Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction.

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into the metabolite 15-keto PGE2, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.

Semiparametric Allocation of Subjects to Cohort Strata.

BACKGROUND: We illustrate a method for stratum assignment in small cohort studies that avoids modeling assumptions. METHODS: Off-the-shelf software ( rgenoud ) made stratum assignments to minimize a loss function built on within-stratum and population-adjusted Euclidean distances. RESULTS: In 100 trials using simulated data of 300 records with a binary treatment and four dissimilar covariate treatment predictors, minimizing a loss based on Euclidean distance reduced covariate imbalance by a median of 99%. Stratification by propensity score and weighting records by the inverse of their probability of treatment reduced imbalance by 76%-89% and 83%-94%, respectively. Loss minimization applied to a cohort of 361 children undergoing immunotherapy achieved nearly complete elimination of covariate differences for important treatment predictors. CONCLUSION: With the availability of semiparametric stratum-assignment algorithms, analysts can tailor loss functions to meet design goals. Here, a loss function that emphasized covariate balance performed well under limited testing.

Validation of alopecia coding in US claims data among women of childbearing age.

BACKGROUND: Accurately identifying alopecia in claims data is important to study this rare medication side effect. OBJECTIVES: To develop and validate a claims-based algorithm to identify alopecia in women of childbearing age. METHODS: We linked electronic health records from a large healthcare system in Massachusetts (Mass General Brigham) with Medicaid claims data from 2016 through 2018 to identify all women aged 18 to 50 years with an ICD-10 code for alopecia, including alopecia areata, androgenic alopecia, non-scarring alopecia, or cicatricial alopecia, from a visit to the MGB system. Using eight predefined algorithms to identify alopecia in Medicaid claims data, we randomly selected 300 women for whom we reviewed their charts to validate the alopecia diagnosis. Positive predictive values (PPVs) were computed for the primary algorithm and seven algorithm variations, stratified by race. RESULTS: Out of 300 patients with at least 1 ICD-10 code for alopecia in the Medicaid claims, 286 had chart-confirmed alopecia (PPV = 95.3%). The algorithm requiring two diagnosis codes plus one prescription claim for alopecia treatment identified 55 patients (PPV = 100%). The algorithm requiring 1 diagnosis code for alopecia plus 1 procedure claim for intralesional triamcinolone injection identified 35 patients (PPV = 100%). Across all 8 algorithms tested, the PPV varied between 95.3% and 100%. The PPV for alopecia ranged from 94% to 100% in White and 96%-100% in 48 non-White women. The exact date of alopecia onset was difficult to determine in charts. CONCLUSION: At least one recorded ICD-10 code for alopecia in claims data identified alopecia in women of childbearing age with high accuracy.

Use patterns of systemic immunomodulators in the United States before and after dupilumab approval in adults with atopic dermatitis.

PURPOSE: The patterns of dupilumab use, the first systemic drug approved for the treatment of atopic dermatitis (AD), is not well understood in the context of off-label systemic medications. OBJECTIVE: To describe patterns of prescribing, switching and discontinuing systemic AD drugs, before and after the approval of dupilumab and understand variables associated with dupilumab prescription. METHODS: Using longitudinal claims data, we identified patients with AD who initiated a systemic therapy (dupilumab, cyclosporine, methotrexate, azathioprine, mycophenolate) from March 2015 to February 2021, with a washout period of 1 year. We used Sankey plots to visualize longitudinal patterns of use at 3, 6, and 12 months and logistic regression to determine associates of dupilumab prescription. RESULTS: The number of patients starting systemic treatment increased from 319 before dupilumab approval to 1358 after. Dupilumab use increased from 72% to 84%. In 2019-2020, 36% of patients discontinued systemic treatment within a year compared to 62% in 2015-2016. 92% of patients who started dupilumab in 2020-2021 had received no other systemic treatment before. Patients <60 years and those who used steroid-sparing topical treatments were more likely to receive dupilumab. CONCLUSION: Among new users of a systemic treatment for AD, dupilumab was most used treatment by far.

Longitudinal utilization of systemic immunomodulators before and after dupilumab approval in children with atopic dermatitis.

In our cohort study, we sought to describe the utilization patterns of systemic immunomodulators in children with atopic dermatitis (AD) and how utilization changed after approval of dupilumab, the first systemic drug approved for the treatment of AD. Using US nationwide claims data, we identified children with AD who initiated a systemic therapy (dupilumab, cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil) from March 2015 to February 2021 and used Sankey plots to describe patterns of starting, switching, and discontinuing these drugs. Dupilumab use among children increased from 19.4% before approval in children to 88.3% after approval in 2019-20. Adherence to dupilumab may suggest better tolerance and improved outcomes in children with AD.

Decreased risk of treatment failure with vedolizumab and thiopurines combined compared with vedolizumab monotherapy in Crohn's disease.

OBJECTIVE: While infliximab combined to thiopurines is more effective than infliximab monotherapy in patients with Crohn's disease (CD) and UC, the impact of adding thiopurines to vedolizumab remains controversial. We emulated two target trials comparing the effectiveness of combination therapy versus vedolizumab monotherapy in CD and UC. DESIGN: Based on two US and the French nationwide healthcare databases, patients with CD and UC who initiated vedolizumab were identified. The study methodology, including confounding adjustment and outcome definitions, were previously validated in successful emulations of the SONIC and SUCCESS trials. Risk ratios for treatment failure based on hospitalisation or surgery related to disease activity, treatment switch, or prolonged corticosteroids use, were estimated after 1:1 propensity score (PS) matching. RESULTS: Among a total of 10 299 vedolizumab users, 804 CD and 1088 UC pairs of combination therapy versus vedolizumab monotherapy users were PS matched. Treatment failure occurred at week 26 in 236 (29.3%) and 376 (34.3%) patients with CD and at week 16 in 236 (21.7%) and 263 (24.2%) patients with UC initiating combination therapy and vedolizumab monotherapy, respectively. The risk of treatment failure was decreased with combination therapy compared with vedolizumab monotherapy in CD (RR 0.85, 95% CI: 0.74 to 0.98) and to a lesser extent in UC (RR 0.90, 95% CI: 0.77 to 1.05). Findings were consistent across databases. CONCLUSION: Using validated methodologies, combination therapy with vedolizumab and thiopurines was associated with lower treatment failure compared with vedolizumab monotherapy in CD but not UC across the USA and France.

Occurrence of inflammatory bowel disease in patients with chronic inflammatory skin diseases: a cohort study: Classification: Epidemiology.

BACKGROUND: Several studies have linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) in a range of data sources with mixed conclusions. OBJECTIVES: We compared the incidence of IBD - ulcerative colitis (UC) and Crohn disease (CD) - in patients with a CISD vs. similar persons without a CISD. METHODS: In this cohort study using nationwide, longitudinal, commercial insurance claims data from the USA, we identified adults and children who were seen by a dermatologist between 2004 and 2020, and diagnosed with either psoriasis, atopic dermatitis, alopecia areata, vitiligo or hidradenitis suppurativa. Comparator patients were identified through risk-set sampling; they were eligible if they were seen by a dermatologist at least twice and not diagnosed with a CISD. Patient follow-up lasted until either IBD diagnosis, death, disenrolment or end of data stream, whichever came first. IBD events, UC or CD, were identified via validated algorithms: hospitalization or diagnosis with endoscopic confirmation. Incidence rates were computed before and after adjustment via propensity-score decile stratification to account for IBD risk factors. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated to compare the incidence of IBD in CISD vs. non-CISD. RESULTS: We identified patients with atopic dermatitis (n = 123 614), psoriasis (n = 83 049), alopecia areata (n = 18 135), vitiligo (n = 9003) or hidradenitis suppurativa (n = 6806), and comparator patients without a CISD (n = 2 376 120). During a median follow-up time of 718 days, and after applying propensity-score adjustment for IBD risk factors, we observed increased risk of both UC (HRUC 2·30, 95% CI 1·61-3·28) and CD (HRCD 2·70, 1·69-4·32) in patients with hidradenitis suppurativa, an increased risk of CD (HRCD 1·23, 1·03-1·46) but not UC (HRUC 1·01, 0·89-1·14) in psoriasis, and no increased risk of IBD in atopic dermatitis (HRUC 1·02, 0·92-1·12; HRCD 1·08, 0·94-1·23), alopecia areata (HRUC 1·18, 0·89-1·56; HRCD 1·26, 0·86-1·86) or vitiligo (HRUC 1·14, 0·77-1·68; HRCD 1·45, 0·87-2·41). CONCLUSIONS: IBD was increased in patients with hidradenitis suppurativa. CD alone was increased in patients with psoriasis. Neither UC nor CD was increased in patients with atopic dermatitis, alopecia areata or vitiligo. What is already known about this topic? Several studies have linked various chronic inflammatory skin diseases (CISDs) with inflammatory bowel disease (IBD) utilizing a range of data sources, with mixed conclusions. What does this study add? This large-scale, claims-based cohort study expands current knowledge by providing background rates for IBD across multiple CISDs using consistent methods and within a single, nationally representative patient population. We observed a relative increased risk of IBD in patients with hidradenitis suppurativa, but the overall incidence rate difference of IBD was generally low. Crohn disease alone was significantly increased in patients with psoriasis, and neither ulcerative colitis nor Crohn disease was increased in patients with atopic dermatitis, vitiligo or alopecia areata.

Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy.

PURPOSE: To understand the validity of real-world evidence (RWE) studies in ulcerative colitis (UC), we emulated the SUCCESS randomized controlled trial (RCT) on the effectiveness of infliximab plus thiopurines, using US and French healthcare insurance claims data. METHODS: The SUCCESS trial showed improved remission with infliximab plus thiopurines combined compared to infliximab monotherapy in patients with UC. Based on two US commercial claims databases (IBM MarketScan and Optum) and the French nationwide health insurance database (SNDS) from 2004 through 2019, all patients with UC who initiated combination therapy or infliximab alone were identified. The primary outcome of treatment failure was emulated by: Hospitalization related to UC or colectomy, treatment switch to another biologic or immunosuppressant, or use of corticosteroids 16 weeks after infliximab initiation. We estimated risk ratios with 95% confidence intervals after 1:1 propensity score (PS) matching. RESULTS: Among 620 PS-matched pairs of combination therapy and infliximab monotherapy users, treatment failure occurred in 124 (20%) of patients initiating combination therapy and 170 (27%) during monotherapy. Like in SUCCESS, the risk of treatment failure was decreased with combination therapy in the overall cohort (RR = 0.73; 95% CI: 0.60-0.90). Findings were consistent across MarketScan, Optum, and SNDS: RR = 0.76 (0.57-1.02), 0.82 (0.54-1.24), and 0.61 (0.41-0.90). Similar results were observed for each component endpoint. CONCLUSIONS: RWE results across three large claims databases were consistent with RCT findings. These findings provide support for the use of RWE to assess treatment effectiveness in UC.

Comparative safety of systemic immunomodulatory medications in adults with atopic dermatitis.

BACKGROUND: Severe atopic dermatitis (AD) is increasingly treated with systemic immunomodulatory drugs, yet their safety is unclear. OBJECTIVE: We evaluated the comparative risk of serious bacterial and opportunistic infections among patients with severe AD using systemic immunomodulatory medications in routine care. METHODS: In a population-based claims data study, we identified adult patients with AD who were treated with systemic drugs. The incidence of serious bacterial and opportunistic infections leading to hospitalization was computed by using International Classification of Disease diagnosis codes. Relative risks (RRs) were computed after 1-to-1 propensity score matching. RESULTS: Up to 232,611 patients with AD were eligible. The incidence of serious infections was 7.53 (7.18-7.89) risk per 1,000 patients among systemic nonbiologic-treated patients, 7.38 (5.68-9.57) risk per 1,000 patients among phototherapy-treated patients, and 2.6 (0.45-14.3) risk per 1,000 patients among dupilumab users. After matching, cyclosporine had a significantly reduced 6-month risk (RR 0.87) and prednisone (RR 1.78), azathioprine (RR 1.89), and mycophenolate (RR 3.31) showed increased risks compared with methotrexate. A small number of dupilumab users showed no increased risk (RR 0.33, 95% confidence interval 0.03-3.20). LIMITATIONS: Some comparisons involved small population sizes. CONCLUSION: In this population-based study of adult AD patients, cyclosporine and methotrexate have the lowest 6-month risks of serious infections. Increased risks were observed for prednisone, azathioprine, and mycophenolate relative to methotrexate.

Dupilumab and the risk of conjunctivitis and serious infection in patients with atopic dermatitis: A propensity score-matched cohort study.

BACKGROUND: Dupilumab is an effective treatment for moderate to severe atopic dermatitis (AD) with limited safety data in clinical practice. OBJECTIVE: To assess the 6-month risk of conjunctivitis and serious infections in patients with AD who initiated dupilumab. METHODS: In a cohort study using US claims data, we compared the risk of conjunctivitis and serious infections in patients with AD who initiated either dupilumab, methotrexate (MTX), cyclosporine, or mycophenolate. Relative risks (RRs) were computed after 1:1 propensity score matching. RESULTS: We identified 1775 dupilumab, 1034 MTX, 186 cyclosporine, and 257 mycophenolate users. The 6-month risk for any conjunctivitis was 6.5% for dupilumab, 3.3% for MTX, 4.8% for cyclosporine, and 1.2% for mycophenolate initiators. After PS matching, the RR of any conjunctivitis was increased in dupilumab users versus MTX (RR, 2.45; 95% confidence interval [CI], 1.47-4.08), versus cyclosporine (RR, 1.56; 95% CI, 0.69-3.50), and versus mycophenolate (RR, 7.00; 95% CI, 2.12-23.2). The risk of serious infection was 0.6% in dupilumab and 1.0% in MTX initiators (RR, 0.90; 95% CI, 0.37-2.20). LIMITATIONS: Analyses were based on few events, and differential surveillance is a concern. CONCLUSIONS: Although dupilumab shows a low risk of serious infections, it is associated with a clinically meaningful increase in conjunctivitis that needs to be managed in practice.

Serious infection risk in children with psoriasis on systemic treatment: A propensity score-matched population-based study.

BACKGROUND: Psoriasis is increasingly treated with systemic medications, yet their safety is not well characterized in children. OBJECTIVE: We sought to estimate the 6-month risk of serious infections in children with psoriasis treated with biologics, systemic nonbiologics, and phototherapy. METHODS: Using insurance claims data, we identified children aged <18 years with psoriasis and compared the frequency of serious infections in those initiating biologics, systemic nonbiologics, and phototherapy. Relative risks were estimated before and after 1:1 propensity score matching. RESULTS: Among 57,323 children with psoriasis, the 6-month risk of infection was 4.2 per 1000 patient-years in 722 biologic initiators, 5.1 in 988 systemic nonbiologic initiators, and 1.1 in 2657 phototherapy initiators. The relative risk (95% confidence interval) of infection in biologics vs nonbiologics was 0.67 (0.11-3.98), in biologics vs phototherapy was 1.50 (0.25-8.95), and in nonbiologics vs phototherapy was 5.00 (0.59-42.71). The background risk of infection in children with psoriasis was 1 per 1000, almost double the risk compared with children without psoriasis (relative risk, 1.84; 95% confidence interval, 1.15-1.97). CONCLUSIONS: We found no meaningful difference in infection risk between biologics vs nonbiologics and no robust difference between systemic users vs phototherapy. Independent of treatment, children with psoriasis had a higher risk of infection than those without psoriasis.

Rationale and Design of the Brigham Cohort for psoriasis and psoriatic arthritis registry (COPPAR).

BACKGROUND: Psoriasis (PsO) and psoriatic arthritis (PsA) are related conditions with poorly defined transition among them, risk factors for progression, complex treatment algorithms, and biomarkers for treatment response and long-term outcomes. We describe the development of a PsO/PsA registry at an academic medical center. METHODS: We developed a single-center PsO/PsA longitudinal disease registry including biorepository that captures relevant disease markers and treatment choices in a circumscribed population with a defined catchment area. We searched the electronic medical record for patients with visits in the last year for PsO or PsA. They formed the potentially eligible registry population. Baseline patient and provider questionnaires were developed using standardized measures, including demographics, comorbidities, medications, specific disease characteristics, functional status, quality of life, mental health, and resource use. An abbreviated set of items was collected every six month and at visits with treatment changes or disease flares. Biospecimens included blood (serum, plasma, DNA, RNA) and skin biopsy samples, with repeat collections of serum and plasma. Data from the EMR to augment the registry questionnaires are available on all patients. DISCUSSION: Searching the Brigham EMR system from 2013 through 2014, we found 1694 patients with PsO and 1028 with PsA. Their mean age was 55 years and 53% were female. Of these 17% had diabetes, 38% hyperlipidemia, and 45% hypertension. The median BMI was 29.6. PsA patients used more systemic prednisone, MTX, and TNF alpha inhibitors (47%, 60%, and 66%) compared to PsO patients (28%, 20% and 21%). We have collected plasma in 410 patients, DNA/RNA in 453 patients. In conclusion, we have developed a PsO/PsA registry to better define longitudinal disease characteristics, perform biomarker studies, and examine treatment trends.

Prevalence of Pretreatment Testing Recommended for Patients With Chronic Inflammatory Skin Diseases.

Importance: Laboratory testing for the presence of tuberculosis, hepatitis, and other conditions before starting most systemic immunomodulatory agents is recommended in patients with chronic inflammatory skin diseases (CISD) but current testing patterns in the US are unclear. Objective: To determine the prevalence of pretreatment testing that is recommended for patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis). Design, Setting, and Participants: This descriptive analysis of US commercial insurance claims databases from December 31, 2002, to December 31, 2020, included adult patients with CISD (psoriasis, hidradenitis suppurativa, or atopic dermatitis) who started an immunomodulatory agent, including methotrexate, tumor necrosis factor α inhibitors, interleukin (IL)-17Ai, ustekinumab, IL-23i, dupilumab, or apremilast. Main Outcomes and Measures: The proportion of patients who underwent the screening tests as suggested by professional societies-including for tuberculosis, hepatitis, and liver function; complete blood cell counts; and lipid panels-were determined within 6 months before and during 2 years after treatment start. Results: A total of 122 308 patients with CISDs (median [IQR] age, 49 [38-58] years; 63 663 [52.1%] male) starting systemic immunomodulatory treatment in the US were included. Treatment for patients with CISDs comprised methotrexate (28 684), tumor necrosis factor α inhibitors (40 965), ustekinumab (12 841), IL-23i (6116), IL-17Ai (9799), dupilumab (7787), or apremilast (16 116). Complete blood cell count was the most common test, performed in 41% (3161/7787) to 69% (19 659/28 684) of individuals before initiation across treatments. Between 11% (889/7787) and 59% (3613/6116) of patients had tuberculosis screening within 6 months before treatment, and 3% (149/4577) to 26% (1559/6097) had updated tests 1 year later. Between 13% (1006/7787) and 41% (16 728/40 965) had hepatitis panels before treatment. Low pretreatment testing levels before apremilast (15% [2331/16 116] to 45% [7253/16 116]) persisted a year into treatment (9% [816/8496] to 36% [2999/8496]) and were similar to dupilumab (11% [850/7787] to 41% [3161/7787] vs 3% [149/4577] to 25% [1160/4577]). Conclusions and Relevance: In this descriptive analysis of patients with CISDs starting systemic immunomodulatory treatment in the US, less than 60% received the recommended pretreatment testing. Additional research is required to understand whether variations in testing affect patient outcomes.

Concepts of Designing and Implementing Pharmacoepidemiology Studies on the Safety of Systemic Treatments in Dermatology Practice.

The U.S. Food and Drug Administration and clinical guidelines use evidence from pharmacoepidemiology studies to inform prescribing decisions and fill evidence gaps left by randomized controlled trials (RCTs). The long-term safety and infrequent adverse reactions are not well-understood when RCTs are short and involve few patients, as is the case for most systemic immunomodulating drugs in dermatology. A better understanding of the design and implementation of pharmacoepidemiology studies will help practitioners assess the accuracy of etiologic findings and use them with confidence in clinical practice. Conducting pharmacoepidemiology studies follows a structured approach, which we discuss in this article: (i) a design layer connects the research question with the appropriate study design, and considering which hypothetical RCT one ideally would want to conduct reduces inadvertent investigator errors; (ii) a measurement layer transforms longitudinal patient-level data into variables that identify the study population, patient characteristics, treatment, and outcomes; and (iii) the analysis focuses on the causal treatment effect estimation. The review and interpretation of pharmacoepidemiology studies should consider issues beyond a typical review of RCTs, chiefly the lack of baseline randomization and the use of secondary data. Well-designed and well-conducted pharmacoepidemiologic studies complement dermatology practice with critical information on prescribing systemic medications.

Venous Thromboembolism in Patients With Bullous Pemphigoid.

Importance: Studies have linked bullous pemphigoid (BP) with venous thromboembolism (VTE) across several data sources finding 6-fold to 15-fold increased incidence rates. Objective: To determine the incidence of VTE in patients with BP compared with similar controls. Design, Setting, and Participants: This cohort study used insurance claims data from a nationwide US health care database from January 1, 2004, through January 1, 2020. Patients with dermatologist-recorded BP were identified (≥2 diagnoses of BP [International Classification of Diseases, Ninth Revision (ICD-9) 694.5 and ICD-10 L12.0] recorded by dermatologists within 1 year). Risk-set sampling identified comparator patients without BP and free of other chronic inflammatory skin diseases. Patients were followed-up until the first of the following events occurred: VTE, death, disenrollment, or end of data stream. Exposures: Patients with BP compared with those without BP and free of other chronic inflammatory skin diseases (CISD). Main outcome: Venous thromboembolism events were identified and incidence rates were computed before and after propensity-score (PS) matching to account for VTE risk factors. Hazard ratios (HRs) compared the incidence of VTE in BP vs non-CISD. Results: Overall, 2654 patients with BP and 26 814 comparator patients without BP or another CISD were identified. The mean (SD) age in the BP group was 73.0 (12.6) years and 55.0 (18.9) years in the non-CSID group. With a median follow-up time was 2 years, the unadjusted incidence rate (per 1000 person-years) of outpatient or inpatient VTE was 8.5 in the BP group compared with 1.8 in patients without a CISD. Adjusted rates were 6.7 in the BP group compared with 3.0 in the non-CISD group. Age-specific adjusted incidence rates (per 1000 person-years) in patients aged 50 to 74 years was 6.0 (vs 2.9 in the non-CISD group) and in those aged 75 years or older was 7.1 (vs 4.53 in the non-CISD group). After 1:1 propensity-score matching including 60 VTE risk factors and severity markers, BP was associated with a 2-fold increased risk of VTE (2.24 [1.26-3.98]) vs those in the non-CISD group. When restricting to patients aged 50 years or older, the adjusted relative risk of VTE was 1.82 (1.05-3.16) for the BP vs non-CISD groups. Conclusions: In this nationwide US cohort study, BP was associated with a 2-fold increased incidence of VTE after controlling for VTE risk factors in a dermatology patient population.

Risk of Infection in Children With Psoriasis Receiving Treatment With Ustekinumab, Etanercept, or Methotrexate Before and After Labeling Expansion.

Importance: Psoriasis in children is increasingly treated with systemic medications, yet their risk of serious infection is not well characterized in clinical practice. Pediatric clinical trials for these medications were often small and placebo controlled. Objective: To estimate the 6-month rate of infections among children with psoriasis who started treatment with ustekinumab, etanercept, or methotrexate. Design, Setting, and Participants: This cohort study used insurance claims data from clinical practices across the US on children aged 17 years or younger with psoriasis who were receiving treatment with a topical medication for psoriasis and started new treatment with ustekinumab, etanercept, or methotrexate. The analysis was stratified by the time before pediatric labeling (2009-2015) and after pediatric approval (2016-2021). Patient follow-up started 1 day after initiating treatment and ended at 6 months. Exposures: New treatment with ustekinumab, etanercept, and methotrexate. Main Outcomes and Measures: During follow-up, the frequency of inpatient serious infections and outpatient infections requiring treatment was compared. Event rates and rate ratios were estimated after propensity score decile stratification. Results: After exclusions, we identified 2338 patients (1368 girls [57.8%]) who initiated new treatment with a targeted immunomodulating agent. In all, 379 patients started treatment with ustekinumab, 779 patients started treatment with etanercept, and 1180 patients started treatment with methotrexate from 2009 through 2021. The propensity score-adjusted incidence rate of serious infection was 18.4 per 1000 person-years (3 events) for ustekinumab users, 25.6 per 1000 person-years (9 events) for etanercept users, and 14.9 per 1000 person-years (8 events) for methotrexate users. The adjusted rate of outpatient infections was 254.9 per 1000 person-years (39 events) for ustekinumab users, 435.7 per 1000 person-years (139 events) for etanercept users, and 433.6 per 1000 person-years (209 events) for methotrexate users. The adjusted rate ratio of outpatient infections was 0.58 (95% CI, 0.41-0.83) for ustekinumab vs etanercept, 0.66 (95% CI, 0.48-0.91) for ustekinumab vs methotrexate, and 0.95 (95% CI, 0.75-1.21) for etanercept vs methotrexate. Rate ratios were similar during the off-label use era and after pediatric labeling. Conclusions and Relevance: Among children with psoriasis who started treatment with immunomodulating agents, serious infections were infrequent. This cohort study suggests that there was no increase in the risk of outpatient infections for children who started treatment with ustekinumab compared with etanercept or methotrexate.

Incidence of Bacterial and Nonbacterial Conjunctivitis in Patients With Atopic Dermatitis Treated With Dupilumab: A US Multidatabase Cohort Study.

BACKGROUND: Dupilumab-associated conjunctivitis in patients with atopic dermatitis (AD) is not fully characterized. OBJECTIVE: The aim of the study was to characterize the incidence of bacterial and nonbacterial conjunctivitis among patients with AD who initiated dupilumab. METHODS: Pooling longitudinal claims data from 2 US databases, we identified AD patients who newly filled either dupilumab or methotrexate, mycophenolate or cyclosporine, between March 2017 and January 2020. Outcomes were conjunctivitis and its subtypes, bacterial, allergic, and keratoconjunctivitis. Patient follow-up lasted 6 months and 1:1 propensity score (PS) matching-controlled confounding. RESULTS: Within 6 months of treatment initiation, the incidence of conjunctivitis was 6.6% in 3744 dupilumab initiators; bacterial conjunctivitis, 1.5%; allergic conjunctivitis, 2.2%; keratoconjunctivitis, 0.8%; and conjunctivitis requiring ophthalmic medication, 2.7%. After PS matching, dupilumab doubled the risk of conjunctivitis compared with methotrexate (relative risk [RR] 2.12; 1.56-2.91), mycophenolate (RR = 2.43; 1.32-4.47), or cyclosporine (RR = 1.83; 1.05-3.20). Risk of bacterial conjunctivitis was 1.6- to 4.0-fold increased with wide confidence intervals, and allergic conjunctivitis was increased 2.7- to 7-fold. There was no increased risk of keratoconjunctivitis. Patients with comorbid asthma had a further increased risk of conjunctivitis. CONCLUSIONS: One in 15 patients treated with dupilumab developed conjunctivitis driven by bacterial and allergic conjunctivitis and not keratoconjunctivitis. This risk was further increased with comorbid asthma.