Biologic therapies are widely prescribed immunomodulatory agents. There are concerns that compared with treatment with conventional systemic therapy, long-term biologic treatment for common ...immune-mediated inflammatory diseases, namely inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis, may be associated with increased risk of melanoma.
To examine whether biologic treatment of IBD, RA, or psoriasis is associated with an increased risk of melanoma compared with conventional systemic therapy.
Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for articles published from January 1, 1995, to February 7, 2019, for eligible studies.
Randomized clinical trials, cohort studies, and nested case-control studies quantifying the risk of melanoma in biologic-treated patients with IBD, RA, and psoriasis compared with patients treated with conventional systemic therapy were included.
Two reviewers independently extracted key study characteristics and outcomes. Study-specific risk estimates were pooled, and random- and fixed-effects model meta-analyses were conducted. Heterogeneity was assessed using the I2 statistic. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines were followed.
The pooled relative risk (pRR) of melanoma in biologic-treated patients with IBD, RA, and psoriasis compared with biologic-naive patients treated with conventional systemic therapy.
Seven cohort studies comprising 34 029 biologic-treated patients and 135 370 biologic-naive patients treated with conventional systemic therapy were eligible for inclusion. Biologic treatment was positively associated with melanoma in patients with IBD (pRR, 1.20; 95% CI, 0.60-2.40), RA (pRR, 1.20; 95% CI, 0.83-1.74), or psoriasis (hazard ratio, 1.57; 95% CI, 0.61-4.09) compared with those who received conventional systemic therapy, but the differences were not statistically significant. Adjustment for other risk factors was absent from most studies.
The findings suggest that clinically important increases in melanoma risk in patients treated with biologic therapy for common inflammatory diseases cannot be ruled out based on current evidence. However, further studies with large patient numbers that adjust for key risk factors are needed to resolve the issue of long-term safety of biologic therapy.
Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection ...could improve patient outcomes and treatment cost-effectiveness.
We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti–TNF-α) and ustekinumab (anti–IL-12/23).
This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables.
HLA-C*06:02–negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio OR, 2.95; P = 5.85 × 10−7), and the difference was greater in HLA-C*06:02–negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10−5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10−4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1.
This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.
The multimorbid burden and use of systemic immunosuppressants in people with psoriasis may confer greater risk of adverse outcomes of coronavirus disease 2019 (COVID-19), but the data are limited.
...Our aim was to characterize the course of COVID-19 in patients with psoriasis and identify factors associated with hospitalization.
Clinicians reported patients with psoriasis with confirmed/suspected COVID-19 via an international registry, Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection. Multiple logistic regression was used to assess the association between clinical and/or demographic characteristics and hospitalization. A separate patient-facing registry characterized risk-mitigating behaviors.
Of 374 clinician-reported patients from 25 countries, 71% were receiving a biologic, 18% were receiving a nonbiologic, and 10% were not receiving any systemic treatment for psoriasis. In all, 348 patients (93%) were fully recovered from COVID-19, 77 (21%) were hospitalized, and 9 (2%) died. Increased hospitalization risk was associated with older age (multivariable-adjusted odds ratio OR = 1.59 per 10 years; 95% CI = 1.19-2.13), male sex (OR = 2.51; 95% CI = 1.23-5.12), nonwhite ethnicity (OR = 3.15; 95% CI = 1.24-8.03), and comorbid chronic lung disease (OR = 3.87; 95% CI = 1.52-9.83). Hospitalization was more frequent in patients using nonbiologic systemic therapy than in those using biologics (OR = 2.84; 95% CI = 1.31-6.18). No significant differences were found between classes of biologics. Independent patient-reported data (n = 1626 across 48 countries) suggested lower levels of social isolation in individuals receiving nonbiologic systemic therapy than in those receiving biologics (OR = 0.68; 95% CI = 0.50-0.94).
In this international case series of patients with moderate-to-severe psoriasis, biologic use was associated with lower risk of COVID-19–related hospitalization than with use of nonbiologic systemic therapies; however, further investigation is warranted on account of potential selection bias and unmeasured confounding. Established risk factors (being older, being male, being of nonwhite ethnicity, and having comorbidities) were associated with higher hospitalization rates.
Patients with psoriasis enrolled in clinical trials of biologics may not be representative of the real-world population. There is evidence that patients ineligible for such trials have a greater risk ...of serious adverse events (SAEs), but the effect on drug discontinuation and effectiveness are unknown.
To determine whether (1) drug discontinuation, (2) effectiveness, and (3) rates of SAEs differ in patients with psoriasis categorized as eligible or ineligible for clinical trials.
An observational study using 157 dermatology centers in the United Kingdom and Republic of Ireland was carried out wherein we applied the eligibility criteria of clinical trials of biologic therapies for psoriasis to patients who were being followed up in the British Association of Dermatologists Biologic Interventions Register (BADBIR) and being prescribed biologics as part of standard clinical care. Patients with psoriasis registered to BADBIR who were taking etanercept (enbrel only; n = 1509), adalimumab (n = 4000), and ustekinumab (n = 1627) with at least 1 follow-up visit. Eligibility criteria were extracted from phase 3 licensing trials for etanercept, adalimumab, and ustekinumab for the treatment of moderate to severe psoriasis. Patients in BADBIR with a missing baseline Psoriasis Area and Severity Index (PASI) or baseline PASI value less than 10 (etanercept) or less than 12 (adalimumab; ustekinumab) but who would otherwise be eligible were investigated separately. Eligibility categories applied to BADBIR included: eligible, ineligible, insufficient baseline PASI only, and missing baseline PASI only.
(1) Drug discontinuation: cumulative incidence at 12 months by stop reason per eligibility category and drug; (2) effectiveness: linear regression of absolute change in PASI from baseline to 6 and 12 months; and (3) SAEs: incidence rate ratio (IRR) at 12 months between eligibility categories per drug.
The mean (SD) age of the 7136 patients included in the analysis was 45 (13) years and 2924 (41%) were women and 4212 (59%) were men. Of 7136 patients, 839 (56%) etanercept, 2219 (56%) adalimumab, and 754 (46%) ustekinumab registrations were categorized as eligible. The most common reasons for ineligibility were diabetes (etanercept, 143 9%; ustekinumab, 201 12%) and nonchronic plaque psoriasis (adalimumab, 157 4%). Patients categorized as ineligible (etanercept, 367 24%; adalimumab, 282 7%; ustekinumab, 394 24%) achieved a smaller absolute change in PASI after 6 and 12 months (adalimumab, ustekinumab), and had significantly higher rates of SAEs compared with the eligible category (etanercept: IRR, 1.9; 95% CI, 1.4-2.6; adalimumab: IRR, 2.0; 95% CI, 1.5-2.6; ustekinumab: IRR, 2.8; 95% CI, 2.1-3.8). No significant differences in drug discontinuation were observed between categories.
Clinical trial effectiveness and safety outcomes are not representative of real-world patients in BADBIR patients categorized as ineligible for such trials.
Little is known about the drug survival of second-line biologic therapies for psoriasis in routine clinical practice. We assessed drug survival of second-line biologic therapies and estimated the ...risk of recurrent discontinuation due to adverse events or ineffectiveness in patients with psoriasis who had failed a first biologic therapy and switched to a second in a large, multicenter pharmacovigilance registry (n = 1,239; adalimumab, n = 538; etanercept, n = 104; ustekinumab, n = 597). The overall drug survival rate in the first year after switching was 77% (95% confidence interval = 74–79%), falling to 58% (55–61%) in the third year. Female sex, multiple comorbidities, concomitant therapy with cyclosporine, and a high Psoriasis Area and Severity Index at switching to the second-line biologic therapy were predictors of overall discontinuation (multivariable Cox proportional hazard model). Compared to adalimumab, patients receiving etanercept were more likely to discontinue therapy (hazard ratio = 1.87, 95% confidence interval = 1.24–2.83), whereas patients receiving ustekinumab were more likely to persist (hazard ratio = 0.46; 95% confidence interval = 0.33–0.64). Discontinuation of the first biologic therapy because of adverse events was associated with an increased rate of second drug discontinuation because of adverse events (hazard ratio = 2.55; 95% confidence interval = 1.50–4.32). In conclusion, drug survival rates differed among biologic therapies and decreased over time; second-line discontinuation because of adverse events was more common among those who discontinued first-line treatment for this reason. The results of this study should support clinical decision making when choosing second-line biologic therapy for patients with psoriasis.
Objective
Musculoskeletal symptoms are commonly reported following acute COVID‐19. It is unclear whether those with musculoskeletal symptoms subsequently develop inflammatory rheumatic ...musculoskeletal disease (iRMD). This review seeks to identify evidence for an association between acute COVID‐19 and subsequent iRMD diagnosis.
Methods
A rapid review of the literature using a systematic search of Medline, EMBASE and two COVID‐19 databases was undertaken until August 2022. Case studies, case series, cross‐sectional, case‐control, and cohort studies reporting patients with an incident iRMD following COVID‐19 were included. Title and screening were conducted by one reviewer and full text screening by two reviewers. Data extraction and quality appraisal were by one reviewer, with a second verifying. Study‐type specific critical appraisal tools were used.
Results
Results were narratively synthesized. A total of 80 studies were included (69 case reports, 10 case series and 1 cross‐sectional study). Commonly reported iRMDs were “reactive arthropathies” (n = 47), “inflammatory arthropathies unspecified” (n = 18), rheumatoid arthritis (n = 12) and systemic lupus erythematosus (n = 11). The cross‐sectional study reported 37% of those with COVID‐19 developed “post COVID arthritis.” Time from diagnosis of COVID‐19 to iRMD presentation ranged from 0 to 120 days. Several mechanisms were proposed to explain the association between COVID‐19 and iRMD development: autoimmune processes, aberrant inflammatory responses, colonization of joint spaces, direct damage from the severe acute respiratory syndrome coronavirus 2 virus and genetic predisposition.
Conclusion
The level of evidence of the studies included in this review was low and the quality generally poor. Prospective observational studies are required to confirm associations and likely impact of post COVID‐19 iRMDs at a population level.
Treatments for psoriasis may be less effective in everyday practice than in clinical trials. Emulating a target trial using data from the British Association of Dermatologists Biologics and ...Immunomodulators Register (BADBIR) can provide treatment effect estimates that are robust and can inform both clinicians and regulatory bodies.
To assess the comparative effectiveness of ustekinumab and secukinumab in patients with psoriasis, and to test whether the relative effectiveness estimate of the CLEAR trial, a randomized clinical trial that compared secukinumab with ustekinumab for psoriasis, can be replicated.
This comparative effectiveness research study used a target trial emulation approach and was performed between November 2007 and August 2019. Data were obtained from BADBIR, a multicenter longitudinal pharmacovigilance register of patients with moderate to severe psoriasis in the United Kingdom and Republic of Ireland. Participants had chronic plaque psoriasis, were 18 years or older, and had at least 1 record of a Psoriasis Area and Severity Index (PASI) of 12 or higher before their initiation to secukinumab or ustekinumab. Propensity score (PS) 1:1 matched analysis and inverse probability treatment weighted analysis were performed.
The primary outcomes were the risk ratio (RR) and the risk difference (RD) for achieving PASI of 2 or lower after 12 months of therapy for secukinumab compared with ustekinumab. Methods to account for missing outcome data were complete case analysis, nonresponder imputation, last observation carried forward, inverse probability of censoring weighting, and multiple imputation. Regulatory and estimate agreement metrics were used to benchmark the effect estimates in this study against those in the CLEAR trial.
A total of 1231 patients were included in the analysis, with 917 receiving ustekinumab and 314 receiving secukinumab. Secukinumab was superior to ustekinumab in all analyses, except under the nonresponder imputation method, in the proportion of participants achieving a PASI of 2 or lower (PS-weighted complete case analysis: RR, 1.28 95% CI, 1.06-1.55; RD, 11.9% 1.6-22.1). All analyses, except for nonresponder imputation, reached regulatory agreement in both PS-matching and PS-weighted analyses.
This comparative effectiveness study found that secukinumab resulted in more patients achieving a PASI of 2 or lower after 12 months of therapy compared with ustekinumab in patients with psoriasis. Target trial emulation in this study resulted in regulatory and estimate agreement with the CLEAR randomized clinical trial; further such studies may help fill the evidence gap when comparing other systemic therapies for psoriasis.
To investigate the impact of pre-existing painful musculoskeletal conditions on healthcare utilization and costs among patients with five common conditions: acute coronary syndrome (ACS), stroke, ...cancer, dementia and pneumonia.OBJECTIVETo investigate the impact of pre-existing painful musculoskeletal conditions on healthcare utilization and costs among patients with five common conditions: acute coronary syndrome (ACS), stroke, cancer, dementia and pneumonia.Using primary and secondary care services data from electronic health records, a negative binomial regression model was used to compare resource use while a two-part model was used to compare costs across the five conditions, between those with and without a pre-existing musculoskeletal pain.METHODSUsing primary and secondary care services data from electronic health records, a negative binomial regression model was used to compare resource use while a two-part model was used to compare costs across the five conditions, between those with and without a pre-existing musculoskeletal pain.The study included 760,792 patients (144,870 with ACS, 121,208 with stroke, 231,702 with cancer, 134,638 with dementia, and 128,374 with pneumonia) in the complete case analysis. Pre-existing musculoskeletal pain had an incident rate ratio of above one for most healthcare resources over the follow-up period and an adjusted additional mean cumulative total healthcare costs per patient of £674.59 (95%CI 570.30 to 778.87) for ACS; £613.34 (95%CI 496.87 to 729.82) for stroke; £459.26 (95%CI 376.60 to 541.91) for cancer; and £766.23 (95%CI 655.06 to 877.39) for dementia over five years after diagnosis; and £200.85 (95%CI 104.16 to 297.55) for pneumonia over one year after diagnosis compared to those without musculoskeletal pain.RESULTSThe study included 760,792 patients (144,870 with ACS, 121,208 with stroke, 231,702 with cancer, 134,638 with dementia, and 128,374 with pneumonia) in the complete case analysis. Pre-existing musculoskeletal pain had an incident rate ratio of above one for most healthcare resources over the follow-up period and an adjusted additional mean cumulative total healthcare costs per patient of £674.59 (95%CI 570.30 to 778.87) for ACS; £613.34 (95%CI 496.87 to 729.82) for stroke; £459.26 (95%CI 376.60 to 541.91) for cancer; and £766.23 (95%CI 655.06 to 877.39) for dementia over five years after diagnosis; and £200.85 (95%CI 104.16 to 297.55) for pneumonia over one year after diagnosis compared to those without musculoskeletal pain.This study highlights that individuals with painful musculoskeletal conditions have higher healthcare utiliszation and costs than those without painful musculoskeletal conditions. Given the high occurrence of musculoskeletal pain in patients with other conditions, effective management strategies are needed to reduce the burden on healthcare resources.CONCLUSIONThis study highlights that individuals with painful musculoskeletal conditions have higher healthcare utiliszation and costs than those without painful musculoskeletal conditions. Given the high occurrence of musculoskeletal pain in patients with other conditions, effective management strategies are needed to reduce the burden on healthcare resources.
Most information on the comparative effectiveness and survival of methotrexate and adalimumab in the treatment of psoriasis is from randomised control trials which may not translate to the every-day ...clinical setting.
To determine the real-world effectiveness and survival of methotrexate and adalimumab in patients with moderate-to-severe psoriasis registered to the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).
Eligible patients were registered to BADBIR, ≥ 16 years of age, receiving a first course of methotrexate or adalimumab between 2007-2021 and with ≥6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (PASI) ≤ 2 reported ≥13 weeks after treatment start date until stop date. Average treatment effect (ATE) was estimated using inverse probability of treatment weighting with propensity score including baseline covariates. Results of ATE were presented as Risk Ratios (RR). Flexible parametric model estimated adjusted standardised average survival, defined as treatment discontinuation associated with ineffectiveness or occurrence of adverse events (AEs) at 6, 12 and 24 months. Restricted mean survival time (RMST) at 2 years of treatment exposure was calculated.
6,575 patients (median age 44 years; 44% female) were analysed with 2,659 (40%) prescribed methotrexate and 3,916 (60%) adalimumab. The proportion of patients achieving PASI ≤ 2 was higher in the adalimumab cohort (77%) compared with methotrexate (37%). Adalimumab was more effective than methotrexate RR (95% confidence interval (CI)), 2.20 (1.98, 2.45). Overall survival associated with ineffectiveness or AEs was lower in methotrexate compared with adalimumab cohort at 6 months Survival estimate (95% CI), 69.7 (67.9, 71.5) vs. 90.6 (89.8, 91.4), 1 year 52.5 (50.4, 54.8) vs. 80.6 (79.5, 81.8) and 2 years 34.8 (32.5, 37.2) vs. 68.6 (67.2, 70.0), respectively. The difference in RMST for overall, or when stratified by ineffectiveness and AEs was RMST (95% CI) years, 0.53 (0.49, 0.58), 0.37 (0.33, 0.42) and 0.29 (0.25, 0.33), respectively.
Patients on adalimumab were twice as likely to be clear or nearly clear of psoriasis and were less likely to discontinue their medication as compared to patients on methotrexate. Findings from this real-world cohort provide important information to aid clinicians managing psoriasis patients.
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