Cysteamine Isobionic-Amide Complex Versus Kligman's Formula for the Treatment of Melasma: Equal Efficacy and Rapid Onset of Action.

BACKGROUND: Modified Kligman's formula (mKF) is the gold standard treatment for melasma; however, its prolonged use is not recommended due to side effects. Cysteamine is a potent, safe, and effective depigmenting agent. Here, we conducted a double-blind, randomized, and placebo-controlled clinical trial to assess the efficacy of cysteamine isobionic-amide -- a complex with enhanced depigmenting efficacy -- and compared it to mKF for the treatment of melasma. METHODS: This study involved a total of 80 patients divided into 3 groups: cysteamine-isobionic amide, placebo, or mKF. The modified Melasma Area Severity Index (mMASI) score and spectrophotometric evaluation were conducted at baseline, week 4, week 8, and week 16. Dermatological assessment, patients’ feedback, and satisfaction including quality-of-life scores were also collected. RESULTS: At week 4, cysteamine isobionic-amide and mKF groups showed an equivalent onset of action in terms of mMASI and skin pigmentation contrast reduction. The 2 groups significantly reduced melasma severity and improved the overall skin condition with a comparable efficacy at week 16. Quality of life of melasma patients was significantly improved in the cysteamine isobionic-amide group at week 8 and further at week 16 (P<0.001) compared to the mKF group. Patients’ feedback and satisfaction were higher with the cysteamine isobionic-amide product compared to mKF. CONCLUSION: Cysteamine isobionic-amide provided a rapid onset of action and was as effective as the mKF for the treatment of melasma. The data suggest that cysteamine isobionic-amide could potentially be an acceptable alternative to mKF for the long-term treatment of melasma. J Drugs Dermatol. 2024;23(2):9-16.  doi:10.36849/JDD.7428.

Feasibility of oral tranexamic acid for vitiligo patients with melasma.

Melasma and vitiligo are both common pigmentary disorders, and the treatment is challenging. Oral tranexamic acid (TA) is effective for refractory melasma; however, the feasibility of TA in vitiligo patients with melasma was not studied. To evaluate the treatment outcomes and adverse effects of oral TA in vitiligo patients with melasma. We conducted a retrospective analysis of vitiligo patients who received oral TA for melasma in a tertiary dermatologic center from January 2017 to August 2020. We enrolled 32 patients with concomitant vitiligo and melasma on the face. The mean duration of the improvement of melasma that patients reported is around 1.64 months of treatment. The first sign of repigmentation of the vitiligo lesions occurred at 1 month of treatment. 84.38% of the patients achieved a mild to good degree of improvement of melasma (0%-75% improvement), whereas 81.25% of the patients achieved a moderate to excellent degree of improvement of vitiligo (25%-100% improvement) via physician global assessments. No significant adverse event was noted. No patients experience vitiligo disease deterioration during TA treatment. Oral TA may be a feasible option for melasma in vitiligo patients.

Deep Cutaneous Neoscytalidium dimidiatum Infection: Successful Outcome with Amphotericin B Therapy.

Phaeohyphomycosis is a term used to describe a heterogenous group of cutaneous and systemic mycotic infections caused by melanized fungi. Many fungi have been reported as pathogens of this disease. The disease spectrum ranges from superficial cutaneous infections, deep cutaneous infections, to systemic infections with internal organ involvement. We report two cases of deep cutaneous phaeohyphomycosis on the foot clinically presenting as cellulitis with abscess formation. The pathogens were isolated from the lesion and both were identified as Neoscytalidium dimidiatum by their colony morphology, microscopic features, and sequences of internal transcribed spacers of ribosomal DNA. Both patients did not respond to the therapy with voriconazole and itraconazole, but improved after intravenous amphotericin B.

Phytochemicals in Skin Cancer Prevention and Treatment: An Updated Review.

Skin is the largest human organ, our protection against various environmental assaults and noxious agents. Accumulation of these stress events may lead to the formation of skin cancers, including both melanoma and non-melanoma skin cancers. Although modern targeted therapies have ameliorated the management of cutaneous malignancies, a safer, more affordable, and more effective strategy for chemoprevention and treatment is clearly needed for the improvement of skin cancer care. Phytochemicals are biologically active compounds derived from plants and herbal products. These agents appear to be beneficial in the battle against cancer as they exert anti-carcinogenic effects and are widely available, highly tolerated, and cost-effective. Evidence has indicated that the anti-carcinogenic properties of phytochemicals are due to their anti-oxidative, anti-inflammatory, anti-proliferative, and anti-angiogenic effects. In this review, we discuss the preventive potential, therapeutic effects, bioavailability, and structure-activity relationship of these selected phytochemicals for the management of skin cancers. The knowledge compiled here will provide clues for future investigations on novel oncostatic phytochemicals and additional anti-skin cancer mechanisms.

Cutaneous Exophiala oligosperma Infection in a Patient with Bullous Pemphigoid with a Review of the Literature.

Phaeohyphomycosis is an infection caused by a heterogeneous group of melanized fungi. Human infections due to members of genus Exophiala are rare but may occur at any part of the body. We herein report a case of an 85-year-old male with a history of bullous pemphigoid who presented with a chronic, non-healing wound on his right dorsal hand for a month. Direct microscopy of a pus sample from the base of the ulcer revealed strands of pigmented, moniliform hyphae. The isolate was identified as E. oligosperma based on morphological characters and sequencing of the rDNA internal transcribed spacers (ITS) and partial beta-tubulin gene. The patient received a three-month course of oral itraconazole with no recurrence.

Evaluation of Laser-Assisted Trans-Nail Drug Delivery with Optical Coherence Tomography.

The nail provides a functional protection to the fingertips and surrounding tissue from external injuries. The nail plate consists of three layers including dorsal, intermediate, and ventral layers. The dorsal layer consists of compact, hard keratins, limiting topical drug delivery through the nail. In this study, we investigate the application of fractional CO2 laser that produces arrays of microthermal ablation zones (MAZs) to facilitate drug delivery in the nails. We utilized optical coherence tomography (OCT) for real-time monitoring of the laser-skin tissue interaction, sparing the patient from an invasive surgical sampling procedure. The time-dependent OCT intensity variance was used to observe drug diffusion through an induced MAZ array. Subsequently, nails were treated with cream and liquid topical drugs to investigate the feasibility and diffusion efficacy of laser-assisted drug delivery. Our results show that fractional CO2 laser improves the effectiveness of topical drug delivery in the nail plate and that OCT could potentially be used for in vivo monitoring of the depth of laser penetration as well as real-time observations of drug delivery.

A comparative study of an advanced skin imaging system in diagnosing facial pigmentary and inflammatory conditions.

Visual assessment, while the primary method for pigmentation and erythema evaluation in clinical practice, is subjective, time-consuming, and may lead to variability in observations among clinicians. Objective and quantitative techniques are required for a precise evaluation of the disease's severity and the treatment's efficacy. This research examines the precision and utility of a newly developed skin imaging system in assessing pigmentation and erythema. Sixty participants were recruited, and their facial images were analyzed with the new OBSERV 520 x skin imaging system, compared to DERMACATCH for regional analysis and VISIA for full-face examination. The degree of skin pigmentation was clinically graded using the MASI scores evaluated by dermatologists. The data revealed positive correlations between the novel skin imaging system and the two conventional instruments in quantifying pigmentation and erythema, whether in regional or full-face analysis. Furthermore, the new skin imaging system positively correlated with the clinical MASI scores (r = 0.4314, P < 0.01). In contrast, our study found no significant correlation between the traditional system and clinical assessment, indicating a more substantial capacity for hyperpigmentation assessment in the new system. Our study validates the innovative skin imaging system's accuracy in evaluating pigmentation and erythema, demonstrating its feasibility for quantitative evaluation in both clinical and research purposes.

Feasibility of High-Cellular-Resolution Full-Field, Artificial-Intelligence-Assisted, Real-Time Optical Coherence Tomography in the Evaluation of Vitiligo: A Prospective Longitudinal Follow-Up Study.

Vitiligo, a psychologically distressing pigmentary disorder characterized by white depigmented patches due to melanocyte loss, necessitates non-invasive tools for early detection and treatment response monitoring. High-cellular-resolution full-field optical coherence tomography (CRFF-OCT) is emerging in pigmentary disorder assessment, but its applicability in vitiligo repigmentation after tissue grafting remains unexplored. To investigate the feasibility of CRFF-OCT for evaluating vitiligo lesions following tissue grafting, our investigation involved ten vitiligo patients who underwent suction blister epidermal grafting and laser ablation at a tertiary center between 2021 and 2022. Over a six-month period, clinical features, dermoscopy, and photography data were recorded. Utilizing CRFF-OCT along with artificial intelligence (AI) applications, repigmentation features were captured and analyzed. The CRFF-OCT analysis revealed a distinct dark band in vitiligo lesion skin, indicating melanin loss. Grafted areas exhibited melanocytes with dendrites around the epidermal-dermal junction and hair follicles. CRFF-OCT demonstrated its efficacy in the early detection of melanocyte recovery and accurate melanin quantification. This study introduces CRFF-OCT as a real-time, non-invasive, and in vivo evaluation tool for assessing vitiligo repigmentation, offering valuable insights into pigmentary disorders and treatment responses.

COVID-19 vaccine-associated vitiligo: A cross-sectional study in a tertiary referral center and systematic review.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to infect patients globally, vaccination remains one of the primary methods to combat this prolonged pandemic. However, there are growing reports of coronavirus disease 2019 (COVID-19) vaccines possibly triggering autoimmunity, irrespective of the vaccine's design. This phenomenon has been observed in patients with vitiligo, with a rising number of cases reporting new-onset or worsening vitiligo following COVID-19 vaccinations. In this study, the authors present the most extensive case series of COVID-19 vaccine-associated vitiligo to date, along with a systematic review of the literature. The aim is to assist physicians in the clinical evaluation of patients with vitiligo with regard to future vaccinations.

Targeting the elevated IFN-γ in vitiligo patients by human anti- IFN-γ monoclonal antibody hampers direct cytotoxicity in melanocyte.

BACKGROUND: Vitiligo is an autoimmune disease that progressively destroys melanocytes in the skin, resulting in patchy disfiguring depigmentation. The direct pathological effect of IFN-γ, CXCL10 to the melanocytes in vitiligo has been reported, but there are contradictory results to which cytokine exerts the critical cytotoxic effect on melanocytes. OBJECTIVE: The overarching goal was to study the direct toxicity of highly expressed cytokine in vitiligo skin lesions to melanocytes. METHODS: We obtained the interstitial fluid analyte from lesion and non-lesion skin of vitiligo patients and healthy control and sent for high sensitivity multiplex cytokine panel. We further performed functional study to identify the direct toxicity effect of the highly expressed cytokines. RESULTS: We found a significant elevation of IFN-γ, CXCL9, CXCL10, CXCL11 in the vitiligo skin. Ex vivo melanocyte studies support the direct role of IFN-γ per se in melanocyte cell loss, increased oxidative stress and melanogenesis disruption. Interestingly, we found that IFN-γ regulated cell death through oxidative stress-related ferroptosis cell death, which may initiate autoimmunity in vitiligo. In contrast to blocking selected cell death pathway, our in vitro study supports the rescue effect of human anti-IFN-γ monoclonal antibody 2A6Q to IFN-γ induced cell death, oxidative stress, and loss of function in melanocytes by interrupting IFN-γ signaling, which may be a potential therapeutic option for vitiligo. CONCLUSION: This study further confirms the direct of toxicity effect of IFN-γ per se towards melanocyte in vitiligo skin and the potential utility of human anti-IFN-γ monoclonal antibody in treating vitiligo.

In Vivo Identification of Skin Photodamage Induced by Fractional CO2 and Picosecond Nd:YAG Lasers with Optical Coherence Tomography.

Fractional laser treatment is commonly used for dermatological applications, enabling effective induction of collagen regeneration and significantly reducing recovery time. However, it is challenging to observe laser-induced photodamage beneath the tissue surface in vivo, making the non-invasive evaluation of treatment outcomes difficult. For in vivo real-time study of the photodamage induced by fractional pulsed CO2 and Nd:YAG lasers commonly utilized for clinical therapy, a portable spectral-domain optical coherence tomography (SD-OCT) system was implemented for clinical studies. The photodamage caused by two lasers, including photothermal and photoacoustic effects, was investigated using OCT, together with the correlation between photodamage and exposure energy. Additionally, to investigate the change in the optical properties of tissue due to photodamage, the attenuation coefficients and damaged areas of normal skin and laser-treated skin were estimated for comparison. Finally, the recovery of the exposed skin with both lasers was also compared using OCT. The results show that OCT can be a potential solution for in vivo investigation of laser-induced tissue damage and quantitative evaluation.

Optimizing surgical outcome of auricular keloid with a novel multimodal approach.

Various treatments are available for auricular keloids, but none has an absolute advantage. A practical and safe therapy to optimize the surgical outcome for auricular keloids is needed. We adopted a multimodal treatment of surgical enucleation, core fillet flap reconstruction, intraoperative corticosteroid injection, and immediate postoperative radiotherapy. There were no routine intralesional corticosteroid injections during follow-up. Keloid recurrences, complications, and risk factors for recurrences were analyzed. The outcome was compared with other published literatures. 45 auricular keloids were included in this study. 85.7% were female with an average age of 27.1 ± 7.5 years, and averaged size was 1.8 × 1.2 ± 0.9 × 0.6 cm. 71.1% were located at ear helix with 28.9% at the ear lobe. Nine keloids were classified as Chang-Park classification type I, 30 for type II, two for type III, and four for IV. The average radiation dosage was 1578.6 cGy. The recurrence rate was 6.7% at an average 24.1-month follow-up. There were no complications of surgery, radiotherapy, and intralesional corticosteroid injection. Our recurrence rate was lower than those in mono-adjuvant therapies of intraoperative corticosteroid injection or radiotherapy. This one-session multimodal approach optimizes treating auricular keloids with a low recurrence rate and minimal post-radiation and long-term corticosteroid injection-related complications.

Anti-IL-17A antibody-associated de novo vitiligo: Case report and review of literature.

Interleukin (IL)-17 inhibitor is a biological therapy approved for moderate to severe psoriasis and psoriatic arthritis. The common adverse events of IL-17 inhibitor include injection site reaction, infections, nasopharyngitis, and headache. However, vitiligo associated with the use of IL-17 inhibitors was rarely reported in the previous literature. Here we described a woman who developed de novo vitiligo after 4 months of IL-17A inhibitor treatment for psoriasis and psoriatic arthritis. Upon discontinuation of IL-17A inhibitor and shifting to a broader T cell inhibitor-cyclosporine, our patient had control of both psoriasis and vitiligo and achieved 75% repigmentation after 3 months of oral cyclosporine without phototherapy. Due to the increasing use of anti-IL-17 biologics in psoriasis patients, clinicians should inquire about vitiligo's history before treatment and inform patients of the possible adverse effects.

Riehl's Melanosis: A Multimodality, In Vivo, Real-Time Skin Imaging Study with Cellular Resolution Optical Coherence Tomography and Advanced Skin Diagnosis System in a Tertiary Medical Center.

BACKGROUND: Riehl's melanosis is a psychologically devastating hyperpigmentary disorder that typically occurs on the face and neck. The study of Riehl's melanosis is limited due to its rarity, variable morphology, and lack of noninvasive diagnostic tools. Recent advances in skin imaging analysis and diagnostic systems improve diagnostic accuracy and enable the noninvasive, real-time evaluation of pigmentary disease. A comprehensive study of Riehl's melanosis clinical morphology with multimodality and in vivo skin imaging systems has yet to be reported. OBJECTIVES: To investigate the clinical features and in vivo advanced skin imaging findings of Riehl's melanosis. METHODS: We retrospectively investigated the clinical characteristics, dermoscopic, and histopathological features of Riehl's melanosis. We further utilized multimodality skin imaging analysis systems, including a cellular resolution optical coherence tomography (OCT) and new skin diagnosis system, to investigate the features of Riehl's melanosis. In addition, we compared OCT findings with histopathological features and clinical assessment. RESULTS: We evaluated 30 patients with Riehl's melanosis at a tertiary medical center from 2010 to 2022. The average age was 47.7 ± 12.3 (mean ± SD) years, predominantly female patients (female: n = 23; male: n = 7). Cellular resolution OCT imaging from lesion skin shows increased melanocyte capping, disrupted basement membrane, telangiectatic blood vessels, and melanophages in the dermis. The advanced skin diagnosis system captured subclinical erythema of the skin, highlighting the inflammatory nature of the disease. The results correlated well with histopathological findings. LIMITATIONS: This is a single-center, cross-sectional study. CONCLUSIONS: We highlight the features of Riehl's melanosis through a novel cellular resolution OCT and photographic skin diagnosis system. A multimodality skin diagnosis system can serve as a real-time, in vivo, noninvasive method for evaluating pigmentary disorders.

Skin Interstitial Fluid and Plasma Multiplex Cytokine Analysis Reveals IFN-γ Signatures and Granzyme B as Useful Biomarker for Activity, Severity and Prognosis Assessment in Vitiligo.

Background: The course of vitiligo is unpredictable, with periods of disease flare-ups and prolonged recovery periods. It is essential to establish a biomarker profile as a substitute marker for disease activity to predict disease activity, severity, and prognosis prediction. The use of localized skin interstitial fluid as biomarkers has recently gained interest, but extensive studies of the association between skin interstitial fluid, plasma, and the disease course is lacking. This study aims to evaluate the cytokine expression profiles in the skin and plasma and the utility of the biomarker panel in assessing disease activity, severity, and prognosis in patients with vitiligo. Methods: In this prospective cohort study, 86 patients and 34 healthy controls were recruited from the outpatient department of a tertiary medical center from March 2019 to September 2021. All patients were of Asian ethnicity. Two independent investigators evaluated disease activity and severity with longitudinal follow-ups for treatment response for a-12 month period. Ultrasensitive multiplex cytokine panel and single-molecule counting technology immunoassays were used to study the cytokine expression in skin interstitial fluid and plasma. Results: IFN-γ and its' signature cytokines, including CXCL9, CXCL10, and GzmB, are most highly expressed in the vitiligo patients' lesion skin interstitial fluid and plasma compared to healthy control. By way of comparison, no significant changes in IL-1ß, IL-13, IL-15, IL-17A, IL-18 were observed. Receiver operating characteristic analysis revealed that IFN-γ is the most sensitive and specific marker in predicting disease activity, followed by CXCL10 and GzmB. CXCL-9 was sensitive and specific in diagnosing vitiligo disease severity. The decrease in IFN-γ expression level is positively correlated with the treatment response. Conclusion: IFN-γ, CXCL9, CXCL10, and GzmB are highly expressed in vitiligo patients' lesion skin and plasma and may serve as biomarkers for the clinical activity, severity, and prognosis prediction in vitiligo patients. Among all, IFN-γ exerts the highest predictive value in disease activity and treatment response, supporting the critical role of IFN-γ in the pathogenesis of vitiligo.

A comparative study of suction blister epidermal grafting and automated blister epidermal micrograft in stable vitiligo.

The automated blister epidermal micrograft (ABEM) is a newly introduced surgical transplantation for refractory vitiligo. Comparative analysis of other surgical methods is lacking. We conducted a retrospective study to compare the efficacy, safety, and experience of ABEM with conventional suction blister epidermal graft (SBEG). A total of 118 anatomically based vitiligo lesions from 75 patients were included. The primary outcome was the degree of repigmentation; the patient and operator experience were evaluated. SBEG had a significantly greater incidence of repigmentation (p < 0.001), as measured by the Physician Global Assessment, as well as improvements in the Vitiligo Area Scoring Index, particularly on the face/neck area (p < 0.001). ABEM, on the contrary, had reduced donor harvest time, a better patient operative experience, and more significant Dermatology Life Quality Index improvements. In a subgroup of 38 lesions from ten patients who received both SBEG and ABEM concomitantly, there was no difference in the degree of repigmentation in the same recipient area. Overall, the degree of repigmentation for SBEG is higher than ABEM, especially in the mobilized region, and the cost is less expensive. On the contrary, ABEM requires less procedure learning curve and can supply a greater transplanting zone with shorter donor site recovery. Understanding the benefits and drawbacks of two blister grafting procedures is essential for optimal surgical outcomes for vitiligo grafting.

Efficacy and safety of automated epidermal micrograft in patients with stable segmental and nonsegmental vitiligo.

Vitiligo is a common, psychologically devastating pigmentary disorder. Surgical graftings are used to treat stable vitiligo when medical treatment fails. An automated epidermal micrograft harvesting (AEMH) system was first designated to treat wounds, and very few studies investigated the application of AEMH in vitiligo. In this study, we investigated the efficacy and safety of the AEMH system in patients with stable segmental and nonsegmental vitiligo. The rate of repigmentation and adverse events was recorded bimonthly for at least 12 months. We analyzed the efficacy based on patient characteristics, vitiligo subtypes, and different anatomical locations. A total of 56 depigmented lesions from 34 patients were included. 95.50% of the automated epidermal micrografts were successfully grafted at the recipient sites. There was a significant improvement in Vitiligo Area Scoring Index (VASI) and Dermatologic Life Quality Index (DLQI) in patients treated with AEMH (p < 0.001). The rate of repigmentation by VASI score improves from 96.25 ± 8.59 to 48.30 ± 28.16 after the treatment (p < 0.001). Treatment outcomes were comparable between the patients of segmental and stable nonsegmental vitiligo. The face and neck region achieved a better outcome, followed by the trunk (chest, abdomen, back, and axilla), limbs, and the worse outcome was found in the acral region (p < 0.014). Conclusively, AEMH is an effective treatment procedure with limited adverse events in patients with stable vitiligo. This harvesting method may be a feasible option for vitiligo surgical treatment.

Diabetic Patients With Rosacea Increase the Risks of Diabetic Macular Edema, Dry Eye Disease, Glaucoma, and Cataract.

PURPOSE: Inflammation plays a role in diabetic eye diseases, but the association between rosacea and eye diseases in patients with diabetes remains unknown. DESIGN: This retrospective cohort study used claims data from the National Health Insurance Research Database in Taiwan to investigate the association between rosacea and eye diseases in patients with diabetes. MATERIALS AND METHODS: Taiwanese patients diagnosed as having diabetes mellitus between January 1, 1997, and December 31, 2013, and using any hypoglycemic agents were included and divided into rosacea and nonrosacea groups. After applying 1:20 sex and age matching and exclusion criteria, 1:4 propensity score matching (PSM) was conducted to balance the covariate distribution between the groups. The risk of time-to-event outcome between rosacea and nonrosacea groups in the PSM cohort was compared using the Fine and Gray subdistribution hazard model. RESULTS: A total of 4096 patients with rosacea and 16,384 patients without rosacea were included in the analysis. During a mean follow-up period of 5 years, diabetic patients with rosacea had significantly higher risks of diabetic macular edema [subdistribution hazard ratio (SHR): 1.31, 95% confidence interval (CI): 1.05-1.63], glaucoma with medical treatment (SHR: 1.11, 95% CI: 1.01-1.21), dry eye disease (SHR: 1.55, 95% CI: 1.38-1.75), and cataract surgery (SHR: 1.13, 95% CI: 1.02-1.25) compared with diabetic patients without rosacea. A cumulative incidence analysis performed up to 14 years after the index date revealed that the risks of developing ocular diseases consistently increased over time. No significant differences in diabetic retinopathy, age-related macular degeneration, retinal vascular occlusion, ischemic optic neuropathy, optic neuritis, uveitis, or retinal detachment were identified according to rosacea diagnosis. However, we observed significant associations between rosacea and psoriasis, irritable bowel syndrome, anxiety, and major depressive disorder among patients with diabetes. CONCLUSIONS: Rosacea is associated with diabetic macular edema, glaucoma, dry eye disease, and cataract development in diabetic patients, as well as increased risks of psoriasis, irritable bowel syndrome, anxiety, and depression in diabetic patients.

Implementation of NUDT15 Genotyping to Prevent Azathioprine-Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population.

Azathioprine (AZA) is commonly used for many autoimmune disorders; however, the limitation of its clinical use is due to potential toxicities, including severe leukopenia. Recent studies have identified genetic NUDT15 variants strongly associated with AZA-induced leukopenia in Asian patients. This study aimed to investigate the strength of above genetic association and evaluate the usefulness of prospective screening of the NUDT15 variants to prevent AZA-induced leukopenia in Chinese patients. AZA-induced leukopenia in patients with autoimmune disorders were enrolled from multiple medical centers in Taiwan/China between 2012 and 2017 to determine the strength of genetic association of NUDT15 or TPMT variants by whole exome sequencing (WES). Furthermore, a prospective study was conducted between 2018 and 2021 to investigate the incidence of AZA-induced leukopenia with and without genetic screening. The WES result showed the genetic variants of NUDT15 R139C (rs116855232) (P = 3.7 × 10-25 , odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1-38.8) and NUDT15 rs746071566 (P = 4.2 × 10-9 , OR = 7.1, 95% CI = 3.7-13.7), but not TPMT, were associated with AZA-induced leukopenia and NUDT15 R139C variant shows the highest sensitivity with 92.5%. Furthermore, the targeted screening of 1,013 participants for NUDT15 R139C enabled those identified as carriers to use alternative immunosuppressants. This strategy resulted in a significant decrease in the incidence of AZA-induced leukopenia compared with historical incidence (incidence rate = from 7.6% decreased to 0.4%; P = 9.3 × 10-20 ). In conclusion, the NUDT15 R139C variant was strongly associated with AZA-induced leukopenia in Chinese patients. The genetic screening of NUDT15 R139C followed by use of alternative immunosuppressants in identified carriers effectively decreased the incidence of AZA leukopenia for patients with autoimmune disorders.

Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response.

Anti-interferon (IFN)-γ autoantibodies (AIGAs) are a pathogenic factor in late-onset immunodeficiency with disseminated mycobacterial and other opportunistic infections. AIGAs block IFN-γ function, but their effects on IFN-γ signaling are unknown. Using a single-cell capture method, we isolated 19 IFN-γ-reactive monoclonal antibodies (mAbs) from patients with AIGAs. All displayed high-affinity (KD < 10-9 M) binding to IFN-γ, but only eight neutralized IFN-γ-STAT1 signaling and HLA-DR expression. Signal blockade and binding affinity were correlated and attributed to somatic hypermutations. Cross-competition assays identified three nonoverlapping binding sites (I-III) for AIGAs on IFN-γ. We found that site I mAb neutralized IFN-γ by blocking its binding to IFN-γR1. Site II and III mAbs bound the receptor-bound IFN-γ on the cell surface, abolishing IFN-γR1-IFN-γR2 heterodimerization and preventing downstream signaling. Site III mAbs mediated antibody-dependent cellular cytotoxicity, probably through antibody-IFN-γ complexes on cells. Pathogenic AIGAs underlie mycobacterial infections by the dual blockade of IFN-γ signaling and by eliminating IFN-γ-responsive cells.