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In patients with ulcerative colitis (UC), the development of an antidrug antibody (ADA) to anti-tumor necrosis factor (TNF)α agent is a crucial problem which aggravates the clinical course of the disease, being cited as one of the most common causes for discontinuing anti-TNFα treatment. This is due to ADA eventually causing secondary LOR, leading to discontinuation of anti-TNFα treatment. Recently, research on the microbiome and relationship between worsening UC and dysbiosis has been conducted. Further, investigations on the association between the microbiome and secondary LOR are increasing. Here, we present the therapeutic effect of fecal microbiota transplantation (FMT) on a 42-year-old man with secondary LOR and high ADA levels. FMT has recently been used for the treatment of, and for overcoming, drug resistance through microbiome modification. Stool samples were collected from the patient before and 4 weeks after FMT. Symptoms, including hematochezia and Mayo endoscopy sub-scores, improved after FMT, while ADA levels decreased by one-third to less than half the value (29 ng/mL) compared to before FMT (79 ng/mL). Additionally, the trough level of infliximab became measurable, which reflects the improvement in the area under the concentration (AUC). Butyricicoccus, Faecalibacterium, Bifidobacterium, Ligilactobacillus, Alistipes, and Odoribacter, which regulate immune responses and alleviate inflammation, also increased after FMT. We report a case in which microbiome modification by FMT increased the AUC of anti-TNFα in a patient who developed secondary LOR during anti-TNFα treatment, thereby improving symptoms and mucosal inflammation.

Vaccines are pivotal for control of the coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBDs) treated with antitumor necrosis factor (TNF)-α have lower serologic response after two COVID-19 vaccine doses. Data regarding a third vaccine dose are scarce. An Israeli multicenter prospective observational study recruited 319 subjects: 220 with IBD (79 treated with anti-TNFα) and 99 healthy control (HC) participants. All patients received two mRNA-BNT162b2 vaccines (Pfizer/BioNTech), 80% of whom received a third vaccine dose. Evaluation included disease activity, anti-spike (S) and nucleocapsid (N) antibody levels, anti-TNFα drug levels, and adverse events (AEs). All participants showed significant serologic response one month after receiving a third dose. However, three months later, the anti-S levels decreased significantly in patients treated with anti-TNFα compared with the non-anti-TNFα and HC groups. A correlation between serologic response to the third vaccine dose and anti-TNF drug levels was not found. No significant AE or IBD exacerbation was observed. Importantly, lower serologic response after the third vaccine dose predicted infection. A third dose of BNT162b2 is effective and safe in patients with IBD. Lower serologic response predicted infection, even in seropositive subjects. Lower serologic responses and their rapid decline suggest a fourth vaccine dose in this patient population.

Psoriasis is a chronic systemic inflammatory disease associated with a higher incidence of cardiovascular disease, especially in patients with moderate to severe psoriasis. It has been estimated that severe psoriasis confers a 25% increase in relative risk of cardiovascular disease, regardless of traditional risk factors. Although the underlying pathogenic mechanisms relating psoriasis to increased cardiovascular risk are not clear, atherosclerosis is emerging as a possible link between skin and vascular affection. The hypothesis that the inflammatory cascade activated in psoriasis contributes to the atherosclerotic process provides the underlying basis to suggest that an anti-inflammatory therapy that improved atherosclerosis would also reduce the risk of MACEs. In this sense, the introduction of biological drugs which specifically target cytokines implicated in the inflammatory cascade have increased the expectations of control over the cardiovascular comorbidity present in psoriasis patients, however, their role in vascular damage processes remains controversial. The aim of this paper is to review the mechanistic link between psoriasis and cardiovascular disease development, as well as analyzing which of the biological treatments could also reduce the cardiovascular risk in these patients, fueling a growing debate on the modification of the general algorithm of treatment.

Background: Patients living with HIV (PLWHIV) can develop autoimmune diseases (AD) needing immunosuppressive treatments (IST). This study aims to describe the impact of IST in PLWHIV. Methods: This was a multicentric retrospective observational study in six HIV referral centers on PLWHIV under IST for AD. Demographic factors, viral co-infections, immunovirological status before and under IST, infectious events, and their descriptions were collected and described focusing on infectious events, immunovirological variations, and IST effectiveness. Results: 9480 PLWHIV were screened for inclusion. Among them, 138 (1.5%) had a history of auto-immune disease, among which 32 (23%) received IST. There was mainly spondyloarthropathy (28%) and the most commonly used IST was methotrexate. The median follow-up under IST was 3.8 years (2.7; 5.9). There were 15 infectious events (0.5 events/individuals) concerning nine patients. At the last medical follow-up, 81% of these were in remission of their AD. Under IST, there was an increase in CD4 during follow-up (629 vs. 827 CD4/mm3, p = 0.04). No HIV virological failure was noted. Conclusions: This study supports a growing evidence base that IST can be used safely and effectively in PLWHIV with careful monitoring.

The efficacy of the COVID-19 mRNA vaccine, including the third vaccination in pediatric inflammatory bowel disease (PIBD) patients is not fully understood. This study aimed to evaluate the humoral immunogenicity of the BNT162b2 vaccine and the changes in durability until 20–28 weeks after the initial vaccine series in PIBD patients on immunosuppressive drugs. The safety of the initial vaccine series and the booster effect of the third vaccination were also evaluated. A single-center, prospective cohort study was conducted, and 63 participants (anti-TNFα: 11; non-anti-TNFα: 31; 5-ASA: 21), with a mean age of 15.2 (range 9.6–17.9) years, were enrolled. All PIBD patients were seroconverted, with no serious short-term AEs. PIBD patients on anti-TNFα had significantly lower antibody titers than those on other medications at all measurement points. Furthermore, antibody titers waned over time with anti-TNFα and were significantly lower at 20–28 weeks than at 3–9 weeks after a two-vaccine series. In all 10 patients (anti-TNFα: 5; non-anti-TNFα including 5-ASA: 5), the third vaccination led to antibody concentrations significantly higher than those at the same time point after the second vaccination. PIBD patients on anti-TNFα need to remain vigilant about COVID-19 even after two vaccinations, and a third vaccination may be considered.

Inflammatory bowel disease (IBD) is an idiopathic and chronic disorder that includes ulcerative colitis (UC) and Crohn’s disease (CD). Both diseases show an uncontrolled intestinal immune response that generates tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells that play a key role in tolerance maintenance in the gastrointestinal mucosa. Although it has been reported that DC recruitment by the intestinal mucosa is more prominent in IBD patients, the specific mechanisms governing this migration are currently unknown. In this study, the expression of several homing markers and the migratory profile of circulating DC subsets towards intestinal chemo-attractants were evaluated and the effect of biological drugs with different mechanisms of action, such as anti-TNFα or anti-integrin α4β7 (vedolizumab), on this mechanism in healthy controls (HCs) and IBD patients was also assessed. Our results revealed that type 2 conventional DCs (cDC2) express differential homing marker profiles in UC and CD patients compared to HCs. Indeed, integrin β7 was differentially modulated by vedolizumab in CD and UC. Additionally, although CCL2 displayed a chemo-attractant effect over cDC2, while biological therapies did not modulate the expression of the homing markers, we paradoxically found that anti-TNF-treated cDC2 increased their migratory capacity towards CCL2 in HCs and IBD. Our results therefore suggest a key role for cDC2 migration towards the intestinal mucosa in IBD, something that could be explored in order to develop novel diagnostic biomarkers or to unravel new immunomodulatory targets in IBD.

Background: The risk of developing non-melanoma skin cancers (NMSCs) in patients with psoriasis is highly debated, and, to date, there is no unambiguous consensus opinion. Psoriasis is known to be related to an increased likelihood of other comorbidities such as psoriatic arthritis, obesity, metabolic syndrome, depression, and cardiovascular disease. Regarding cancer risk, previous studies have reported a greater tendency for the development of cutaneous T-lymphomas and colon, breast, kidney, and lung cancers. Furthermore, data from network meta-analyses have shown that patients with psoriasis have a higher risk of developing squamous cell carcinomas (SCCs) and/or basal cell carcinomas (BCCs). Multiple factors may contribute to the development of NMSCs in psoriatic patients, ranging from immunosuppression induced by biologic agents to previous phototherapy. However, the extent to which each factor may impact this risk has not been entirely assessed. The aim of this study was to evaluate the risk of developing NMSCs in patients with psoriasis observed for at least 5 years, by directly comparing patients only treated with phototherapy and patients treated with anti-tumor necrosis factor α (TNFα) agents, naive to other systemic treatments or phototherapy. Methods: We conducted a single-center retrospective study at Siena University Hospital, Italy, on 200 adult patients with psoriasis divided into two groups: (i) group 1, including 100 patients treated with narrow-band UVB phototherapy (nb-UVB), and (ii) group 2, including 100 patients treated with anti-TNFα. The patients included in group 2 had to be naive to cDMARDs and biologics and treated with anti-TNFα continuously for 5 years without loss of efficacy. All patients were observed for 5 years and underwent annual dermatologic examinations to assess for the occurrence of BCC or SCC. Results: A total of 34 out of 100 patients treated with phototherapy had one BCC or one SCC and 10 out of 34 developed two skin cancers. In particular, five had both types (one BCC and one SCC), and five had two BCCs. Conclusions: The results of our study highlight how the risk of developing NMSCs is greater in patients undergoing phototherapy compared to those treated with anti-TNFα. It also draws attention to the consideration that patients with scalp psoriasis might need closer follow-up as they could be more at risk of developing NMSCs.

Patients with different autoimmune inflammatory diseases (AIID) on biological therapy are at risk of pneumococcal disease. Adults with inflammatory arthropathies, connective tissue diseases, psoriasis, or inflammatory bowel disease on biological therapy such as anti-TNFα, rituximab, tocilizumab, abatacept, or anakinra were included in this study. Patients completed a protocol combining the pneumococcal vaccines PCV13 and PPV23. Immune response against pneumococcal serotypes 1, 3, 7F, 14, 19A, and 19F were assessed evaluating functional antibodies by an opsonophagocytosis killing assay (OPKA). In this study, 182 patients with AIID completed the sequential vaccination protocol. Patients on etanercept tended to achieve OPKA titers against a larger number of serotypes than the rest of patients on other biological therapies, while adalimumab was associated to a lower number of serotypes with OPKA titers. Rituximab was not associated with a worse response when compared with the rest of biological agents. Not glucocorticoids, nor synthetic disease-modifying antirheumatic drugs, interfered with the immune response. OPKA titers against serotype 3 which is one of the most prevalent, was obtained in 44% of patients, increasing up to 58% in those on etanercept. Hence, almost 50% of patients on biological therapy achieved functional antibodies after the administration of a complete pneumococcal vaccination protocol.

Objective: To explore the relationship between laboratory, functional, disease activity markers and bone mineral density (BMD) loss in patients with spondyloarthropathies (SpAs). Methods: A cohort of 41 SpA patients were followed up for 4 years. Disease activity indices, spinal mobility and laboratory tests, BMD using were monitored at the baseline and 4-year follow-up. The 4% BMD loss at either of the proximal femurs was defined as significant. Results: Over the 4-year study period, 27% of SpA patients experienced femoral BMD loss. Baseline BMD > 0.85 g/cm2 (p = 0.011) was the baseline factor associated with BMD loss at 4-year follow-up. Several clinical and functional tests were helpful in identifying the BMD loss at follow-up: CRP > 15.6 mg/L (sens. 91%, spec. 70%), ESR > 29 mm/h (sens. 82%, spec. 73%), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) > 4.75 (sens. 91%, spec. 62%). At follow-up anti-TNFα treatment history, stable or improved lateral flexion and intermalleolar distance (NPV, accordingly, 95%, 88% and 87%), made BMD loss unlikely. Deterioration of the physician assessment of global disease activity (PAGDA) score from baseline to follow-up was a remarkable predictor of BMD loss (PPV = 0.83), while stable or improved score excluded the BMD loss (NPV = 0.83). According to multiple logistic regression analysis, baseline BMD value and follow-up CRP levels, when considered together, identify BMD status correctly in 85% of SpA patients (Nagelkerke R2 = 0.676). Conclusion: Baseline BMD, anti-TNFα treatment, PAGDA score, spinal mobility tests and disease activity markers are useful factors in predicting the BMD loss in SpA patients and can provide surrogate information on BMD status.

Cytokine patterns and immune activation in patients with Coronavirus 2019 (COVID-19) seem to resemble the case of rheumatoid arthritis (RA), psoriasis and inflammatory bowel disease (IBD). Biological drugs, such as anti-tumor necrosis factor α (TNFα) and interleukin (IL) inhibitors, appear to be protective against adverse outcomes of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). However, these treatments are associated with an increased risk of secondary infections. The aim of the study was to examine the association between the use of immunomodulatory drugs and the risk of SARS-CoV-2-associated positivity, hospitalization and death compared to other commonly prescribed treatment regimens among patients with immune-mediated inflammatory diseases., Methods: All patients with RA, Psoriasis and IBD were included in this observational analysis and treated with anti-TNFα, IL-inhibitors, Methotrexate (MTX) and Sulfasalazine drugs during the year 2020-2021. The population consisted of 932 patients and demographic, clinical and pharmacological data were analyzed., Results: Although no significant differences were observed between patients treated with biological and synthetic drugs in terms of hospitalization and death, the multivariate logistic model showed that the type of drug influences the possibility of COVID-19 positivity., Conclusions: The results of this analysis support the use of biological drugs and justify further research investigating the association of these biological therapies with COVID-19 outcomes.

Repeated intra-articular hemorrhages lead to hemophilic arthropathy in severe hemophilia. Inflammation and pro-inflammatory cytokines (e.g., tumor necrosis factor alpha (TNFα)) might be involved in this pathogenesis. We hypothesized that anti-TNFα may provide adjuvant protection for hemophilic arthropathy management. We measured TNFα in synovial lavage from hemophilia mice subjected to hemarthrosis induction and synovial fluid from patients with hemophilic arthropathy ( n = 5). In hemophilia mice, recurrent hemarthroses were induced, anti-TNFα was initiated either from day (D)7 after one hemarthrosis episode or D21 after three hemarthroses episodes ( n ≥ 7/treatment group). In patients with hemophilic arthropathy (16 patients with 17 affected joints), a single dose of anti-TNFα was administered intra-articularly. Efficacy, characterized by synovial membrane thickness and vascularity, was determined. Elevated TNFα in synovial lavage was found in the hemophilia mice and patients with hemophilic arthropathy. Hemophilia mice subjected to three hemarthroses developed severe synovitis (Synovitis score of 6.0 ± 1.6). Factor IX (FIX) replacement alone partially improved the pathological changes (Synovitis score of 4.2 ± 0.8). However, anti-TNFα treatment initiated at D7, not D21, significantly provided protection (Synovitis score of 1.8 ± 0.9 vs. 3.9 ± 0.3). In patients with hemophilic arthropathy, intra-articular anti-TNFα significantly decreased synovial thickness and vascularity during the observed period from D7 to D30. Collectively, this preliminary study seems to indicate that TNFα may be associated with the pathogenicity of hemophilic arthropathy and anti-TNFα could provide adjuvant protection against hemophilic arthropathy. Further studies are required to confirm the preliminary results shown in this study.