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Fanning the Flames: IRAK2 Signaling in Differentiated Epithelium Potentiates Skin Inflammation [Comment]

Castillo, Rochelle; Subudhi, Ipsita; Naik, Shruti
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.
PMID: 34560916
ISSN: 1523-1747
CID: 5063102

A characterization of the gut and cutaneous microbiome of monozygotic twins discordant for psoriatic disease [Meeting Abstract]

Manasson, J; Stapylton, M; Medina, R; Castillo, R; Girija, P V; Heguy, A; Ubeda, C; Clemente, J; Scher, J
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
PMCID:
EMBASE:637275572
ISSN: 2326-5205
CID: 5164682

Methotrexate hampers immunogenicity to BNT162B2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease [Meeting Abstract]

Haberman, R; Herati, R; Simon, D; Samanovic, M; Tuen, M; Blank, R; Koralov, S; Atreya, R; Tascilar, K; Allen, J; Castillo, R; Cornelius, A; Rackoff, P; Solomon, G; Adhikari, S; Azar, N; Rosenthal, P; Izmirly, P; Samuels, J; Golden, B; Reddy, S; Neurath, M; Abramson, S B; Schett, G; Mulligan, M; Scher, J
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
PMCID:
EMBASE:637275567
ISSN: 2326-5205
CID: 5164692

Evaluation of SARS-CoV-2 IgG antibody reactivity in patients with systemic lupus erythematosus: analysis of a multi-racial and multi-ethnic cohort

Saxena, Amit; Guttmann, Allison; Masson, Mala; Kim, Mimi Y; Haberman, Rebecca H; Castillo, Rochelle; Scher, Jose U; Deonaraine, Kristina K; Engel, Alexis J; Belmont, H Michael; Blazer, Ashira D; Buyon, Jill P; Fernandez-Ruiz, Ruth; Izmirly, Peter M
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.
PMCID:8159192
PMID: 34075358
ISSN: 2665-9913
CID: 4891502

Induction of remission in biologic-naive, severe psoriasis and PsA with dual anti-cytokine combination

Haberman, Rebecca H; Castillo, Rochelle; Scher, Jose U
PMID: 33369644
ISSN: 1462-0332
CID: 4937242

Corrigendum to: Focal small bowel thrombotic microvascular injury in COVID-19 mediated by the lectin complement pathway masquerading as lupus enteritis

Plotz, Benjamin; Castillo, Rochelle; Melamed, Jonathan; Nuovo, Gerard; Magro, Cynthia; Rosenthal, Pamela; Belmont, H Michael
PMID: 34096576
ISSN: 1462-0332
CID: 4906012

Methotrexate Hampers Immunogenicity to BNT162b2 mRNA COVID-19 Vaccine in Immune-Mediated Inflammatory Disease

Haberman, Rebecca H; Herati, Ramin Sedaghat; Simon, David; Samanovic, Marie; Blank, Rebecca B; Tuen, Michael; Koralov, Sergei B; Atreya, Raja; Tascilar, Koray; Allen, Joseph R; Castillo, Rochelle; Cornelius, Amber R; Rackoff, Paula; Solomon, Gary; Adhikari, Samrachana; Azar, Natalie; Rosenthal, Pamela; Izmirly, Peter; Samuels, Jonathan; Golden, Brian; Reddy, Soumya; Neurath, Markus; Abramson, Steven B; Schett, Georg; Mulligan, Mark J; Scher, Jose U
Objective/UNASSIGNED:To investigate the humoral and cellular immune response to mRNA COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment. Methods/UNASSIGNED:Established patients at NYU Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunization. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analyzed for humoral response. Cellular immune response to SARS-CoV-2 was further analyzed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany were also analyzed for humoral immune response. Results/UNASSIGNED:Although healthy subjects (n=208) and IMID patients on biologic treatments (mostly on TNF blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, IMID patients do not demonstrate an increase in CD8+ T cell activation after vaccination. Conclusions/UNASSIGNED:In two independent cohorts of IMID patients, methotrexate, 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 methotrexate to increase the chances of immunization efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines. KEY MESSAGES/UNASSIGNED:These results suggest that patients on methotrexate may need alternate vaccination strategies such as additional doses of vaccine, dose modification of methotrexate, or even a temporary discontinuation of this drug. Further studies will be required to explore the effect of these approaches on mRNA vaccine immunogenicity.
PMCID:8132259
PMID: 34013285
ISSN: n/a
CID: 4877422

Focal small bowel thrombotic microvascular injury in COVID-19 mediated by the lectin complement pathway masquerading as lupus enteritis [Letter]

Plotz, Benjamin; Castillo, Rochelle; Melamed, Jonathan; Magro, Cynthia; Rosenthal, Pamela; Belmont, H Michael
PMCID:7665776
PMID: 33147605
ISSN: 1462-0332
CID: 4835212

EVALUATION OF SARS-COV-2 IGG ANTIBODY REACTIVITY IN A MULTI-RACIAL/ETHNIC COHORT OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS [Meeting Abstract]

Saxena, A; Guttmann, A; Masson, M; Kim, M Y; Haberman, R H; Castillo, R; Scher, J U; Deonaraine, K K; Engel, A J; Michael, Belmont H; Blazer, A D; Buyon, J P; Fernandez-Ruiz, R; Izmirly, P M
Background Patients with Systemic Lupus Erythematosus (SLE) represent a unique population at risk for COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. This study was initiated to evaluate for the presence of SARS-CoV-2 IgG antibodies in SLE patients with and without prior COVID-19-related symptoms or COVID-19 RT PCR testing. Methods A total of 329 patients with SLE from two cohorts, one serially monitored for COVID-19 in Spring 2020 (the Web-based Assesment of Autoimmune, Immune-Mediated and Rheumatic Patients (WARCOV) and one undergoing routine surveillance (NYU Lupus Cohort) were tested for SARS-CoV-2 IgG via commercially available immunoassays processed through hospital or outpatient laboratories between April 29, 2020 and February 9, 2021. Results Overall, 16% of 329 patients had a reactive SARSCoV- 2 IgG antibody test. Seropositive patients were more likely to be Hispanic. Other demographic variables, lupus-specific factors and immunosuppressant use were not associated with reactivity. Of the 29 patients with prior RT-PCR confirmed COVID-19, 83% developed an antibody response despite 62% being on immunosuppressants. Six percent of patients who had symptoms suspicious for COVID-19 but negative concurrent RT-PCR testing developed an antibody response. Twenty-three percent of patients who had COVID- 19-related symptoms but no RT-PCR testing and 5% of patients who had no symptoms of COVID-19 developed an antibody response. Among patients initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially. In COVID- 19-confirmed patients high percentages had antibody positivity beyond 30 weeks from disease onset, 88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks. Conclusions Most patients with SLE and confirmed COVID- 19 were able to produce a serologic response despite use of a variety of immunosuppressants. These findings provide reassurances regarding the efficacy of humoral immunity and possible reinfection protection in patients with SLE
EMBASE:638287648
ISSN: 2053-8790
CID: 5292912

Leveraging the United States Epicenter to Provide Insights on COVID-19 in Patients with Systemic Lupus Erythematosus

Fernandez-Ruiz, Ruth; Masson, Mala; Kim, Mimi Y; Myers, Benjamin; Haberman, Rebecca H; Castillo, Rochelle; Scher, Jose U; Guttmann, Allison; Carlucci, Philip M; Deonaraine, Kristina K; Golpanian, Michael; Robins, Kimberly; Chang, Miao; Belmont, H Michael; Buyon, Jill P; Blazer, Ashira D; Saxena, Amit; Izmirly, Peter M
OBJECTIVE:To characterize patients with Systemic Lupus Erythematosus (SLE) affected by COVID-19 and to analyze associations of comorbidities and medications on infection outcomes. METHODS:Patients with SLE and RT-PCR-confirmed COVID-19 were identified through an established New York University lupus cohort, query of two hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web-based questionnaire and review of medical records. Baseline characteristics were obtained for all patients with COVID-19 to analyze risk factors for hospitalization. Data were also collected from asymptomatic patients and those with COVID-19-like symptoms who tested negative or were not tested. Statistical analyses were limited to confirmed COVID-19-positive patients. RESULTS:A total of 226 SLE patients were included: 41 patients with confirmed COVID-19; 19 patients who tested negative for COVID-19; 42 patients with COVID-19-like symptoms who did not get tested; and 124 patients who remained asymptomatic without testing. Of those SLE patients with COVID-19, 24 (59%) required hospitalization, four required intensive care unit-level of care, and four died. Hospitalized patients tended to be older, non-white, Hispanic, have higher BMI, history of nephritis, and at least one comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least one comorbidity, and BMI as independent predictors of hospitalization. CONCLUSION/CONCLUSIONS:In general, the variables predictive of hospitalization in our SLE patients were similar to those identified in the general population. Further studies are needed to understand additional risk factors for poor COVID-19 outcomes in patients with SLE.
PMID: 32715660
ISSN: 2326-5205
CID: 4540102