Snapshot Dx Quiz: September 2018 Detailed Answers Cynthia X. Wang, BA 1 Milan J. Anadkat, MD 1,2 1 Washington University School of Medicine, St. Louis, Missouri 2 Division of Dermatology, St. Louis, Missouri WHAT IS YOUR DIAGNOSIS? Figure 1. Image credit: Milan Anadkat, Washington University in St. Louis. Questions 2 & 3 refer to the article by Jabbari et al. (http://dx.doi.org/10.1016/j.jid.2018.01.032)
1. What is your diagnosis? a. Telogen effluvium b. Frontal fibrosing alopecia c. Tinea capitis d. Alopecia areata e. Traction alopecia ANSWER: D. Alopecia areata Alopecia areata (AA) is a hair loss disorder caused by T-cell mediated autoimmune inflammation of the hair follicles leading to early entry of anagen hairs into the telogen phase (Messenger et al., 1986). It is characterized by rapid onset of hair loss in patchy, well-circumscribed areas of the scalp or body without any evident epidermal changes. AA usually involves limited regions of the scalp but approximately 5% of cases extend to involve 100% of the scalp, known as alopecia totalis (AT), or the entire body, known as alopecia universalis (AU). The diagnosis of AA can usually be obtained through clinical examination. A classic finding on trichoscopy is the presence of exclamation point hairs, which are short, broken-off hairs that are thinner towards the root. The lifetime risk of AA has been estimated to be approximately 2% with essentially equal frequency in both genders and peak incidence in the 20s and 30s (Mirzoyev et al., 2014). Some cases have shown a genetic basis with presentation in multiple family members. AA also has been associated with other autoimmune diseases, including vitiligo, psoriasis, and lupus erythematosus (Chu et al., 2011). Unfortunately, there is currently no definitive treatment for AA, although many medications have shown varying degrees of success. There is a paucity of robust, randomized controlled trials (RCTs) investigating treatments in AA, making evidence based management challenging. First-line treatment generally involves intralesional corticosteroids for isolated patches of hair loss, despite the fact there are no published RCTs investigating this usage. Other treatments for patients with more extensive hair loss or who cannot tolerate injections include topical corticosteroids and topical immunotherapy (Alkhalifah et al., 2010b). For most patients, the condition will resolve spontaneously within a year regardless of treatment, although many will experience more than one episode. However, there is evidence that the longer a patient goes without regrowth, the smaller the likelihood that hair will regrow. In general, it appears that patients with more extensive disease, such as AT or AU, a younger age at onset, and a history of atopy have a worse prognosis (Alkhalifah et al., 2010a). Discussion of incorrect answers A. Telogen effluvium is a nonscarring alopecia characterized by hair shedding due to an increased proportion of hairs entering the telogen phase of the hair growth cycle, often as a result of physiological or emotional stress. As opposed to the irregular, spotty distribution of hair loss in this image, hair loss with telogen effluvium is diffuse and generally would not progress to this extent.
B. Frontal Fibrosing Alopecia (FFA) is a type of primary cicatricial alopecia that leads to a distinctive pattern of progressive frontotemporal hair recession and eyebrow loss. The patient in this picture has separate patches of hair loss all across the scalp, as opposed to the progressive frontal hairline recession seen in FFA. C. Tinea capitis involves a cutaneous infection of the scalp with a dermatophyte fungus, most commonly Tricophyton or Microsporum. It presents with pruritus and scalp scaling with bald patches and broken hairs. The condition can cause scarring and resultant permanent hair loss. Although the patchy, circumscribed nature of tinea capitis can sometimes resemble AA, epidermal changes including scaling would be seen during an active infection. E. Traction alopecia is a form of scarring alopecia caused by constant, excessive tension on the hair from tight hairstyles or pulling. The irregular pattern of hair loss exhibited by this patient is not in a pattern indicative of traction.
2. Which of the following is TRUE? A. Alopecia areata is a primary scarring alopecia caused by lymphocytic inflammation and destruction of the hair follicles. B. In mouse models of AA, cytotoxic CD8 (+) NKG2d (+) T cells were necessary but not sufficient for induction of AA. C. Multiple TNF-α inhibitors have shown efficacy in the treatment of alopecia areata in small randomized clinical trials, including etanercept, adalimumab, and infliximab. D. Tofacitinib is a recombinant IL-1 inhibitor that is FDA-approved for the treatment of moderate-to-severe rheumatoid arthritis. E. Tofacitinib has been demonstrated to prevent and reverse AA in mouse models of AA. ANSWER: E. Tofacitinib has been demonstrated to prevent and reverse AA in mouse models of AA. Tofacitinib is an inhibitor of Janus kinase (JAK) enzymes with preferential inhibition of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3) (Dhillon, 2017). Janus kinases are important tyrosine kinase enzymes that are associated with cell-surface receptors; the extracellular binding of these cell-surface receptors causes activation of receptor-associated JAKS, which in turn act as binding sites for activators of transcriptions (STATs) that are responsible for the transcription of particular genes. This JAK-STAT signalling pathway plays an important role in the immune system and its dysregulation has been implicated in many diseases, including the dermatologic conditions of psoriasis, atopic dermatitis, and alopecia areata. Unlike other biologic agents such as TNF-α inhibitors, tofacitinib has shown considerable promise for the treatment of AA in animal models and small studies of patients. In a previous mouse study, both tofacitinib and ruxolitinib (another JAK kinase inhibitor) successfully prevented the development of AA and the expansion of CD8+ NKG2D+ T cells in mice grafted with skin from an AA-affected mouse, while the mice who did not receive the JAK inhibitors almost universally developed AA (Xing et al., 2014). Likewise, JAK inhibitors have been shown to cause significant hair regrowth in human AA patients in multiple retrospective studies and small case series, as well as a previous open-label, single-arm trial involving 66 subjects with severe AA (Kennedy Crispin et al., 2016). Discussion of incorrect answers A. AA is a non-scarring alopecia. This mechanisms stated would describe certain scarring alopecias including FFA and central centrifugal cicatricial alopecia. B. In mouse models of AA, cytotoxic CD8 (+) NKG2D (+) T cells were necessary AND sufficient for induction of AA. These cells produce IFN-γ and other inflammatory cytokines that lead to downstream activation of the JAK-STAT signalling pathway. C. No biologic agents have previously shown significant benefit in the treatment of AA. In fact, a previous study with etanercept showed no efficacy of etanercept for the management of
moderate-to-severe alopecia areata (Strober et al., 2005). AA has also been reported to occur during treatment with other TNF-α inhibitors as well, such as adalimumab and infliximab (Tauber et al., 2014). D. IL-1 inhibition describes the mechanism of anakinra, a recombinant human IL-1 receptor antagonist that is another FDA-approved biologic agent for rheumatoid arthritis.
3. Which of the following is FALSE according to the article by Jabbari et al.? A. For the patients who achieved a global overall improvement in SALT score at treatment discontinuation, average hair regrowth was greater than 50%. B. Percent hair regrowth was similar between the lower dose of tofacitinib, 5 mg BID, and the higher dose, 10 mg BID. C. Hair growth was seen as soon as four weeks after initiation of the effective dose of tofacitinib. D. Patients with patch-type AA, alopecia totalis, and alopecia universalis exhibited similar percentages of hair regrowth at the end of study treatment. E. Tofacitinib was well-tolerated in the study patients with no serious adverse events. ANSWER: B. Percent hair regrowth was similar between the lower dose of tofacitinib, 5 mg BID, and the higher dose, 10 mg BID. In the study by Jabbari et al., the authors undertook an open-label, phase 2 clinical trial to investigate the use of oral tofacitinib in moderate-to-severe AA. Patients were treated with an initial dose of oral tofacitinib 5 mg twice daily for at least one month, then 10 mg + 5 mg daily for at least 1 month, and finally 10 mg twice daily if the patient still had not shown terminal hair regrowth on the scalp. The primary efficacy endpoint was clinical response as defined by > 50% percent hair regrowth as measured by the Severity in Alopecia Tool (SALT), a scoring system that represents extent of hair loss and is determined visually by using four views of the scalp. Eight out of the 12 patients met this cutoff of > 50% hair regrowth from baseline by SALT assessment. Moreover, 11 out of 12 patients achieved a global improvement in SALT score at the end of treatment, with an average of 56.8% regrowth in these 11 responders (Answer A). This improvement did not differ between patch-type AA, AT, and AU, with an average of 52.2% regrowth in the subjects with AT/AU, and 52.1% in those with patch-type AA (Answer D). The medication was also generally well-tolerated by all the patients with no serious adverse events (answer E), although one patient dropped out due to the primary physician s concern for hypertension. Ultimately, the effective dose of tofacitinib in this trial appeared to be 10 mg BID (Answer B is false the correct answer). Of the eight patients who reached the primary efficacy end point (> 50% hair regrowth), all but one patient failed to respond to the lower doses, but then responded as soon as four weeks after starting 10 mg BID (Answer C). Nevertheless, this phase 2 clinical trial provides further evidence that tofacitinib may be beneficial for hair regrowth in the treatment of AA. Discussion of incorrect answers A, C, D, E: All these statements are true findings of the study by Jabbari et al. (See explanation of correct answer).
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