findings in the clinic. Our new observation of the rush phenomenon in a black tattoo with a papulo-nodular pattern, triggering or preceding abrupt and widespread activity in the skin, calls for an explanation. It is likely that autoimmunity plays a role. However, carbon itself is inert and has seemingly never been reported to be an active allergen or epitope in the medical literature. Carbon black pigments have a negative or positive surface charge depending on the coating and surfactants and also chemisorbed oxygen complexes on their surface depending on manufacturing [17]. It is noteworthy that rush phenomenon also appeared in cases with granulomatous inflammation. There was no direct indication that tattoo reactions in black tattoos associated with sarcoidosis were manifestations of allergy in the traditional sense, as documented in a study using patch testing, which showed negative readings also in papulo-nodular reactions [18]. However, the standardised allergy patch test is not applicable to autoimmune reactions or to allergic reactions caused by haptens. As discussed in the review by Kluger [2], the chronological link of tattoo first sarcoidosis after and vice versa is a clinical reality that cannot be denied nor concluded. What comes first may vary and may depend on the strength and balance of trigger and predisposition. It appears to be a sound hypothesis (applicable also to granulomatous tattoo reactions) that exogenous triggers, especially black pigment forming foreign bodies in the 684 Sepehri/Hutton Carlsen/Serup

7 tissue and some autoantigenic stimuli in combination with individual predisposition, lead to sarcoidosis with granuloma formation. It is recommended that patients with systemic sarcoidosis should avoid tattoos, since foreign bodies in the skin can act as a nidus for granuloma formation. Several types of cutaneous foreign bodies are known to induce cutaneous granuloma formation, but only some, including carbon black, may be suggested to have an adjuvant effect and promote autoimmunity [19]. It has also been reported that rescue workers, who helped during the World Trade Center disaster, have an increased incidence of developing sarcoidosis or sarcoid-like granulomatous pulmonary disease due to exogenic airway exposure to dust, representing foreign bodies [2]. Foreign bodies in tissue (with or without tissue reaction or granuloma formation) may promote allergic responses, as already known from vaccination against tetanus and diphtheria containing aluminium hydroxide as an adjuvant important for the allergenic effect of the epitope of the vaccine, which is typically a protein. Aluminium forms foreign body clusters in the injection site, which clinically may result in cumbersome granulomatous reactions resembling sarcoidosis [21 24]. Also, other particulates are used to promote allergic sensitisation, as exemplified by the classical Freund adjuvant composed of inactivated and dried mycobacteria [25]. Thus, the aggregation and agglomeration of black pigment in tattoos forming foreign bodies in the skin may exert an adjuvant effect that may help to sensitise the individual to tissue proteins or some chemical ingredient or metabolite of the tattoo ink, leading to autoimmune activation. Black tattoos with papulo-nodular reactions should be seen as markers of sarcoidosis involving other organs. The association is strong and important for treatment, and we propose that any patient with a black tattoo with the papulo-nodular pattern is screened for manifestations of sarcoidosis in all typical target organs, in particular the lungs, the eyes, and the general skin. Punch biopsy is indispensable. Choice of treatment strongly depends on the individual case. We documented the effectiveness of dermatome shaving in treating local reactions in the tattoos, thereby eliminating the trigger [26]. In systemic active disease and in rush phenomenon we use oral corticoid as first-line treatment. The sarcoidosis disease is interdisciplinary, and treatment should be coordinated with relevant specialties. In conclusion, clinicians should, in the diagnostic evaluation of tattoo reactions, be aware of the association between black tattoos, a papulo-nodular reaction pattern, sarcoid granulomas, and sarcoidosis involving other organs. Acknowledgements We are grateful to the Department of Pathology, Bispebjerg University Hospital, particularly Dr. Regitze Henrik-Nielsen and Dr. Vera Skødt, specialists in dermato-histopathology, who evaluated all skin biopsies. Statement of Ethics The Tattoo Clinic at Bispebjerg University Hospital works under the ethical approval No. H-A issued by the regional ethics committee and under the ethical standards of the hospital regarding any aspect of patient care. The Helsinki declaration II was followed. Disclosure Statement The authors have no conflicting interests to disclose. References 1 Madden JF: Reactions in tattoos. Arch Dermatol 1939; 4: Kluger N: Sarcoidosis on tattoos: a review of the literature from 1939 to 211. Sarcoidosis Vasc Diffuse Lung Dis 213; 3: Thum CK, Biswas A: Inflammatory complications related to tattooing: a histopathological approach based on pattern analysis. Am J Dermatopathol 215; 37: Shinohara MM, Nguyen J, Gardner J, Rosenbach M, Elenitsas R: The histopathologic spectrum of decorative tattoo complications. J Cutan Pathol 212; 39: De Cuyper C, Pérez-Cotapos M-L: Dermatologic Complications with Body Art, Tattoos, Piercings and Permanent Make-Up. Heidelberg, Springer, 21, chapt 2, pp Sowden JM, Byrne JP, Smith AG, Hiley C, Suarez V, Wagner B, Slater DN: Red tattoo reactions: X-ray microanalysis and patch-test studies. Br J Dermatol 1991; 124: Høgsberg T, Loeschner K, Löf D, Serup J: Tattoo inks in general usage contain nanoparticles. Br J Dermatol 211; 165: Høgsberg T, Jacobsen NR, Clausen PA, Serup J: Black tattoo inks induce reactive oxygen species production correlating with aggregation of pigment nanoparticles and product brand but not with the polycyclic aromatic hydrocarbon content. Exp Dermatol 213; 22: Høgsberg T, Hutton Carlsen K, Serup J: High prevalence of minor symptoms in tattoos among a young population tattooed with carbon black and organic pigments. J Eur Acad Dermatol Venereol 213; 27: Papulo-Nodular Reactions in Black Tattoos as Markers of Sarcoidosis 685

8 1 Haimovic A, Sanchez M, Judson MA, Prystowsky S: Sarcoidosis: a comprehensive review and update for the dermatologist. Part I. Cutaneous disease. J Am Acad Dermatol 212; 66: Serup J, Sepehri M, Hutton Carlsen K: Classification of Tattoo Complications in a Hospital Material of 493 Adverse Events. Dermatology DOI: / Ackerman AB: Histologic Diagnosis of Inflammatory Skin Diseases: A Method by Pattern Analysis, ed 2. Philadelphia, Lea & Febiger, Bresnitz EA, Strom BL: Epidemiology of sarcoidosis. Epidemiol Rev 1983; 5: Hosoda Y, Sasagawa S, Yasuda N: Epidemiology of sarcoidosis: new frontiers to explore. Curr Opin Pulm Med 22; 8: Iannuzzi MC, Rybicki BA, Teirstein AS: Sarcoidosis. N Engl J Med 27; 357: Dempsey OJ, Paterson EW, Kerr KM, Denison AR: Sarcoidosis. BMJ 29; 339:b Misra SK, Chang HH, Mukherjee P, Tiwari S, Ohoka A, Pan D: Regulating Biocompatibility of Carbon Spheres via Defined Nanoscale Chemistry and a Careful Selection of Surface Functionalities. Sci Rep 215; 5: Serup J, Hutton Carlsen K: Patch test study of 9 patients with tattoo reactions: negative outcome of allergy patch test to baseline batteries and culprit inks suggests allergen(s) are generated in the skin through haptenization. Contact Dermatitis 214; 71: Shapiro PE: Noninfectious granulomas; in Elder D, et al (eds): Lever s Histopathology of the Skin, ed 8. Philadelphia, Lippincott-Raven, Izbicki G, Chavko R, Banauch GI, et al: World Trade Center sarcoid-like granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest 27; 131: Psaltis NM, Gardner RG, Denton WJ: Systemic sarcoidosis and red dye granulomatous tattoo inflammation after influenza vaccination: a case report and review of literature. Ocul Immunol Inflamm 214; 22: Lindblad EB: Aluminium compounds for use in vaccines. Immunol Cell Biol 24; 82: McFadden N, Lyberg T, Hensten-Pettersen A: Aluminum-induced granulomas in a tattoo. J Am Acad Dermatol 1989; 2: Erdohazi M, Newman RL: Aluminium hydroxide granuloma. Br Med J 1971; 3: Baldridge JR, Ward JR: Effective adjuvants for the induction of antigen-specific delayed-type hypersensitivity. Vaccine 1997; 15: Sepehri M, Jørgensen B, Serup J: Introduction of dermatome shaving as first line treatment of chronic tattoo reactions. J Dermatolog Treat 215; 26: Sepehri/Hutton Carlsen/Serup