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Background/Objectives: Despite intensive research of the novel coronavirus SARS-CoV-2 and COVID-2019 caused by it, factors affecting the severity of the disease remains poorly understood. Clinical manifestations of COVID-2019 may vary from asymptomatic form to pneumonia, acute respiratory distress syndrome (ARDS) and multiorgan failure. Features of individual genetic landscape of patients can play an important role in development of the pathological process of COVID-19. In this regard the purpose of this study was to investigate the influence of polymorphic variants in genes (ADD1, CAT, IL17F, IL23R, NOS3, IFNL3, IL6, F2, F13A1, ITGB3, HIF1A, MMP12, VEGFA), associated with cardiovascular, respiratory and autoimmune pathologies, on the severity of COVID-19 and post-COVID syndrome in patients from Russia. Method(s): The study included 200 patients recovered from COVID-19. Two groups of patients were formed in accordance with clinical manifestations: with mild and moderate forms of the disease. The polymorphic variants were analysed with real-time PCR using commercial kits (Syntol). Result(s): 13 SNPs (rs4961;rs1001179;rs612242;rs11209026;rs2070744;rs8099917;rs1800795;rs1799963;rs5985;rs5918;rs11549465;rs652438;rs699947) were genotyped and comparative analysis of allele frequency distribution was carried out in two groups of patients recovered from COVID-2019. Conclusion(s): Identification of polymorphic variants in genome associated with severity of pathological processes in patients infected with SARS-CoV-2 can contribute to the identification of individuals with an increased risk of severe infection process and can also serve as a basis for developing personalized therapeutic approaches to the treatment of post-COVID syndrome.
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Background/Objectives: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease (COVID-19) enters the lung tissue through exocytosis, leading to the release of a large amount of pro-inflammatory cytokines called 'cytokine storm'. The aim was to provide more insight into relationship between plasma cytokines profile and fatal outcome of COVID-19. Method(s): Plasma cytokines (IL-17F,GM-CSF,IFNg,IL-10,CCL20/ MIP3a,IL-12P70,IL-13, IL-15,IL-17A,IL-22,IL-9,IL-1b,IL-33,IL-2,IL-21,IL-4,IL-23,IL-5,IL-6,IL-17E/IL-25,IL-27,IL-31,TNFa,TNFb,IL-28A) were detected in 30 patients with severe COVID-19 by a Luminex assay system with Milliplex Human Th17 Magnetic Premix 25 Plex Kit (HT17MG-14K-PX-25, Merk-Millipore, USA) according to the instructions. Patients were followed up for 30 days since admission to intensive care. 18 patients died and 12 patients survived during the period of observation. The control group comprised 10 individuals who had never been diagnosed with COVID-19. Result(s): IL-10 and CCL20/MIP3a plasma levels were elevated in non-survivors patients with COVID-19 compared to controls (p = 0.0027, p = 0.012, respectively). IL-15, IL-6, IL-27 plasma levels were higher in survivors with COVID-19 compared to controls (p = 0.049, p = 0.026, p = 0.00032, respectively). Interestingly, IL-15, IL-27 plasma levels were increased in non-survivors with COVID-19 compared to controls and survivors with severe COVID-19 (IL-15: p = 0.00098, p = 0.00014, respectively;IL-27: p = 0.011, p < 0.0001, respectively). Receiver operating characteristic (ROC) analysis has been conducted for IL-15 and IL-27. Cut-off value was estimated as 25.50 pg/ml for IL-15 and 1.51 pg/ml for IL-27. Conclusion(s): Our study demonstrated a more pronounced immune response in non-surviving patients with severe COVID-19. IL-15, IL-27 could be considered as a sensitive biomarker of the fatal outcome from COVID-19.
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Introduction: Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission atWeek (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Method(s): Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore >=2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IV->GUS 200mg IV;GUS 200mg IV->GUS 200mg SC;GUS 400mg IV->GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure). Matching IV or SC PBO was administered to maintain the blind. Result(s): Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. AtWk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6 % (29/105) of patients randomized to PBO IV (both p< 0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV->200mg SC group and 50.0% (19/38) in the GUS 400mg IV->200mg SC group achieved clinical response at Wk 24. Clinical response atWk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV->GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar toWk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion(s): Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified. (Figure Presented).
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Different vaccines have been developed to counteract the SARS-CoV2 pandemic. A competent immune system is a prerequisite for the development of appropriate immune protection after vaccination. Therapy with biologics for psoriasis patients, however, aims to suppress certain immune responses in the skin thus interfering with the inflammatory cascade. The purpose of this study was to investigate the measurable immune response of psoriasis patients receiving biologic therapy differs from healthy controls not receiving biologic treatment. Therefore, we collected blood samples within a fixed time frame (4 to 8 weeks) after complete two times vaccination against COVID19. We examined IgG and IgA antibody titer via ELISA analysis. The psoriatic group comprised persons under treatment with IL-17 inhibitors, IL-23 inhibitors and TNF alpha inhibitors. There was no significant difference between the psoriatic patients and control subjects concerning the time span between vaccination and blood sampling. The results showed significantly lower anti-COVID19 IgG antibody titers lower in patients under biologic treatment compared to the healthy control group without treatment. These results may help to adjust recommendations for future vaccinations in vulnerable immune suppressed patients.Copyright © 2023
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Background: Infections with SARS-CoV- 2 cause the coronavirus disease 2019 (COVID-19) pandemic. Alterations in immune cells of COVID-19 patients may predict the subsequent severity of disease. The changes in composition of immune cells in COVID-19 patients include lymphopenia, lower neutrophil to lymphocyte-ratios and an eosinopenia in about 50 to 80% of hospitalized patients. Eosinophils and neutrophils can interact with T cells via immune checkpoints receptors such as programmed death (PD)-1 on T cells and its counterpart PD-ligand 1 (PD-L1) on eosinophils or neutrophils. There are only limited studies on PD-1 and PD-L1 expressions in viral infections, we aimed to elucidate the interplay of T cells and other peripheral cells by analysing the immune checkpoints PD-1 and PD-L1 in expression during COVID-19. Method(s): Using flow cytometry, we have now analysed the immune checkpoint receptor expressions on whole blood cells from a total of 38 COVID-19 patients. The patient cohort comprises all ages and both sexes with the disease severity ranging from mild, moderate to severe, with ~10% mortality. We have further been investigating 21 biomarkers (G-CSF, GM-CSF, IFN-gamma, TGF-beta1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-23, IL-33, IP-10, MCP-1, MIP-1beta, TNF-alpha, and YKL-40) in plasma on a cohort of 76 COVID-19 patients using the MesoScale Multiplex Assay platform, with 48 healthy controls. Result(s): PD-L1 expression on eosinophils was significantly lower in COVID-19 patients in initial stages of infection, relative to healthy controls. There was an inverse relationship between disease progression and the expression of PD-1 on CD8+ T cells. These data suggests that analysis of PD-L1- PD1 cell networks in immune cells of EDTA blood of COVID-19 patients can predict disease outcomes. While most detectable biomarkers are strongly increased in COVID samples overall compared to healthy controls, the more severe the disease the higher the blood biomarker concentration. Conclusion(s): Taken together, the analysis of PD-L1- PD1 cell networks in immune cells together with plasma biomarkers of COVID-19 patients can predict disease outcomes.
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Background: Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission at Week (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Method(s): Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore >=2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IVGUS 200mg IV;GUS 200mg IV->GUS 200mg SC;GUS 400mg IV->GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure 1). Matching IV or SC PBO was administered to maintain the blind. Result(s): Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. At Wk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6% (29/105) of patients randomized to PBO IV (both p<0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV->200mg SC group and 50.0% (19/38) in the GUS 400mg IV->200mg SC group achieved clinical response at Wk 24. Clinical response at Wk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV->GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar to Wk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion(s): Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified.
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Psoriasis is a chronic inflammatory disease associated with a de-fective epidermal barrier, in which the immune system is already activated in lesional sites of the skin, and it is thus possible that affected individuals can have different immunologic rates of viral response. This is especially impor-tant in the era of the novel coronavirus disease (COVID-19) that is affecting the entire world. Patients with psoriasis are often receiving systemic therapy which includes immunosuppressive and biologic therapy, so this new infec-tious disease has raised concerns among dermatologists regarding psoriasis treatment. Some of the risk factors of psoriasis are obesity, diabetes mellitus, and hypertension - all of which are diseases linked with negative outcomes and higher severity of COVID-19. Psoriasis is mediated by inflammatory cells and proinflammatory cytokines such as IL-17, IL-23, IFN-gamma, and TNF-alpha, and patients with skin diseases have been shown to be more susceptible to CO-VID-19 infection, but with a less severe disease course. As an anti-inflamma-tory agent, vitamin D could play a significant role in the future as a possible treatment for reducing the risk and severity of psoriasis and COVID-19. It has been suggested that patients treated with biologic therapy should continue treatment, as it has not been shown to cause severe complications of the CO-VID-19 disease. Preventive measures, including vaccination, should be taken to minimize the risk of infection and severity of the clinical outcome.Copyright © 2022, Croatian Dermatovenerological Society. All rights reserved.
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Ulcerative colitis is a relapsing and remitting inflammatory bowel disease of the large intestine. Risk factors include recent Salmonella or Campylobacter infection and a family history of ulcerative colitis. Diagnosis is suspected based on symptoms of urgency, tenesmus, and hematochezia and is confirmed with endoscopic findings of continuous inflammation from the rectum to more proximal colon, depending on the extent of disease. Fecal calprotectin may be used to assess disease activity and relapse. Medications available to treat the inflammation include 5-aminosalicylic acid, corticosteroids, tumor necrosis factor-alpha antibodies, anti-integrin antibodies, anti-interleukin-12 and -23 antibodies, and Janus kinase inhibitors. Choice of medication and method of delivery depend on the location and severity of mucosal inflammation. Other treatments such as fecal microbiota transplantation are considered experimental, and complementary therapies such as probiotics and curcumin have mixed data. Surgical treatment may be needed for fulminant or refractory disease. Increased risk of colorectal cancer and use of immunosuppressive therapies affect the preventive care needs for these patients. (Am Fam Physician. 2022;105(4):406-411. Copyright © 2022 American Academy of Family Physicians.)Copyright © 2022 American Academy of Family Physicians. All rights reserved.
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Background: Current research on COVID-19-related outcomes in patients with psoriasis, particularly regarding influence of treatments, are subject to lack of comparator group, selection bias, and insufficient statistical power.1 Accordingly, it remains uncertain whether immunomodulatory treatments for psoriasis enhance or decrease the risk of severe COVID-19-related outcomes, including hospitalization. Objective(s): To compare the risk of COVID-19-related hospitalization according to immunomodulator treatment type in patients with psoriasis Methods: Retrospective cohort study of the Explorys database in the United States between March 1st, 2020 and December 31st, 2020. Psoriasis diagnosis was defined by at least 2 ICD-9 or ICD-10 diagnosis codes prior to March 1st, 2020. Drug exposure was classified as biologic or traditional immunosuppressive (methotrexate, cyclosporine, apremilast) treatment based on prescription order in the 3 months preceding March 1st, 2020. Biologic treatments included TNFalpha, IL-12/IL-23, IL-17A, IL-23 and JAK inhibitors. The primary outcome was defined as hospital admission with diagnosis of COVID-19 or positive lab test occurring between admission and discharge date. Propensity score weighting was used to compare COVID-19-related hospitalization between treatment groups, adjusting for comorbidities and demographic characteristics. Result(s): A total of 51,606 psoriasis patients aged 18-88 were included. Crude cumulative incidence of COVID-19 hospitalization per 1,000 psoriasis patients was 3.4 in the biologic group (9/2,669), 9.5 in the traditional immunosuppressive group (15/1,585), and 3.9 in those receiving neither drug class (184/47,352). Incidence was 4.7 (6/1,282) and 14 (13/898) per 1,000 patients among those receiving TNF-alpha inhibitors and methotrexate, respectively. After propensity-score weighting, risk of COVID-19-related hospitalization for patients receiving any biologic was lower than that of patients receiving traditional immunosuppressives (RR 0.39, 95% CI 0.16, 0.92), and those receiving neither drug class (RR 0.66, 95% CI 0.32, 1.34). TNF-alpha inhibitor use was associated with lower risk of hospitalization relative to methotrexate use (adjusted RR 0.39, 95% CI 0.14, 1.06). Adjusted relative risk of hospitalization for methotrexate users relative to those receiving neither drug class was 2.78 (95% CI 1.47, 5.26). Conclusion(s): During the first wave of the pandemic in 2020, psoriasis patients using biologics were at lower risk of COVID-19-related hospitalization compared to those using traditional immunosuppressives, particularly methotrexate. Methotrexate use was associated with a substantial increase in risk of hospitalization relative to those who did not receive systemic treatments.
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Purpose : Patients on systemic immunomodulatory therapy (IMT) for uveitis are at higher risk of infection and infectious complications. While other medical specialties have studied the safety of IMT in non-ocular, autoimmune conditions vis-à-vis coronavirus disease 2019 (COVID-19), little is known about the effects of these drugs in uveitis patients specifically. The objective of this study was to determine if uveitis patients with COVID-19 were at higher risk of hospitalization for this pandemic illness and whether systemic IMT affected this risk. Methods : Retrospective cohort study of uveitis patients in 2020 in the United States. The Symphony health insurance claims dataset was used. Inclusion criteria were an ICD10 code for COVID-19, a code for any form of non-infectious uveitis or scleritis, and age 18 or greater. Drugs studied included methotrexate, mycophenolate, azathioprine, tacrolimus, cyclosporine, adalimumab, infliximab, tocilizumab, rituximab, and JAK, IL-17, and IL-12/23 inhibitors. The main outcome measure was adjusted odds of hospitalization for COVID19. Multivariable logistic regression was used to adjust for major risk factors for severe COVID-19 disease, including age, biological sex, cardiac, pulmonary, hepatic, and renal disease, obesity, organ transplant, stroke, and certain cancers. Results : 3,974,272 patients in the dataset were diagnosed with COVID-19 in 2020. Of these, 6389 (0.16%) had established diagnoses of uveitis or scleritis. Within the uveitis group, mean age was 54 years (SD 16), and 62% were female. 708 (11.1%) of the uveitis patients were hospitalized for COVID-19, significantly greater than the 7.3% rate amongst all adult, COVID-19-positive patients in the dataset (p < 0.001) and the CDC estimate of 7.5% for the US population in 2020 (p < 0.001). No agent showed a statistically significant effect on hospitalization. The higher rate of hospitalization in uveitis patients was partly, though not completely, explained by higher rates in uveitis-associated autoimmune conditions in the dataset as a whole. Conclusions : Uveitis patients have a greater risk of hospitalization for COVID-19 compared with the general population. As a whole, conventional IMT and biologics do not increase the risk of COVID-19 hospitalization amongst uveitis patients infected with the virus.
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Background: Although it prevents severe forms of the disease, vaccination does not completely protect against the occurrence of COVID19 disease. If, DMARDs used have been associated with variable humoral response to SARS-CoV-2 vaccination, the impact of their use after SARS-CoV-2 natural infection have been poorly studied. Objectives: To characterize humoral response after SARS-CoV-2 infection and viral persistence in the nasopharyngeal sphere (NP), stools and blood of patients with rheumatic disease under DMARDs, and compared to healthy controls. Methods: Prospective monocentric longitudinal study including patients with rheumatoid arthritis or spondyloarthritis under DMARDs and with a confrmed SARS-CoV-2 infection (positive NP PCR and/or positive serology and/or pathognomonic thoracic tomography (CT)) during the frst or second wave of the COVID pandemic. Patients were followed up until one year after infection and humoral response was assessed before vaccination. Serum IgG and IgA antibodies against spike (S) and nucleocapsid (N) proteins were measured at every visit. Viral persistence was assessed at the early visit in the NP and stools using conventional RT-PCR and in the blood using a high sensitive technique (droplet digital PCR). Results: Between June 2020 and July 2021, we include 96 patients (50 SpA and 46 RA) with a mean age of 53 +/-14 years and 20 healthy controls (mean age 49 ± 16 years) corresponding to relatives of patients (spouses, children) living together and infected at the same time. The immune responses were analyzed according to 6 treatment groups: methotrexate (MTX)/salazopyrine (SLZ) monotherapy (n=17/2);anti-TNF monotherapy (n=24), anti-TNF + MTX (n=23);rituximab (RTX) (n=11);anti-IL17 or-23 (n=8);others (n=11). Visits were made at 1 month (29 ±13 days;n=18), 3 months (110 ±23 days;n=67), 6 months (231 ±35 days;n=48) and 12 months (368 ± 19 days;n=19) after infection. The anti-S and anti-N IgG Ab titers were not signifcantly different in the 6 treatment groups and the control population at 3 months. A signifcant decrease in anti-S IgA Ab titers was noted in the group treated with RTX (p=0.007) and with molecules targeting the IL17/23 pathway (p=0.007). A similar but non-signifcant trend was observed in these same treatment groups for anti-N IgA Ab (p=0.07). The titers of anti-SARS-CoV-2 antibodies at M3, was not associated with a severe COVID disease. Detection of SARS-Cov-2 RNA in stools and serum was negative for all samples taken at 1 month or 3 months. 4 patients (2 RA treated with abatacept/RTX and 2 SpA treated with anti-TNF/secukinumab) had a positive RT-PCR NP with low to very low viral load at the 1-month visit (mean Ct 36). None of these 4 patients had had a severe form of COVID19 infection. Conclusion: DMARDs-treated patients with previous proven COVID-19 did not seem to alter IgG Ab response but RTX and anti-IL17/-IL-23 might alter IgA humoral response. This lower immune response was not associated with a more severe disease. In these patients, new infection may not be considered as a full boost for the immune system. DMARDs did not induce viral persistence in the serum, the NP or in the stool.
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Background: To our knowledge, no published work has described precisely the severity and evolution of SARS-CoV-2 infection in patients with spondyloarthritis (SpA). Data on COVID-19 from cohorts of patients with immune-mediated infam-matory diseases concern small samples of SpA. Objectives: Our objective was to describe the severity and course of COVID-19 in a large cohort of patients with SpA, including axial SpA (axSpA) and psoriatic arthritis (PsA), and to identify factors associated with severe forms. Methods: Patients: individuals with Spondyloarthritis (SpA) from the French RMD COVID-19 cohort (observational, national, multicenter cohort) with a diagnosis of COVID-19 (clinical, PCR, CT or serology) were included. Data collected: demographics, type of SpA, comorbidities, treatments, severity of COVID-19. Severity of COVID-19 was graded according to care needed: mild = outpatient care;moderate = non-intensive hospital treatment;severe = intensive care unit admission or death;severe = moderate or severe. Statistical analyses: Logistic regression models were used to identify factors associated with these severe forms. All variables with p <0.20 in the univariate analysis were proposed in the multivariate model. Treatment variables (non-ste-roidal anti-infammatory drugs (NSAIDs), methotrexate (MTX), sulfasalazine (SLZ), TNF inhibitors (TNFi), IL-17 inhibitors (IL-17i) and IL-23p19/p40 inhibitors (IL-23p19/p40i)) were included in the models, even if p≥0.20. Results: Between March 2020 and April 2021, 626 SpAs reported COVID-19 with a mild course in 508 cases (81.1%), moderate in 93 cases (14.8%), and severe in 25 cases (3.9%), including 6 deaths. The cohort analyzed included 349 women (55.8%), mean age 49.3 ± 14.1 years, mean BMI 27.1 ± 5.4 with 403 axSpA (64.4%), 187 PsA (29.9%) and 36 other SpA, duration of disease 11.3 ± 9.8 years;352 (56.2%) had at least one comorbidity, of which obesity (23.6%), hypertension (15.5%), and smoking (10.4%) were the most frequent. Among them, 104 were treated with NSAIDs (16.6%), 186 with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) including 156 MTX, and 460 (73.5%) with biological DMARDs (379 TNFi, 57 IL-17i, 15 IL-23p19/p40i, 9 others). The following variables were associated with severe COVID-19 outcomes: age, body mass index, chronic obstructive lung disease, cardiovascular disease, diabetes, hypertension, interstitial lung disease, renal failure, and corticosteroids intake. The factors independently associated with severe COVID-19 outcomes were cor-ticosteroid intake (3.15 [CI95%: 1.46-6.76], p 0.004), and age (OR=1.06 [CI95%: 1.04-1.08], p <0.001] while anti-TNF (OR=0.26 [CI95%: 0.09-0.78], p=0.01]) was protective. NSAIDs intake (OR=0.97 [CI95%: 0.48-1.98]), SLZ (OR=7.9 [CI95%: 0.60-103]), or anti-IL17 (OR=0.37 [CI95%: 0.10-1.31]) was not associated with infection severity. Conclusion: The course of COVID-19 was mild for the majority of SpA patients (81.1%). Corticosteroid intake was associated with more severe COVID-19 outcomes, whereas TNFi were found to be protective.
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Background: Patients with immune-mediated infammatory diseases are inherently susceptible to infections and are at high risk of developing COVID-19. COVID-19 vaccination in patients with rheumatoid and musculoskeletal disease (RMD) is strongly recommended [1]. BNT162b2 is the most used COVID-19 vaccine in Japan. The safety and efficacy of this vaccine has been demonstrated in the general population [2], but patients receiving immunosuppressive therapy were excluded from the study. Although data on the immunogenicity of COVID-19 vaccine in the immunocompromised adult population is rapidly increasing, the immunogenicity of mRNA COVID-19 vaccine in RMD patients receiving medication has been reported in various and still inadequate ways. Furthermore, the immunogenicity of mRNA COVID-19 vaccine may vary depending on the medication. In addition, most of these data were reported from Western countries, and data on Japanese patients with RMD are limited. Objectives: To investigate serum antibody titre against SARS-CoV-2 spike protein following BNT162b2 vaccination in Japanese RMD patients on various immunomodulatory treatment. Methods: Two hundred and twelve RMD outpatients undergoing treatment at Kagawa University Hospital and 43 healthy volunteers, who had received two doses of BNT162b2, were included in the study. Serum sample was collected at least 14 days after the second dose. Antibody titer against SARS-CoV-2 spike protein in serum was measured by ELISA (Elecsys Anti-SARS-CoV-2 S RUO). We analyzed the relationship between clinical characteristics, including the type of disease and treatment of RMD, and antibody titer against SARS-CoV-2 spike protein. Results: The antibody titer against SARS-CoV-2 spike protein in RMD patients was signifcantly lower than that in healthy subjects. In the analysis with therapeutic agents, the mean antibody titer in RMD patients treated with rituximab (RTX) was much lower than that in healthy controls. Patients treated with baricitinib, azathioprine, mycophenolate mofetil, abatacept, TNF inhibitors, cyclosporine, IL-6 inhibitors, methotrexate (MTX), or glucocorti-coids (GC) had only moderately lower antibody titers. Patients treated with tacrolimus, an immunosuppressive drug commonly used for treatment in Japan, showed a slight decrease in antibody titer, but the difference was not signifcant compared with healthy subjects. IL-17 and IL-23 inhibitors did not impair the humoral response. In addition, the combination of MTX with various immunosuppressive agents reduced titers, although this was not statistically signifcant. Conclusion: Many of the immunosuppressants impaired the immunogenicity to BNT162b2 in Japanese RMD patients. The degree of decline of antibody titers differed according to immunosuppressant. MTX potentially impairs the immunogenicity of BNT162b2 also in the case of concomitant use with other immunosuppressant.
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Background: Some factors associated with severe COVID-19 outcomes have been identifed in patients with psoriasis (PsO) and infammatory/autoimmune rheumatic diseases, namely older age, male sex, comorbidity burden, higher disease activity, and certain medications such as rituximab. However, information about specifcities of patients with PsO, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), including disease modifying anti-rheumatic drugs (DMARDs) specifcally licensed for these conditions, such as IL-17 inhibitors (IL-17i), IL-23/IL-12 + 23 inhibitors (IL-23/IL-12 + 23i), and apremilast, is lacking. Objectives: To determine characteristics associated with severe COVID-19 outcomes in people with PsO, PsA and axSpA. Methods: This study was a pooled analysis of data from two physician-reported registries: the Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection (PsoProtect), comprising patients with PsO/PsA, and the COVID-19 Global Rheumatology Alliance (GRA) registry, comprising patients with PsA/axSpA. Data from the beginning of the pandemic up to 25 October, 2021 were included. An ordinal severity outcome was defned as: 1) not hospitalised, 2) hospitalised without death, and 3) death. A multivariable ordinal logistic regression model was constructed to assess the relationship between COVID-19 severity and demographic characteristics (age, sex, time period of infection), comorbidities (hypertension, other cardiovascular disease [CVD], chronic obstructive lung disease [COPD], asthma, other chronic lung disease, chronic kidney disease, cancer, smoking, obesity, diabetes mellitus [DM]), rheumatic/skin disease (PsO, PsA, axSpA), physician-reported disease activity, and medication exposure (methotrexate, lefunomide, sulfasalazine, TNFi, IL17i, IL-23/IL-12 + 23i, Janus kinase inhibitors (JAKi), apremilast, glucocorticoids [GC] and NSAIDs). Age-adjustment was performed employing four-knot restricted cubic splines. Country-adjustment was performed using random effects. Results: A total of 5008 individuals with PsO (n=921), PsA (n=2263) and axSpA (n=1824) were included. Mean age was 50 years (SD 13.5) and 51.8% were male. Hospitalisation (without death) was observed in 14.6% of cases and 1.8% died. In the multivariable model, the following variables were associated with severe COVID-19 outcomes: older age (Figure 1), male sex (OR 1.53, 95%CI 1.29-1.82), CVD (hypertension alone: 1.26, 1.02-1.56;other CVD alone: 1.89, 1.22-2.94;vs no hypertension and no other CVD), COPD or asthma (1.75, 1.32-2.32), other lung disease (2.56, 1.66-3.97), chronic kidney disease (2.32, 1.50-3.59), obesity and DM (obesity alone: 1.36, 1.07-1.71;DM alone: 1.85, 1.39-2.47;obesity and DM: 1.89, 1.34-2.67;vs no obesity and no DM), higher disease activity and GC intake (remission/low disease activity and GC intake: 1.96, 1.36-2.82;moderate/severe disease activity and no GC intake: 1.35, 1.05-1.72;moderate/severe disease activity and GC intake 2.30, 1.41-3.74;vs remission/low disease activity and no GC intake). Conversely, the following variables were associated with less severe COVID-19 outcomes: time period after 15 June 2020 (16 June 2020-31 December 2020: 0.42, 0.34-0.51;1 January 2021 onwards: 0.52, 0.41-0.67;vs time period until 15 June 2020), a diagnosis of PsO (without arthritis) (0.49, 0.37-0.65;vs PsA), and exposure to TNFi (0.58, 0.45-0.75;vs no DMARDs), IL17i (0.63, 0.45-0.88;vs no DMARDs), IL-23/IL-12 + 23i (0.68, 0.46-0.997;vs no DMARDs) and NSAIDs (0.77, 0.60-0.98;vs no NSAIDs). Conclusion: More severe COVID-19 outcomes in PsO, PsA and axSpA are largely driven by demographic factors (age, sex), comorbidities, and active disease. None of the DMARDs typically used in PsO, PsA and axSpA, were associated with severe COVID-19 outcomes, including IL-17i, IL-23/IL-12 + 23i, JAKi and apremilast.
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Background: The impact of immunosuppressants on COVID-19 vaccination response and durability in patients with immune-mediated infammatory diseases (IMID) is yet to be fully characterized. Humoral response may be attenuated in these patients especially those on B cell depleting therapy and higher doses of corticosteroids, but data regarding other immunosuppressants are scarce. Objectives: We aimed to investigate antibody and T cell responses and durability to SARS-CoV-2 mRNA vaccines (BNT162b and/or mRNA 1273) in IMID patients on immunomodulatory maintenance therapy other than B-cell depleting therapy and corticosteroids. Methods: This prospective observational cohort study examined the immuno-genicity of SARS-CoV-2 mRNA vaccines in adult patients with IMIDs (psoriatic arthritis, psoriasis, infammatory bowel disease and rheumatoid arthritis) with or without maintenance immunosuppressive therapies (anti-TNF, methotrexate/azathioprine [MTX/AZA], anti-TNF + MTX/AZA, anti IL12/23, anti-IL-17, anti-IL23) compared to healthy controls. Automated ELISA for IgGs to spike trimer, spike receptor binding domain (RBD) and the nucleocapsid (NP) and T-cell release of 9 cytokines (IFNg, IL2, IL4, IL17A, TNF) and cytotoxic molecules (sFasL, GzmA, GzmB, Perforinin) in cell culture supernatants following stimulation with spike or NP peptide arrays were conducted at 4 time points: T1=pre vaccination, T2=me-dian 26 days after dose 1, T3=median 16 days after dose 2 and T4=median 106 days after dose 2. Neutralization assays against four SARS-CoV-2 variants (wild type, delta, beta and gamma) were conducted at T3. Results: We followed 150 subjects: 26 healthy controls and 124 IMID patients: 9 untreated, 44 on anti-TNF, 16 on anti-TNF with MTX/AZA, 10 on anti-IL23, 28 on anti-IL12/23, 9 on anti-IL17, 8 on MTX/AZA (Table 1). Most patients mounted antibody and T cell responses with increases from dose 1 to dose 2 (100% sero-conversion at T3) and some decline by T4, with variability within groups. Antibody levels and neutralization efficacy was lower in anti-TNFgroups (anti-TNF, anti-TNF + MTX/AZA) compared to controls and waned by T4 (Figure 1). T cell responses were not consistently different between groups. Pooled data showed a higher antibody response to mRNA-1273 compared to BNT162b. Conclusion: Following 2 doses of mRNA vaccination there is 100% seroconver-sion in IMID patients on maintenance therapy. Antibody levels and neutralization efficacy in anti-TNF group are lower than controls, and wane substantially by 3 months after dose 2. These fndings highlight the need for third dose in patients undergoing treatment with anti-TNF therapy and continued monitoring of immunity in these patient groups, taking into consideration newer variants and additional vaccine doses.
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Background: Risankizumab, an interleukin-23 inhibitor, was efficacious and well tolerated in phase 2 and 3 clinical studies in patients with psoriatic disease. Objectives: To report long-term risankizumab safety in patients with psoriatic disease. Methods: Risankizumab safety data to March 25, 2021 were pooled from 17 phase 1-3 clinical trials in plaque psoriasis (PsO) and 4 phase 2/3 trials in pso-riatic arthritis (PsA). Adverse events (AEs) of safety interest were reported for patients receiving ≥1 dose risankizumab. Results: Among 3197 patients with PsO (9982.6 patient years' [PY] exposure;median (range) treatment duration, 3.7 years [1 day-6.9 years]) and 1542 patients with PsA (1594.9 PY;1. 0 year [84 days-2.0 years]), rates of treatment-emergent AEs (158.3 and 160.8 events (E)/100PY), serious AEs (7.6 and 8.4 E/100PY) and AEs leading to discontinuation (1.9 and 2.3 E/100PY) were similar. Nasopharyn-gitis (PsO 14.5 E/100PY, PsA 7. 9 E/100PY) and upper respiratory infection (PsO 7. 8 E/100PY, PsA 5.6 E/100PY) were the most common infections;sepsis and pneumonia for PsO (0.1 E/100PY each) and COVID-19 for PsA (0.4 E/100PY) were the most common serious infections. Rates of opportunistic fungal infections were <0.1 and 0.1 E/100PY in PsO/PsA patients. Rates of non-melanoma skin cancer (NMSC) were 0.7 and 0.4 E/100PY, and malignant tumors excluding NMSC were 0.6 and 0.3 E/100PY in PsO/PsA patients. Rates of major adverse cardiovascular events were 0.5 and 0.4 E/100PY in PsO/PsA patients. Conclusion: Rates of AEs of safety interest remained low in this largest and longest safety reporting for risankizumab to date, supporting the safety of risankizumab for the long-term treatment of patients with psoriatic disease.
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Background: Comorbidities, particularly cardio-metabolic disorders, are highly prevalent in patients with psoriatic arthritis (PsA) and they were associated with an increased risk of atherosclerotic cardiovascular disease, which have been associated with higher morbidity and mortality. Whether PsA enhances the risk of SARS-CoV-2 infection or affects the disease outcome remains to be ascertained. Objectives: To describe the sociodemographic, clinical and treatment characteristics of patients with PsA with confrmed SARS-CoV-2 infection from the SAR-COVID registry and to identify the variables associated with poor COVID-19 outcomes, comparing them with those with rheumatoid arthritis (RA). Methods: Cross-sectional observational study including patients ≥18 years old, with diagnosis of PsA (CASPAR criteria) and RA (ACR/EULAR 2010 criteria), who had confrmed SARS-CoV-2 infection (RT-PCR or serology) from the SAR-COVID registry. Recruitment period was between August 13, 2020 and July 31, 2021. Sociodemographic variables, comorbidities, and treatments were analyzed. To assess the severity of the infection, the ordinal scale of the National Institute of Allergy and Infectious Diseases (NIAID)1 was used, and it was considered that a patient met the primary outcome, if they presented criteria of categories 5 or higher on the severity scale. For this analysis, Chi2 test, Fisher's test, Student's test or Wilcoxon test, and binomial logistic regression using NIAID>=5 as dependent variable were performed. Results: A total of 129 PsA patients and 808 with RA were included. Clinical characteristics are shown in Table 1. Regarding PsA treatment, 12.4% of PsA were receiving IL-17 inhibitors, 5.4% IL12-23 inhibitors, one patient apremilast and one abatacept. The frequency of NIAID≥5 was comparable between groups (PsA 19.5% vs RA 20.1%;p=0.976). (Figure 1). PsA patients with NIAID≥5 in comparison with NIAID<5 were older (58.6±11.4 vs 50±12.5;p=0.002), had more frequently hypertension (52.2% vs 23%;p=0.011) and dyslipidemia (39.1% vs 15%;p=0.017). In the multivariate analysis, age (OR 1.06;95% CI 1.02-1.11) was associated with a worse outcome of the COVID-19 (NIAID≥5) in patients with PsA, while those who received methotrexate (OR 0.34;95% CI 0.11-0.92) and biological DMARDs (OR 0.28;95% CI 0.09-0.78) had a better outcome. Conclusion: Although PsA patients have a higher frequency of cardiovascular and metabolic comorbidities than those with RA, the COVID-19 severity was similar. Most of the patients had mild SARS-CoV-2 infection and a low death rate.
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Among the pathophysiological mechanisms of immune-mediated inflammatory diseases (IMIDs), specific attention has been paid to the abnormal activation of Th17 type immune response related to the dysregulated synthesis of cytokines forming the interleukin (IL)-23 and IL-17 axis. IL-23 blockade is an innovative approach to the treatment of psoriasis and psoriatic arthritis (PsA). Much of the interest has focused on guselkumab (GUS) (TREMFYA, Janssen, Johnson & Johnson, USA), a fully human IgG λ monoclonal antibody (mAb) targeting the p19 IL-23 subunit and the first-in-class treatment approved for patients with psoriasis and PsA. In patients with psoriasis, GUS is at least as effective as other biologic therapies for PsA and is superior to ustekinumab, an anti-IL-12/IL-23 mAb, and secukinumab, an anti-IL-17 mAb. Compared with TNF-α inhibitors, GUS therapy is less likely to cause infections and does not increase the risk of the reactivation of latent TB infection. The new GRAPPA guidelines (2021) recommend GUS (and other IL-23 inhibitors) for patients with PsA resistant to conventional disease-modifying antirheumatic drugs (DMARDs), who have peripheral arthritis, enthesitis, dactylitis, psoriatic skin and nail lesions. The paper discusses new data on the efficacy of GUS in patients resistant to TNF-α inhibitors, its benefits in patients with axial PsA, and safety during the COVID-19 pandemic.
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BACKGROUND Little is known about the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). Although humoral response may be attenuated in patients using immunomodulators (IMM) and TNFinhibitors (anti-TNF), data regarding cellular response are scarce and conflicting. This study was aimed to identify immune response to COVID-19 vaccination in IMID patients. METHODS A prospective observational multicentre cohort study was conducted to examine the immunogenicity of mRNA vaccines to SARS-CoV-2 in adult IMID patients using immunosuppressive therapy (anti-TNF, IMM, anti-TNF+IMM, anti-IL12/23, anti-IL-17, anti-IL-23) or no therapy as compared to healthy controls (HC). Patient details and vaccination history were recorded. Blood samples were drawn at 3 time points: before, 3-4 weeks after first and 2 weeks after second vaccination. Humoral immune response to S and RBD proteins were assessed by ELISA. Neutralization was tested against 4 variants of SARS-CoV-2 by surrogate neutralization ELISA. Cellular immune responses were determined based on analysis of 9 secreted cytokines and cytotoxic molecules after stimulation of PBMC with S peptide pools. Response to N protein was used to assess SARS-CoV-2 exposure. RESULTS A total of 159 subjects (133 IMID patients and 26 HC) were included in this study (median age 42 years [IQR 30-53], 52% male). Of 133 IMID patients, 87 had inflammatory bowel disease, 23 psoriatic arthritis, 18 psoriasis, 11 ankylosing spondylarthritis and 4 rheumatoid arthritis. Of these, 44 used anti-TNF, 9 IMM, 18 anti-TNF+IMM, 33 anti-IL-12/23, 9 anti-IL-17, 10 anti-IL-23 therapy and 10 no therapy. All subjects received 2 doses of mRNA vaccines (2x Pfizer, 2x Moderna or mixed) between December 2020 and September 2021. The vast majority of subjects had minimal binding antibody and T cell responses to N, indicating they were COVID-19 naïve. After dose 1, anti-TNF group had lower IL-2 vs untreated IMID (p<0.01), and the anti-IL-23 group had lower IFN-g vs HC (p<0.01), though there was wide variation in responses within groups. Following dose 2, median responses between groups were mostly similar, but antibody responses were significantly lower in patients on anti-TNF as compared to HC in subjects that received two doses of Pfizer (p=0.01). Pooled data for all subjects combined show a higher response to Moderna over Pfizer in ELISA, neutralization and T cell readouts, and a lower response for those over 60 years of age after dose 2. Longer follow-up is in process to monitor the durability of these responses over time and after third dose. CONCLUSION Immune responses after 2 doses of mRNA vaccines in immunocompromised IMID patients largely reach the level of that of HC albeit antibody responses in the anti-TNF group are weaker and with wide variability between subjects within some groups
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BACKGROUND: The characteristics of SARS-CoV-2 vaccine-induced immunity in inflammatory bowel disease (IBD) patients on immune modifying agents has not been clearly defined due to their exclusion in vaccine trials. Emerging results suggest infliximab impairs antibody response compared to vedolizumab. However there has not been direct comparison to controls. We evaluated this with both humoral and T cell response in IBD patients. METHODS: Antibody and T cell response were analysed in IBD patients who received BNT162b2 (Pfizer–BioNTech) or ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccination from a single Australian centre. The control group were healthcare workers (HCW) without IBD. Blood samples were taken at 4 time points: at baseline V0 (before vaccination);V1 (7- 14 days after vaccine 1);V2 (7-14 days after vaccine 2);V3 (21-42 days after vaccine 2). Antibodies to the S1/2 IgG subunit and receptor-binding protein (RBD) were measured and reported here. RESULTS: 88 (28 ulcerative colitis, 50 Crohn's disease) IBD patients were included and compared to 53 healthy controls (Table 1). IBD patients medications included 6 5ASA (6.8%), 6 immunomodulator monotherapy (6.8%), 14 anti-TNF monotherapy (15.9%), 32 anti-TNF combination therapy with immunomodulator (36%), 16 IL12/23 (18%) and 13 vedolizumab (14%). Pre-vaccine baseline sera showed absence of anti-RBD antibodies in all participants. 84 patients (87%) received BNT162b2 and 4 (4.5%) received ChAdOx1 nCoV-19 vaccines. Geometric mean [SD] anti-S1/2 antibody concentrations at 4 weeks after second vaccination (V3) were significantly lower in IBD TNF treated patients (162.6[1.7]) compared to IBD non TNF treated patients (325.2[1.3]), and healthy controls (325.2[1.3]), p<0.0001 (Figure 1). There was no difference between non-TNF treated patients including those on vedolizumab or IL12/23 compared to controls. Similarly there was a significant difference between anti-RBD IgG titres between TNF and non-TNF IBD patients at V3 but not when compared to controls. There was no difference in RBD IgG and anti-S1/2 antibodies between anti-TNF monotherapy and combination therapy. All healthy controls and most IBD patients seroconverted at V3. 2 patients that failed to seroconvert were on steroid. CONCLUSION: TNF agents influence SARS-CoV-2 vaccine-induced antibody response in IBD patients, with lower anti-S1/2 IgG concentrations compared to non-TNF IBD patients and healthy controls. However, there was no difference in RBD IgG concentrations. It is unclear whether these subtle differences in antibody response in IBD patients on TNF agents is biologically meaningful, as most seroconverted after second dose vaccination. They may translate to differences in antibody longevity, but this is yet to be demonstrated. Neutralising antibody and T cell (CD4+/CD8+/follicular T cell) data from this study to come. (Table Presented) (Figure Presented)