A case of multiple autoimmune syndrome comprising autoimmune thyroid disease, vitiligo, morphea, and lichen sclerosus Hana Gašper1, Vesna Breznik2 ✉ 1Department of Internal Medicine, Slovenj Gradec General Hospital, Slovenj Gradec, Slovenia. 2Department of Dermatology and Venereal Diseases, Maribor University Medical Center, Maribor, Slovenia. 95 2024;33:95-99 doi: 10.15570/actaapa.2024.10 Introduction Autoimmune diseases (ADs) are a heterogeneous pathology char- acterized by abnormalities in both humoral and cell-mediated immunity, resulting in their assault on normal bodily constitu- ents, which leads to inflammation, cell injury, or a dysfunction with clinical manifestations in specific target organs (1). Histori- cally perceived as rare, epidemiological revelations over the last two decades, particularly in Western countries, show a rise in the global prevalence of ADs (2–4). A recently published British population–based study highlights this trend, indicating that ADs afflict nearly 10% of the population, with an average age of onset at 54 years and a female predilection (2:1) (5). Predominant among these diseases are autoimmune thyroid disorders and type 1 diabetes, followed by systemic lupus erythematosus, rheuma- toid arthritis, psoriasis, multiple sclerosis, celiac disease, and in- flammatory bowel diseases (3, 6). Globally, Graves’ disease, celiac disease, and rheumatic disorders have witnessed the most sub- stantial increases in incidence (5). Autoimmune skin disorders, comprising vitiligo, psoriasis, alopecia areata, bullous diseases, and systemic lupus erythematosus, have similarly experienced an escalating path (7). With genetic factors remaining constant, detailed scrutiny has shifted toward exploring environmental in- fluences as potential contributors to the increasing prevalence of ADs. Ongoing evidence points to significant alterations in diet, xenobiotics, air quality, infections, personal lifestyles, stress, and climate change as factors precipitating the surge in AD incidence (8). Polyautoimmunity (PAI) is defined as the presence of more than one AD in an individual. PAI can be overt (fulfilling clinical criteria) or latent (presence of unrelated autoantibodies without clinical criteria fulfilment of the AD), and it can affect one or more organ systems. Various ADs tend to cluster together in specific patterns, suggesting shared genetic susceptibility traits (5). How- ever, the clinical relevance within these clusters of ADs remains unclear (particularly in terms of management and outcome). PAI occurs in 25% to 34% of individuals with ADs, and familial au- toimmunity, especially in females, is a predisposing factor for PAI. The observed female predilection is attributed to hormonal fluctuations and genetic disparities—both direct (i.e., influence of genes on sex chromosomes) and indirect, such as microchimer- ism—alongside sex-specific lifestyle distinctions (9, 10). When three or more ADs coexist, the condition is called multi- ple autoimmune syndrome (MAS), categorizable into three types according to the prevalence of their associations with one anoth- er. This classification proves helpful, particularly when signs of a third disorder emerge. Individuals with MAS often have multiple autoantibodies, some of which are organ-reactive. Although the pathogenesis remains elusive, genetic, infectious, immunologic, and psychological factors are implicated, leading to theorizing that environmental triggers in genetically susceptible individuals precipitate dysregulation of immune processes (9). Of particular interest is the observation that patients manifesting MAS fre- quently exhibit at least one dermatological condition, typically comprising vitiligo, alopecia areata, psoriasis, or morphea. In many reported cases of MAS, vitiligo is the first AD to be diag- nosed, demonstrating a bilateral and symmetrical presentation. Concurrently, autoimmune thyroid disease tends to coexist in these instances. The manifestation of one AD often serves as a sign, guiding the discovery of additional autoimmune conditions. Research also highlights the occurrence of overlap syndromes in varied combinations, although the simultaneous coexistence of five or more ADs proves exceedingly rare (9). Case report A 55-year-old female with a longstanding medical history of au- toimmune thyroid disease (15 years), chronic gastritis (9 years), symmetric vitiligo (5 years), and morphea (2 years) presented to our dermatology clinic due to the progression of her morphea on the abdomen and the emergence of depressed brownish macules on her right upper arm and right calf, as well as a burning whit- ish patch over her right scapula. Her regular therapeutic regimen consisted of systemic sodium levothyroxine and esomeprazole. It is noteworthy that her mother also experienced autoimmune thy- roid disease. Abstract Multiple autoimmune syndrome is a manifestation of polyautoimmunity with the co-occurrence of three or more autoimmune dis- eases in a single patient. We report a unique case of a 55-year-old female patient that presented with four autoimmune diseases: autoimmune thyroid disease, vitiligo, morphea, and lichen sclerosus. She was evaluated for progression of morphea and lichen sclerosus, and we confirmed histopathological overlapping of these two diseases in the same lesion. We discuss the increasing prevalence of autoimmune diseases and similar case reports on dermatological polyautoimmunity. Keywords: multiple autoimmune syndrome, polyautoimmunity, vitiligo, lichen sclerosus, morphea Acta Dermatovenerologica Alpina, Pannonica et Adriatica Acta Dermatovenerol APA Received: 11 November 2023 | Returned for modification: 6 January 2024 | Accepted: 31 January 2024 ✉ Corresponding author: vesna.breznik@ukc-mb.si 96 Acta Dermatovenerol APA | 2024;33:95-99H. Gašper et al. Upon physical examination, we observed symmetrical vitiligo on her face, arms, and knees, affecting approximately 5% of the body surface area (Fig. 1). Sclerotic plaques, characteristic of mor- phea, were observed on her abdomen, accompanied by purplish red halos (Fig. 2). In addition, two suspicious brownish depressed macules, indicative of deep morphea, were identified on her right upper arm and right calf (Fig. 3). Above her right scapula, a well- defined whitish atrophic patch measuring approximately 6 × 4 cm was observed (Fig. 4). Laboratory testing, including a complete blood count, urea, creatinine, liver tests, urine C-reactive protein, thyroid-stimulating hormone, thyroid hormones (T3 and T4), and thyroglobulin, were all within normal ranges. However, her anti- thyroid peroxidase antibodies were found to be elevated at 185 IU/ml (normal value < 35 IU/ml). Antinuclear antibodies and an- tibodies against Borrelia burgdorferi (IgG and IgM) were negative. Further histopathological examination of the depressed lesion located on her right upper arm confirmed the diagnosis of mor- phea through the presence of a perivascular infiltrate comprising lymphocytes and plasma cells, dermal sclerosis, and collagen ho- mogenization. In addition, examination of the skin lesion above her right scapula revealed concurrent occurrence of morphea and lichen sclerosus within the same lesion (Fig. 5). Lichen sclerosus was characterized by the thickening and homogenization of col- lagen bundles in the papillary and reticular dermis, along with follicular plugging, hyperkeratosis, epidermal atrophy, and basal cell hydropic degeneration. We initiated treatment with daily application of topical beta- methasone ointment for a duration of 3 months. Given the pro- gression of the conditions, we subsequently injected intralesional triamcinolone acetonide into the edges of the morphea and lichen sclerosus lesions, administering 40 mg per session thrice, with a 1-month interval between sessions. Afterward, we commenced narrowband UVB phototherapy at a frequency of three times weekly, spanning 30 sessions. Remarkably, this comprehensive therapeutic approach resulted in the stagnation of her morphea, lichen sclerosus, and vitiligo. Figure 1 | Symmetrical, sharply defined depigmented macules present on the hands and knees: vitiligo. Figure 2 | Sclerotic plaques surrounded by lilac halos on the abdomen: plaque morphea. Figure 3 | Depressed brownish macule on the patient’s right calf: deep mor- phea. 97 Acta Dermatovenerol APA | 2024;33:95-99 A case report of multiple autoimmune syndrome in dermatology Discussion ADs may frequently evolve from a single diagnosis and over the years develop into PAI and even MAS in the same patient because new clinical symptoms and laboratory findings emerge over time (11). MAS best illustrates that PAI is more than a coincidence, em- phasizing the shared pathogenesis of several ADs, including simi- lar clinical signs and symptoms, pathophysiological mechanisms, and genetic factors within AD and aggregation of diverse ADs within families (autoimmune tautology). Conflicting perspectives exist on whether the coexistence of ADs contributes to a more se- vere disease course (12). We present what we believe is an extraordinary case of a pa- tient with MAS, initially diagnosed with autoimmune thyroid dis- ease, which later developed into a spectrum of three dermatologi- cal ADs (vitiligo, morphea, and lichen sclerosus). Autoimmune thyroid disease, being the first manifested AD in our patient, is the most prevalent AD globally, affecting 4.8% to 25.8% of women and 0.9% to 7.9% of men (13). According to a meta-analysis by Botello et al., overt PAI was found in 13.5% of patients with auto- immune thyroid disease, whereas latent PAI was present in 17.5% of these patients, mainly involving type 1 diabetes, autoimmune gastritis, pernicious anemia, celiac disease, rheumatoid arthritis, and vitiligo (14). A study by Gupta et al. described 10 MAS cases involving multiple dermatological autoimmune disorders. These cases included individuals with three, four, or even five coexist- ing ADs, such as alopecia areata, vitiligo, lichen planus, type 1 diabetes mellitus, and autoimmune thyroid disease. Among these cases, autoimmune thyroid disease was the most commonly ob- served (15). Over a decade, our patient’s autoimmune thyroid disease pro- gressed to vitiligo, a disorder frequently associated with both cu- taneous (alopecia areata, morphea, and pyoderma gangrenosum) and non-cutaneous ADs (type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and autoimmune thyroiditis), es- pecially in females and older patients (16). The peak incidence of vitiligo seems to be in the second and third decade, but it can ap- pear at any age. The approximate prevalence is 0.1% to 2% of the population (17). A recent study by Rios-Duarte et al. reveals that 17.7% of vitiligo patients have at least one AD comorbidity, with 0.7% of patients having MAS. The most prevalent autoimmune co- morbidities in vitiligo cases include type 1 diabetes (4.5%), rheu- matoid arthritis (2.8%), and systemic lupus erythematosus (2.5%) (16). The concurrence of autoimmune thyroid disease and vitiligo is explained by a hypothesis linking excessive reactive oxygen spe- cies to the destruction of melanocytes and thyrocytes. About 34% of vitiligo patients exhibit positive thyroid antibodies, indicative of latent PAI (18). This discovery bears clinical significance for practitioners engaged in surveillance of these patients (19). Subsequently, after a span of 13 years from the initial diagno- sis of autoimmune thyroid disease, morphea emerged as the third AD in our patient’s clinical profile. This is an uncommon fibrotic disorder, primarily affecting the dermis with possible spread to underlying tissues. Two incidence peaks are noticed: between 2 and 14 years and in the fifth decade of life, primarily in women (female-to-male ratio 4:1). Total annual incidence ranges from four to 27 new cases per million people. Certain stimuli may trig- ger vascular and immune dysregulations in genetically predis- posed individuals. A rare combination of plaque and the deep type of morphea, which was observed in our patient, is strongly associated with familial ADs (20). Furthermore, the coexistence of morphea and segmental vitiligo within the framework of PAI has been documented, especially in the pediatric population. Notably, these lesions often follow a Blaschko linear distribution, suggesting genetic mosaicism (21). Dervis et al. reported another instance of MAS characterized by the combination of morphea, vitiligo, and autoimmune thyroid disease (22). We observed a sim- ilar combination of autoimmune disorders in our patient, along with the additional presence of lichen sclerosus, and we classified this case as overlapping type 2 and 3 MAS (9). Of particular interest in our patient’s clinical case is the mani- festation of a whitish atrophic patch on the scapula, histopatho- logically exhibiting features characteristic of both morphea and lichen sclerosus. Distinguishing between the two can be difficult, but elucidating the clinical nuances of the biopsy site (distinguish- ing an inflammatory border from a sclerotic center) offers valuable insights to pathologists, providing an optimal clinicopathological Figure 4 | Sharply bordered whitish atrophic patch above the right scapula: clinical diagnosis of lichen sclerosus. Figure 5 | Histopathology of the skin lesion above the right scapula shows co-occurrence of lichen sclerosus and morphea in the same lesion. Using tri- chrome blue staining, lichen sclerosus appears in a lighter blue shade (white arrow) and morphea appears in a darker blue shade (black arrow). Morphea histopathologically shows a perivascular infiltrate composed of lymphocytes and plasma cells. Thickened and homogenized collagen bundles at the papil- lary and reticular dermis are seen, similar to the histopathological character- istics of lichen sclerosus. Lichen sclerosus also shows hyperkeratosis (red ar- row), epidermal atrophy, and basal cell hydropic degeneration (green arrows). 98 Acta Dermatovenerol APA | 2024;33:95-99H. Gašper et al. References 1. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345:340–50. 2. Lerner A, Jeremias P, Matthias T. The world incidence and prevalence of autoim- mune diseases is increasing. Int J Celiac Dis. 2015;3:151–5. 3. Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015;278:369–95. 4. Cooper GS, Bynum ML, Somers EC. Recent insights in the epidemiology of auto- immune diseases: improved prevalence estimates and understanding of cluster- ing of diseases. J Autoimmun. 2009;33:197–207. 5. Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs G, Taylor PN, et al. 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Introducing polyautoimmunity: secondary autoimmune diseases no longer exist. Autoimmune Dis. 2012;2012:254319. 11. Agarwal A, Sanghi A, Agarwal M, Agarwal M. “Three in one”—polyautoimmunity with multiple autoimmune syndrome. J Assoc Physicians India. 2018;66:95–7. 12. Fidalgo M, Faria R, Carvalho C, Carvalheiras G, Mendonça D, Farinha F, et al. Mul- tiple autoimmune syndrome: clinical, immunological and genotypic characteri- zation. Eur J Intern Med. 2023;116:119–30. 13. Hu X, Chen Y, Shen Y, Tian R, Sheng Y, Que H. Global prevalence and epidemio- logical trends of Hashimoto’s thyroiditis in adults: a systematic review and meta- analysis. Front Public Health. 2022;10:1020709. 14. Botello A, Herrán M, Salcedo V, Rodríguez Y, Anaya JM, Rojas M. Prevalence of latent and overt polyautoimmunity in autoimmune thyroid disease: a systematic review and meta-analysis. Clin Endocrinol (Oxf). 2020;93:375–89. 15. Gupta S, Aggarwal S, Chopra D. The kaleidoscope of autoimmunity: a report of 10 cases of multiple autoimmune syndrome. J Med Res Innov. 2023;6:22–3. 16. Rios-Duarte JA, Sanchez-Zapata MJ, Silverberg JI. Association of vitiligo with mul- tiple cutaneous and extra-cutaneous autoimmune diseases: a nationwide cross- sectional study. Arch Dermatol Res. 2023;315:2597–603. 17. Ahmed Jan N, Masood S. Vitiligo. StatPearls [Internet]. [Cited 2023 Sep 18]. Avail- able from: https://www.ncbi.nlm.nih.gov/books/NBK559149/. correlation (23). The literature highlights the convergence of clini- cal and histopathological attributes between morphea and lichen sclerosus, speculating they may represent different features along a shared disease spectrum (24). PAI comprising morphea and li- chen sclerosus has been well documented in numerous clinical instances, presenting a formidable challenge in clinical and der- moscopic differential diagnoses of lichen sclerosus (25). Although the etiology of both conditions remains largely unknown, some cases show differentiation based on genetic predispositions (par- ticularly involving predisposing HLA alleles) and environmental triggers (i.e., infection with Borrelia burgdorferi). The prevalence of genital lichen sclerosus is higher in patients afflicted with mor- phea, leading some scholars to consider lichen sclerosus to be the genital manifestation of morphea (26). However, our patient de- nied any symptoms or lesions of the anogenital region. Lichen sclerosus, which was the final AD observed in our pa- tient, is an inflammatory mucocutaneous condition predominant- ly affecting anogenital areas; however, the extragenital type can affect any site on the skin and mucosa, especially the neck, shoul- ders, thighs, and oral cavity. Two incidence peaks are character- istic, correlating with hormonal status (in premenarchal girls and menopausal women, both linked to a low estrogen status). Con- sequently, women are most commonly affected (female-to-male ratio 3:1 to 10:1). The estimated incidence of lichen sclerosus in both sexes is 0.1% to 0.3%. The underestimation of prevalence and incidence highlights the challenges in recognizing and diag- nosing this AD, often leading to the condition being misdiagnosed or overlooked (27). Similar MAS comprising lichen sclerosus, viti- ligo, and autoimmune thyroid disease has been discussed by Kim et al. It has been observed that both nonsegmental vitiligo and lichen sclerosus can exhibit the Koebner phenomenon, wherein mechanical stimulation can induce symptoms in genetically sus- ceptible individuals (28). Although patients with MAS often exhibit multiple autoanti- bodies (9), antinuclear antibodies in our patient were absent, and this led us to forgo broader serological screening for potential la- tent autoimmune diseases. We deemed it questionable to attribute clinical significance to positive autoantibodies in the absence of symptoms or signs of associated disorders. In recent decades, there have been significant changes in the treatment of ADs. Previously, corticosteroids and conventional im- munosuppressant drugs such as methotrexate and azathioprine were used to alleviate symptoms of ADs. The exact mechanisms behind ADs are not fully understood, but knowledge about B-cell and T-cell subsets and cytokine environments provides promis- ing treatment prospects. The field of drugs targeting immune- mediated diseases is rapidly evolving, including various biologic agents, and many drugs in development and clinical trials (29, 30). Our patient’s autoimmune thyroid disease was being man- aged through thyroid hormone replacement therapy, while her vitiligo remained stable and relatively non-disturbing. Our pri- mary therapeutic goal was to halt the progression of symptomatic lichen sclerosus and morphea. To achieve this, we employed a combination of intralesional triamcinolone and narrowband pho- totherapy. This therapeutic approach managed to achieve stagna- tion of the lesions, but not regression. In the event of significant deterioration in any of the cutaneous ADs, systemic corticoster- oids and methotrexate would be considered as treatment options. Conclusions We present a compelling case of a patient diagnosed with MAS, primarily exhibiting cutaneous ADs. Considering the escalating global incidence of ADs, it is plausible that we will encounter a surging prevalence of MAS and PAI in clinical practice. In light of this prediction, we emphasize the importance of long-term clini- cal surveillance for patients affected by PAI because it allows the ongoing monitoring of existing ADs and facilitates the prompt identification of any newly emerging ones based on clinical, se- rological, and relevant auxiliary diagnostic measures as well as incorporation of multidisciplinary management. 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