Alopecia Areata - Effects of Treatment with Upadacitinib - Two Case Reports.

The case study aimed to demonstrate the potential of treating patients with AA using modern treatments, such as JAK 1 inhibitors, specifically upadacitinib.

A 17-year-old male patient attended the Dermatology clinic due to alopecia, which started with a single outbreak which can be seen in Figure 3 . After one month, diffuse alopecia covered the entire scalp - treated with topical clobetasol ointment and prednisone 40 mg/week with no result. Figure 3 The first outbreak of alopecia in a 17-year-old patient. The first outbreak of alopecia in a 17-year-old patient. His medical history consists of early-onset asthma treated with budesonide and formoterol and allergies (Dermatophagoides farinae, canine epidermis, trees, grasses, grain, egg white, duck meat, pork) managed with levocetirizine 5 mg/day. The patient was treated with cyclosporine 250 mg/day and prednisone 40 mg/day, resulting in a good response - visible hair regrowth across the entire scalp. In dermatoscopic examination, there are some exclamation hairs, follicular hair regrowth, and black dots. After five months, the patient reported deterioration, including loss of hair in the underarm and eyebrow areas. The decision to discontinue the cyclosporine and include upadacitinib was made. Treatment with upadacitinib 15 mg/day has brought satisfactory results. After three months, follicular hair regrowth was present throughout the scalp, and short, light eyelashes and light hair regrowth in the chin area were visible as it’s visible in Figure 4 . Figure 4 A 17-year-old patient with loss of all hair on the scalp after 4 months of upadacitinib treatment. A 17-year-old patient with loss of all hair on the scalp after 4 months of upadacitinib treatment. The patient remains under the care of the Dermatology Outpatient Clinic, where treatment is ongoing. Six months after treatment initiation, vellus hair regrowth on the scalp was observed, along with increased eyelash visibility and light hair regrowth in the beard area. The patient reported no complaints throughout the treatment period. At the one-year follow-up, regrowth of dark hair on the scalp was noted. Treatment was completed after 18 months of upadacitinib therapy. Two months after treatment completion, normal hair growth was observed, with no residual areas of alopecia. The patient reports an improvement in well-being and self-esteem.

Alopecia areata (AA) is an autoimmune disease, one of the non-scarring types of hair loss, characterized by the activation of cytotoxic T cells against hair follicles. 1 AA manifests as patches of bald spots on the scalp and may progress to complete hair loss on the scalp (alopecia totalis) or complete hair loss of all hair of the body (alopecia universalis). Hair loss in AA is associated with lymphocyte infiltration around the hair follicles, and IFN-γ plays a role in the immune response. In addition, AA often co-occurs with other autoimmune diseases or allergic conditions and can be triggered or exacerbated by infections or inflammatory processes. One of the diseases that can occur in conjunction is sarcoidosis. While sarcoidosis and AA are distinct diseases, their immune-mediated nature and shared cytokine pathways suggest that coexistence, though rare, is plausible. 2 Recognizing this overlap can help guide diagnosis, biopsy decisions, and treatment planning, particularly when considering therapies like JAK inhibitors, which are gaining more and more recognition in treating a variety of skin conditions. Although much of the current evidence comes from isolated case reports or small series, it reflects a growing enthusiasm and the considerable potential of JAK inhibitors in managing previously treatment-resistant or rare skin disorders. Promising responses have been observed in diseases such as cutaneous sarcoidosis, dermatomyositis, necrobiosis lipoidica, hypereosinophilic syndrome, lichen planus, and mastocytosis. 3 Another group of diseases associated with AA are allergic conditions, such as asthma, eczema, or reactions to pollen, dust, and cats. Each of them contributes to an elevated AA risk, influencing the onset and relapse of AA. 4 , 5 The risk of developing AA in patients with asthma has increased by 1.86 times. 6 There are studies showing efficacy in improving the condition of AA with using upadacitinib. The treatment’s effect is visible not only in patients with various comorbidities, both skin related and internal, but also in patients without any associated conditions. 1 , 7 Upadacitinib’s safety and effectiveness have been noted in recent studies. We can see that upadacitinib administration shows great success in the treatment of AA with comorbidities such as atopic dermatitis and vitiligo, but also without coexisting conditions. Upadacitinib, administered at 15 mg/day, the same dose as our patients, has been an effective and safe treatment option in cases of adolescents with severe AA, as some of the recent studies have concluded. 8 , 9 The drug inhibits phosphorylation of downstream effector proteins, thereby suppressing cytokine signaling in key pathways associated with inflammatory diseases. The compound reversibly inhibits IL-6 and IL-7 cytokine signaling in vivo in a concentration-dependent manner. As a result upadacitinib is an effective drug for the treatment of several chronic inflammatory diseases such as rheumatic, dermatologic, and gastrointestinal diseases. 10

Despite multidisciplinary efforts, the etiology of AA is not fully understood in patients, and its course is unpredictable Some evidence suggests that environmental, immunological, and genetic factors may contribute to the development of the disease or exacerbate its symptoms. The first case presents concomitant AA with sarcoidosis. Sarcoidosis is an autoimmune, multisystem inflammatory disease characterized by the formation of small clusters of inflammatory cells. Described as the “mimic” of many other pathological processes due to the variety of clinical presentations, it can affect any part of the body. Depending on the location, granulomas can cause mild or severe symptoms or no clinical symptoms at all. 11 Lungs, along with the rest of the pulmonary system, are most frequently occupied. The second most common manifestation is cutaneous sarcoidosis. Skin lesions can present in various forms and locations on the body. Clinical presentations may include lupus pernio, nodular sarcoidosis, papular sarcoidosis, plaque sarcoidosis, scar sarcoidosis, or erythema nodosum. 12 In some cases, sarcoidosis may manifest on the scalp as both scarring and non-scarring alopecia. It manifests as diffuse or localized, structureless, orange-yellowish areas. Some focussed linear or branching vessels may also be visible. Whitish lines, follicular plugs, dilated follicles, pigmentation structures, and yellow and/or white scales can also be found. 13 Dermatoscopy is not necessarily considered a reliable tool for differentiating such diseases; consequently, histological assessment is needed. The complex interaction of immunological factors in these diseases, as well as identified cases of their co-occurrence, underscore the need for a multifaceted approach to understanding them and tailoring appropriate treatment. 14 While sarcoidosis and AA are distinct conditions, their shared autoimmune characteristics and inflammatory mechanisms suggest a potential for co-occurrence in some individuals. Countless reports confirm that sarcoidosis can mimic various other alopecias, including acne keloidalis nuchae, frontal fibrosing alopecia, lichen planopilaris, and AA. In the case of our patient, sarcoidosis not only mimics but also occurs in conjunction with primary AA. 15 This highlights the role of histopathological studies in diagnosing and differentiating cutaneous sarcoidosis and various types of alopecias. Recognizing and managing both conditions may require a tailored approach to immunosuppressive therapy, along with ongoing monitoring for the development of additional autoimmune symptoms. A therapy for alopecia that has gained recognition in recent years contains JAK inhibitors. Two of them, baricitinib (JAK ½ inhibitor) for adults and ritlecitinib (JAK 3/TEC inhibitor) for individuals aged 12 or older, have been EMA-approved for treating severe AA. They forever changed the treatment, the chance of recovery, and disease management. 16 , 17 Although only two drugs are approved, many more are being tested, showing encouraging potential in the treatment of AA. Most of the patients experienced visible hair regrowth. 18 JAK inhibitors are gaining increasing recognition in the treatment of dermatological diseases, such as AA, systemic lupus erythematosus, sarcoidosis, and acquired vitiligo. 19 JAK inhibitors appear to have great therapeutic potential. Research has demonstrated their safety and effectiveness in treating sarcoidosis, especially in patients presenting with cutaneous manifestations of the disease. 20 , 21 One of the drugs that has shown promise, with more and more evidence of its efficacy, is upadacitinib. Primarily used in the treatment of inflammatory bowel disease, rheumatoid arthritis, or atopic dermatitis, it has shown efficacy in treating both sarcoidosis and AA. 22–25 Other examples of therapeutic success with upadacitinib include our patient, who has both sarcoidosis and AA. The treatment has not only led to significant hair regrowth but also improved the patient’s mental health. Hair loss can have a profound psychological impact, contributing to anxiety, depression, low self-confidence, and social withdrawal. 26 Our patient experienced similar symptoms, prompting a psychiatric consultation. With ongoing treatment and visible results, the patient’s mental well-being continues to improve. The other patient also presented with AA but with a completely different set of circumstances. His case shows the connection of AA with allergic conditions like allergies (for our patient, canine epidermis, trees, grasses, grain, egg whites, duck meat and pork allergies) and asthma. Asthma is a disease characterized by airway inflammation, presenting with a history of dyspnea, shortness of breath, and cough, which vary in duration and intensity. 27 The cause of asthma remains unclear, but it is known to be influenced by a combination of genetic and environmental factors. 28 A recent study shows that the genetic factor of asthma plays a significant role in increasing the likelihood of other diseases. Amongst the diseases that can be linked to asthma, we can distinguish AA. 6 , 29 Therapeutic options for AA, previously limited mainly to corticosteroids, sensitizers, and immunosuppressive agents, have recently expanded to include innovative treatments. Among these, JAK kinase inhibitors—such as upadacitinib—appear to be the most promising. 1 Treatment yields satisfactory results in patients with comorbidities without exacerbating the disease cause, as demonstrated in our patients. The study has potential limitations. The sample size used in this study containing two people’s cases, might not be sufficient for statistical measurements. Moreover the time frame of the study is short. It gives the information about results over the span of approximately one year after the treatment introduction. For more insight studies throughout few years should be performed. Even though those two cases give some insight into the matter and gives doctors a potential new way of treatment in cases of AA.

Treatment with upadacitinib for AA brings therapeutic success in patients with comorbidities reflected in both the physical and psychological state of the patient. Sarcoidosis and AA are two different diseases that may present similar dermatologic symptoms. During the diagnostic process, it is essential to consider the possible similarities and adjust the diagnosis accordingly to ensure a correct diagnosis and, consequently, effective treatment. The same thing goes for asthma and its connection with AA. Due to the increased likelihood of AA, patients with asthma should be carefully monitored and alerted to the possibility of symptoms.