Faculty Bibliography

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, a summary of the research conducted by the recipients of the 2020 GRAPPA Research Awards was presented by the awardees. The summary of the 4 presentations is provided here.

Immune checkpoint inhibitors (ICIs) are a class of medications targeting mostly the PD-1/PD-L1 and CTLA-4 immune pathways in the treatment of many cancers. Despite the encouraging success of ICIs, they are associated with immune-related adverse events as well as exacerbation of underlying autoimmune conditions. The treatment of these conditions often involves discontinuation of ICI in addition to the utilization of immunomodulatory agents. In this report, we discuss a case in which a patient with metastatic renal cell carcinoma experienced exacerbation of underlying paraneoplastic dermatomyositis after treatment with ICI. He was successfully continued on ICI with the use of intravenous immunoglobulin. The patient experienced adequate control of his myositis but also experienced deepening of his antitumor response.

Aberrant epidermal differentiation is a hallmark of inflammatory skin diseases, including psoriasis and atopic dermatitis. If and how differentiated epidermal cells contribute to inflammatory pathology is unclear. In their new article in the Journal of Investigative Dermatology, Shao et al. (2021) report that IRAK2 signaling downstream of IL-1 and IL-36 links epidermal differentiation and skin inflammation.

Background/Purpose: Psoriasis (PsO) is an inflammatory, immune-mediated skin disorder affecting ~3% of the population worldwide. It is associated with multiple comorbidities, including psoriatic arthritis (PsA), which occurs in up to a third of patients. While genes contribute to the pathogenesis of psoriatic disease, twin studies demonstrate substantial discordance in PsO and PsA, suggesting that epigenetics and environmental factors play a significant role. In fact, there is increasing evidence that the microbiome has an impact on psoriatic disease pathogenesis. However, prior investigations were performed in populations of unrelated individuals and could not discern environmental from genetic influences. To characterize the host-microbiome relationship, we studied the gut and skin microbiome of monozygotic (MZ) twins discordant for psoriatic disease in order to determine disease-specific microbial perturbations that are independent of host-genes.
Method(s): Stool and skin swabs were collected from subjects with psoriatic disease and their unaffected MZ twin siblings (pairs=9, n=18). Non-lesional (NL) or healthy skin was swabbed at three separate sites: bicep, scalp, and elbow/forearm. Fecal samples underwent shotgun metagenomic sequencing to deeply characterize the gut microbiome taxonomy and functional pathways at high resolution. Sequences were processed with the HUMAnN and MetaPhlAn2 pipelines. Skin swab samples underwent 16S rRNA sequencing to characterize the cutaneous bacterial microbiome. Forward sequences were processed with the QIIME2 pipeline and SILVA reference database. Downstream computational analysis was performed using several libraries in R, including DESeq2.
Result(s): In gut samples, the relative abundance of Ruminococcus bromii species was significantly reduced and two pathways related to tetrahydrofolate biosynthesis were upregulated in psoriatic twins compared to their corresponding unaffected siblings (Fig 1; p< 0.05, Mann-Whitney). In NL skin samples from psoriatic twins, there was a significant reduction in alpha diversity and beta diversity differences in microbial communities of the scalp, but not the bicep or elbow/forearm, compared to healthy samples from unaffected twins (Fig 2A-B; p< 0.05, Mann-Whitney and Permanova). Differential analysis of taxa in the scalp identified a higher abundance of the Bacillales order and related taxa, as well as a lower abundance of the Deinococcus genus and related taxa in psoriatic twins compared to their unaffected siblings (Fig 2C; p< 0.05 with FDR correction).
Conclusion(s): This is the first study exploring microbial differences in MZ twins discordant for psoriatic disease. In agreement with our previous results, we found that Ruminococcus is reduced or virtually absent in the gut of psoriatic patients, and may therefore be associated with psoriatic disease. Additionally, we discovered that even healthyappearing NL skin of psoriatic subjects, particularly in the scalp, exhibited microbial perturbations and decreased diversity compared to unaffected twins. A further understanding of these changes and their downstream effects should shed light into the pathogenesis of psoriatic disease beyond genetic susceptibility

Background/Purpose: Patients with immune mediated inflammatory disorders (IMIDs) have an inherently heightened susceptibility to infection and may be considered high risk for developing COVID-19. While data regarding the COVID-19 vaccine's immunogenicity in an immunocompetent adult population is rapidly emerging, the ability of IMID patients to adequately respond to these vaccines is not known. Here, we investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with IMIDs on immunomodulatory treatment Methods: Patients with immune mediated inflammatory disorders (IMIDs) have an inherently heightened susceptibility to infection and may be considered high risk for developing COVID-19. While data regarding the COVID-19 vaccine's immunogenicity in an immunocompetent adult population is rapidly emerging, the ability of IMID patients to adequately respond to these vaccines is not known. Here, we investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with IMIDs on immunomodulatory treatment.
Result(s): The NY cohort baseline characteristics are found in Table 1. The Erlangen cohort consisted of 182 healthy subjects, 11 subjects with IMID receiving TNFi monotherapy, and 20 subjects with IMID on MTX monotherapy. In both cohorts, healthy individuals and those with IMID not on MTX were similar in age, while those IMID patients receiving MTX were generally older. In the NY cohort, of the healthy participants, 96.3% demonstrated adequate humoral immune response. Patients with IMID not on MTX achieved a similar rate of high antibody response rate (91.8%), while those on MTX had a lower rate of adequate humoral response (75.0%) (Figure 1A). This remains true even after the exclusion of patients who had evidence of prior COVID-19 infection (P= 0.014). Of note, 3 out of the 4 IMID patients receiving rituximab did not produce an adequate response. Similarly, in the Erlangen validation cohort, 98.3% of healthy controls, 90.9% of patients with IMID receiving TNFi monotherapy, and 50.0% receiving MTX monotherapy achieved adequate immunogenicity (Figure 1B). These differences remain significant when combining the cohorts, using a stricter definition of adequate response, and in a subgroup analysis by age. Cellular response was also analyzed in a subgroup of the NY cohort before and after second vaccination. Activated CD8+ T cells (CD8+ T cells expressing Ki67 and CD38) and the granzyme B-producing subset of these activated CD8+ T cells, were induced in immunocompetent adults and those with IMID not on MTX, but not induced in patients receiving MTX (Figure 2).
Conclusion(s): In two independent cohorts of IMID patients, MTX, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking MTX to increase the chances of immunization efficacy against SARS-CoV-2, as has been demonstrated for other viral vaccines

Background/UNASSIGNED:Patients with systemic lupus erythematosus (SLE) are at risk of developing COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. We aimed to evaluate the presence of SARS-CoV-2 IgG antibodies in patients with SLE with or without previous COVID-19-related symptoms or RT-PCR-confirmed SARS-CoV-2 infection. Methods/UNASSIGNED:For this analysis, we included patients with SLE from two cohorts based in New York City: the Web-based Assessment of Autoimmune, Immune-Mediated and Rheumatic Patients during the COVID-19 pandemic (WARCOV) study; and the NYU Lupus Cohort (a prospective registry of patients at NYU Langone Health and NYC Health + Hospitals/Bellevue). Patients in both cohorts were tested for SARS-CoV-2 IgG antibodies via commercially available immunoassays, processed through hospital or outpatient laboratories. Patients recruited from the NYU Lupus Cohort, referred from affiliated providers, or admitted to hospital with COVID-19 were tested for SARS-CoV-2 IgG antibodies as part of routine surveillance during follow-up clinical visits. Findings/UNASSIGNED:67 [24%] of 278). Other demographic variables, SLE-specific factors, and immunosuppressant use were not associated with SARS-CoV-2 positivity. Of the 29 patients with COVID-19 previously confirmed by RT-PCR, 18 (62%) were on immunosuppressants; 24 (83%) of 29 patients tested positive for SARS-CoV-2 IgG antibodies. Of 17 patients who had symptoms of COVID-19 but negative concurrent RT-PCR testing, one (6%) developed an antibody response. Of 26 patients who had COVID-19-related symptoms but did not undergo RT-PCR testing, six (23%) developed an antibody response. Of 83 patients who had no symptoms of COVID-19 and no RT-PCR testing, four (5%) developed an antibody response. Among 36 patients who were initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially (88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks). Seven (70%) of ten patients with confirmed COVID-19 had antibody positivity beyond 30 weeks from disease onset. Interpretation/UNASSIGNED:Most patients with SLE and confirmed COVID-19 were able to produce and maintain a serological response despite the use of a variety of immunosuppressants, providing reassurance about the efficacy and durability of humoral immunity and possible protection against re-infection with SARS-CoV-2. Funding/UNASSIGNED:National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Bloomberg Philanthropies COVID-19 Response Initiative Grant.