Tattoo-Induced Exacerbations of Systemic Disease and Uveitis

Abstract

Purpose: To examine an underreported and underdiagnosed phenomenon with implications for the pathophysiological mechanisms of tattoo-induced uveitis. Methods: Two cases highlighting the clinical presentation of tattoo-related uveitis were evaluated. Results: A 28-year-old man with biopsy-proven sarcoidosis and ocular manifestations presented with worsening retinal vasculitis after acquiring a red-ink tattoo. Each subsequent flare followed acquisition of a new tattoo. A 31-year-old woman without systemic sarcoidosis presented with multiple episodes of bilateral intermediate uveitis and macular edema concurrent with inflammatory granulomas to recently acquired black-ink tattoos. A skin biopsy in both patients showed cutaneous noncaseating granulomas. Conclusions: These cases add to those reported in the literature and emphasize the importance of understanding the modifiable factors of inflammatory ocular disease. Future study is necessary to understand the mechanisms of tattoo-related uveitis.

Introduction

Uveitis is characterized by inflammation of the eye in the iris, ciliary body, and choroid and is thought to be responsible for up to 10% of cases of acquired blindness worldwide. Although many cases are deemed idiopathic, uveitis may be precipitated by specific environmental triggers that have not been fully characterized.^1,2

Uveitis is commonly associated with systemic autoimmune diseases, such as sarcoidosis, a multisystem inflammatory disorder characterized by noncaseating granulomas in various organs, most commonly the lungs, the lymphatic system, and the eyes. The diagnosis is based on the clinical presentation, a tissue biopsy demonstrating nonnecrotizing granulomatous inflammation, and the exclusion of alternative causes. Ocular manifestations are reported in 25% to 50% of cases of sarcoidosis, and a recent study has shown that ocular symptoms are most commonly the first clinical presentation. Therefore, these patients may first be seen and diagnosed by ophthalmologists. ³ Anterior uveitis is the most common manifestation of ocular sarcoidosis, and in older or more severely affected patients, inflammation may progress to panuveitis and affect the entire eye. ²

More than one quarter of the population in the United States is estimated to have at least 1 tattoo, which may cause hypersensitivity reactions, including ocular inflammation, in predisposed individuals. ⁴ Previous studies have noted that for reasons unknown, skin manifestations of sarcoidosis tend to affect scars and tattoos.^{5 –7} However, few reports have described the clinical sequelae of tattoos in hypersensitive patients with pathological results. Even less studied is the relationship between acquisition of a tattoo and the manifestation of uveitis.

Here, we report the clinical course of a patient who, after previously remaining stable on immunosuppressive therapy, developed multiple flares of sarcoid-associated ocular complications after receiving new red-ink tattoos on 2 separate occasions. In contrast, a patient with no history of sarcoidosis who developed recurrent uveitis in response to receiving a black-ink tattoo is described.

Case Reports

Case 1

A previously healthy 28-year-old White man was evaluated in the emergency department for acute-onset ocular pain and blurry vision. Ophthalmology was consulted, and the physical examination showed bilateral vitreous hemorrhage. The patient was subsequently treated with antiangiogenic injections for neovascularization, and investigations into the cause of the hemorrhage were initiated. Twelve days after the patient’s original presentation, he was evaluated again for shortness of breath. Laboratory studies found an erythrocyte sedimentation rate of 24 mm/h and an angiotensin-converting enzyme level of 118 U/L (reference range, 14-82 U/L). Chest radiographs showed hilar lymphadenopathy. A bronchoscopy with biopsy was performed, confirming the diagnosis of pulmonary sarcoidosis. Treatment was started with topical and systemic corticosteroids and methotrexate, which initially controlled all symptoms.

Eight months after the initial presentation of symptoms and quiescence on methotrexate, the patient presented again with difficulty breathing and blurry vision. A fundus evaluation found exacerbation of ocular neovascularization, and intraocular antiangiogenic treatment was restarted. At this time, the patient noticed small erythematous bumps around a newly acquired multicolored tattoo in the areas with red ink (Figure 1), for which he was prescribed topical triamcinolone.

Figure 1.

Superficial scaling and granulomatous infiltration in the areas of a red-ink tattoo. The surrounding skin appears unaffected.

Six months later, the patient acquired another tattoo containing red ink and subsequently presented with exertional dyspnea and an acute increase in floaters bilaterally, with a concurrent skin rash overlying the red ink. A cutaneous skin punch biopsy of the tattoo found sarcoid granulomas (Figure 2, A and B). The lesions resolved with an intralesional corticosteroid injection, and disease activity was again stabilized on methotrexate. Subsequently, the patient has been stable without signs of recurrence.

Figure 2.

(A) Hematoxylin and eosin–stained sections reveal well-circumscribed granuloma in the dermis (original magnification ×4). (B) At higher magnification, red granular tattoo pigment can be seen in the macrophages (original magnification ×40).

Case 2

A 31-year-old woman presented for follow-up of bilateral, recurrent, intermediate uveitis with macular edema. On a physical examination, she was found to have localized inflammation of a black-ink tattoo. A complete uveitic workup was notable only for positive antineutrophil antibody but negative for sarcoidosis, with a normal angiotensin-converting enzyme value and normal chest X-ray findings. The patient was started on a topical and systemic corticosteroid regimen, which resolved the intraocular and cutaneous inflammation. Several months later and off all therapy, she returned with new inflammation after obtaining a new black-ink tattoo on the same sleeve. The patient was maintained on the corticosteroid regimen. Results of a skin biopsy revealed “a granulomatous reaction to tattoo and sarcoidosis,” and the patient was counseled to defer further tattoo art. Her disease course stabilized on corticosteroids, and she was transitioned to steroid-sparing agents (mycophenolate mofetil 2 g daily) for treatment of recurrent uveitis.

Conclusions

We describe a temporal relationship between the acquisition of tattoos and flares of uveitis. In the first case, the tattoo granuloma was associated with systemic sarcoidosis, offering new insight into the potential relationship between tattoo acquisition and exacerbation of this autoimmune condition. The exact triggers of disease flares in sarcoidosis are not fully elucidated. Although some associations have been suggested, such as specific environmental exposures and pathogens, it is unclear how cutaneous manifestations of sarcoidosis interact with scars and tattoos. ⁵ The second case demonstrates a possible mechanism of uveitis that acts independently of an autoimmune disease but still requires systemic immunosuppression for control of uveitis. This warrants further investigation.

Sarcoidosis is a disorder of unknown immunopathogenesis, although several explanations have been put forth, including it being secondary to an exogenous insult. Some authors have suggested that tattoos themselves may initially trigger the onset of sarcoidosis. It is thought that the antigens of tattoo pigment (ie, metallic substances and other impurities such as cobalt and nickel) drive a dynamic T helper 1 lymphocyte-mediated delayed hypersensitivity reaction, which results in chronic granuloma formation in genetically predisposed patients.^7,8 These antigens may be inoculated during the tattooing process. They may also be byproducts of previously encountered tattoo components and cause chronic low-grade exposure after a long latency period, resulting in a systemic granulomatous hypersensitivity.^7,9,10 Red ink has the strongest association with inflammatory skin reactions, suggesting that this is the most immunogenic tattoo pigment related to certain compounds (eg, cinnabar). ⁷ Previous studies have postulated that red ink may incite flares of systemic disease, such as systemic sarcoidosis, and long-term reactions in predisposed individuals. Case 1 provides additional evidence of the link between red ink and inflammatory processes. However, it is important to note that these hypersensitivity reactions are not exclusive to red-ink tattoos, as seen in Case 2 and other reports. ⁸

Previous case reports highlighting similar clinical presentations in patients with sarcoidosis have described the relationship between tattoo ink and the inflammatory process. However, these cases do not clarify whether patients were in a quiescent disease state before tattoo acquisition. Therefore, the granulomatous inflammation associated with tattoos in these cases cannot be reliably established as its cause or whether it is simply an indicator of an ongoing sarcoidosis flare. ⁸

In our first patient, the clear timeline of clinical sequelae in relation to tattoo acquisition strongly suggests a causal association between tattoo acquisition and exacerbation of systemic autoimmune disease activity. The precipitation of uveitis in response to tattoo acquisition has also been described in the context of Vogt-Koyanagi-Harada (VKH) disease, another inflammatory syndrome characterized by systemic granuloma formation that affects tissue-containing melanocytes in particular.^8,11

Several theories explaining the association between tattoo acquisition and uveitis in the context of autoimmune disease have been proposed. ⁸ One theory postulates that these granulomas are isolated integumentary manifestations of the underlying autoimmune disease (ie, well-known correlations of cutaneous granulomas in sarcoidosis and characteristic depigmentation in VKH disease).^8,11 The second theory suggests that a granulomatous reaction may occur in response to an exogenous trigger or cross-reaction from the antigenic load of the tattoo pigment, as illustrated by the presence of immune cells and inflammatory markers within areas of tattooed skin acting as a persistent antigenic stimulus. Specific molecules acting as triggers for immune activation that simulate the conditions of tattooing and subsequent inflammatory responses have been found in animal models. A third theory states that the observed uveitis is a distinct entity related to tattoo granulomas that occurs independently of systemic disease. ⁸ Evidence of this includes clinical observations of tattoo-related uveitis without signs of underlying autoimmune disease, as previously reported. ⁸ Given the varying presentation in patients with tattoo-associated uveitis in relation to the presence of sarcoidosis and tattoo granulomas, a combination of the mechanisms discussed is the most likely contributor.

A previous case series described 5 patients affected by uveitis concurrent with indurated tattoos within 6 months of their acquisition. ¹² Similar to our cases, 2 of 7 eyes affected in this cohort had granulomatous panuveitis along with noncaseating granulomas on skin biopsy; however, all patients had a negative workup for sarcoidosis. Although all patients improved clinically with high-dose systemic corticosteroids, some also benefited from tattoo excision, which resulted in the resolution of both uveitis and systemic symptoms. ¹² This points toward tattoo excision as an option for treating and preventing recurrent flares of uveitis and other manifestations in patients who are predisposed to this exaggerated response, although its benefits have not yet been established in patients with sarcoidosis. ⁸

Characterization of these cases shows that patients with sarcoidosis have a longer period of latency between tattoo acquisition and uveitis, with onset being less than 1 year in patients without sarcoidosis and in general more than 1 year in those with the disease. ⁸ Some patients with isolated uveitis may have been underdiagnosed for underlying sarcoidosis or other diseases. Further investigation into the mechanisms of uveitis precipitated by tattoo acquisition and their relationships with autoimmune diseases is necessary to better understand the workup and management of these patients.

These cases highlight an important trigger of uveitic flares with implications for understanding the dynamic relationship between environmental exposures and the disease process. With the current prevalence of tattoos, this report has practical implications for patients with sarcoidosis. Questions remain regarding the characteristics of patients predisposed to an exaggerated response, the association between the intrinsic factors of tattoos (eg, size, pigmentation) and the risk for uveitis and systemic disease, and the potential to underdiagnose underlying autoimmune processes in uveitis patients. These adverse events associated with tattoos should be discussed with anyone pursuing the acquisition of a tattoo. Additional study of the mechanisms of systemic reactions to tattoo acquisition is necessary to elucidate how these presentations can be recognized and managed effectively to improve future outcomes.