ABSTRACT
Alopecia areata (AA) is an immune-mediated condition, clinically manifesting as non-cicatricial patches of alopecia. It is often a self-limiting condition; however, regrowth of hair can take a long period of time, resulting in significant psychological comorbidity. With the recent advances in pathomechanisms of AA, the therapeutic approach to the condition has become more specific, and targeted therapy with small molecules is probably the ideal intervention. Many therapies exist for AA, but none of the systemic agents were approved, until recently, when baricitinib (Janus kinase (JAK1 and JAK2 inhibitor) gained FDA approval for the treatment of adult patients with severe AA. JAK inhibitors (JAKibs) target the γc cytokine and interferon-gamma (IFN-γ) signaling pathway, which is critical to the immunopathogenesis of AA and thus can reverse the hair loss in AA. Although JAKibs are emerging as a promising treatment modality for AA, the ideal JAKib is not yet settled, as there is scant data on H-2-H (head-to-head) comparisons of JAK inhibitors in AA. Moreover, the response achieved with JAKibs is not sustained after treatment discontinuation, with many studies showing a high recurrence rate with tofacitinib and ruxolitinib post-treatment. Also, recent studies have hypothesized that JAK2, with its ubiquitous expression, can cause adverse effects, unlike JAK1, which is associated with multiple major cytokine receptor families and JAK3, which is exclusively associated with the γc cytokine receptor. Thus, JAK3ibs may be associated with a better side effect profile and, in conjunction with their specificity, may replace other JAKibs as the treatment of choice for AA. We herein discuss the role of the JAK/STAT (signal transducer and activator of transcription) pathway in AA, the intricacies of various JAKibs in the management of AA, and emphasize the need for studies on tissue JAK and cytokine expression before arriving at the ideal JAKibs for AA.
ABSTRACT
BACKGROUND: Corticosteroids remain the main therapy in erythema nodosum leprosum (ENL), and long-term usage in chronic or recurrent ENL is a cause of significant morbidity and mortality. Thalidomide exerts dramatic effect in controlling ENL and helps reduce the dose of steroids, but the cost is a hindrance to its usage. METHODS: Patients of ENL (steroid naïve and steroid-dependent) were recruited over a 1-year period. An escalating dose of low-dose thalidomide with a reducing dose of prednisolone was titrated depending on the control of disease activity. The primary aim was to reduce the dose of steroids to the lowest effective dose, and the secondary aim was to stop. RESULTS: Sixteen patients of ENL were studied (mean duration of ENL 22.1 months, 15 severe ENL), and a majority (11/16, 68%) were on steroids with a mean duration of 11.27 months. All patients had steroid-related side effects (cushingoid habitus 81.8%, weight gain 54.5%, diabetes mellitus 9%, hyperlipidemia 18.18%, cataract 18.1%, osteoporosis 36.3%, striae 36.3%, acneiform eruptions 18.1%, and myopathy 9%). Steroids could be tapered in a majority of patients (n = 9) within 3 months (mean 2.44 months) with a low dose of thalidomide (25-150 mg/day, mean 78.3 mg) achieving a significant reduction in prednisolone dose (33.16 mg at baseline; 4.28 mg at 3 months, P < 0.05). Steroids could be stopped in 92% of patients by 3.03 months, and both drugs could be stopped in 80% of cases by 5.83 months. CONCLUSION: The rapid and effective control of ENL with low-dose thalidomide in our series is comparable to the historical efficacy of high-dose thalidomide regimens, making it an affordable therapy in resource-constrained settings and an excellent steroid-sparing agent. The rapid onset of disease control is likely attributable to its action via neutrophils.