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Objective. To date, there is no shared national guideline in Italy for the management of reproductive health in rheumatic diseases (RHRD). The Italian Society for Rheumatology has committed to developing clinical practice recommendations to provide guidance on both management and treatment regarding RHRD in Italy. Methods. Using the GRADE-ADOLOPMENT methodology, a systematic literature review was conducted to update the scientific evidence that emerged after the publication of the reference recommendations from the American College of Rheumatology. A multidisciplinary group of 18 clinicians with specialist experience in rheumatology, allergy and clinical immunology, internal medicine, nephrology, gynecology and obstetrics, and neonatology, a professional nurse, a clinical psychologist, and a representative from the National Association of Rheumatic Patients discussed the recommendations in collaboration with the evidence review working group. Subsequently, a group of stakeholders was consulted to examine and externally evaluate the developed recommendations. Results. Recommendations were formulated for each area of interest: contraception, assisted reproductive technology, preconception counseling, and use of drugs before, during, and after pregnancy and during breastfeeding, considering both paternal and maternal exposure. Conclusions. The new SIR recommendations provide the rheumatology community with a practical guide based on updated scientific evidence for the management of RHRD.

Objective. The aim of the present review was to highlight gender and sex differences in spondyloarthritis (SpA) to achieve a better awareness of the unmet needs of women with SpA. Methods. A literature search of PubMed was performed, including manuscripts in English published in the last twenty years, to select and analyze articles related to SpA and sex and gender differences in epidemiology, genetics, immunology, clinical features, and response to treatment. Results. Women and men with SpA have different disease phenotypes, and this heterogeneity mirrors anatomical, physiological, and hormonal differences, as well as peculiar variability in response to treatment. These underestimated differences, which include several biological factors and intertwined social factors, contribute to diagnostic delay and increased disease burden in women with SpA. Conclusions. This review elucidates gender differences in SpA and raises awareness about the need for gender-related stratification of SpA patients with the concomitant implementation of SpA gender differences in future research and upcoming clinical trials. A deeper knowledge of SpA in women is indispensable to pave the way for real personalized medicine for SpA patients to reduce misdiagnosis and delay in intercepting the disease.

Background/Aim: Prevalence of gastroduodenal endoscopic and histological lesions may modify over time due to different factors. We assessed both macroscopic and histological lesions currently detected at upper endoscopy performed in routine practice. Patients and Methods: Clinical, endoscopic, and histological data of consecutive adult patients referred for upper endoscopy in the 28 participating centres were analysed. Only patients who underwent the first endoscopic examination were considered. Prevalence of erosive/ulcerative lesions, cancers and extensive precancerous lesions in the stomach, and Helicobacter pylori infection was computed. Results: A total of 1,431 patients underwent endoscopy for gastro-oesophageal reflux symptoms (31.5%), dyspepsia (29.4%), or alarm symptoms (18.5%). Erosive oesophagitis or Barrett’s oesophagus was detected in 210 (14.7%) cases, peptic ulcer in 49 (3.4%), and a neoplastic lesion in 17 (1.2%). H. pylori was present in 201 (22.6%) cases, and extensive precancerous lesions on gastric mucosa in 46 (5.6%) patients. Gastric lesions were more prevalent in patients aged ≥50 years (26% vs. 18%; p = 0.001), and peptic ulcers were more frequently detected in patients with H. pylori (9.4% vs. 2.3%; p = 0.001) and in males (5.8% vs. 1.6%; p = 0.001), while neoplastic lesions in patients with alarm symptoms (3.8% vs. 0.6%; p = 0.001). Conclusions: The overall endoscopic lesions were more prevalent in patients aged ≥50 years, peptic ulcer and erosions were more frequent in H. pylori-infected patients, and extensive gastric precancerous lesions were present in less than 6% of cases.

Background and Objectives: This study aimed to evaluate the outcomes of Class II subdivision teenage patients treated with Invisalign® clear aligners (CAs) and elastics. Materials and Methods: A total of 23 individuals aged 14.3 ± 2.5 years were enrolled in this study. The participants were divided into Group 1 (mandibular midline deviation) and Group 2 (maxillary midline deviation). The midline deviation from the facial midline; anteroposterior discrepancy; overjet (OJ), overbite (OB), and Peer Assessment Rating (PAR) scores; upper incisor and lower incisor (L1) positions; and angulation were measured at the beginning (T0) and end (T1) of the orthodontic treatment. Results: Group 1 showed significant higher variations in OJ (−2.3 ± 2.3 vs. −0.6 ± 0.8, p < 0.001), OB (−2.1 ± 2.3 vs. −1.1 ± 1.4, p < 0.001), PAR score (−32.0 ± 11.7 vs. −27.3 ± 13.1, p < 0.001), L1-to-mandibular-plane angle (−3.6 ± 7.0 vs. −1.3 ± 3.2, p < 0.001), and interincisal angle (10.07 ± 8.7 vs. 5.9 ± 5.3, p = 0.007). The midline deviation was the only measurement with higher variation in Group 2. The average distance between the mesiobuccal cusp of the maxillary first molar and the buccal groove of the mandibular first molar was 0.3 ± 0.5 mm. Conclusions: A total of 21 patients achieved bilateral Class I (91% success rate) and demonstrated great improvement (72–96%) in PAR scores. Regardless of the etiology of malocclusion, the orthodontic correction of the Class II subdivision with CAs showed high accuracy and predictable results.

Objective: The current study aimed to better understand the relationship between exposure to non-suicidal self-injury (NSSI) through peers, group conformity characteristics (i.e., over-dependency, need-to-belong), and personal NSSI engagement. Methods: One hundred thirty-eight undergraduate students (n = 40 with history of NSSI) completed an online survey about NSSI history and exposure as well as their interpersonal dependency and need-to-belong in a group. Results: Results indicated that NSSI participants (NSSI+) were more likely to be exposed to NSSI in-person (IP+). NSSI+/IP + participants were more likely to think about NSSI post-media exposure and reported higher over-dependency and need-to-belong than NSSI-/IP-. Conclusions: Findings suggest that being exposed to NSSI in-person and having higher over-dependency and need-to-belong are associated with personal NSSI engagement.

Background: Studies about the endoscopic aspect of non-inflammatory bowel disease (IBD) colitis are scarce. Aims and Objectives: The aim of this retrospective study was to describe the endoscopic appearance of non-IBD colitis (NIC) in an outpatient cohort. Materials and Methods: All cases of NIC, from 2018 to 2021, with a recent outpatient colonoscopy, were enrolled. Diagnosis was based on clinical, endoscopic, and histological characteristics, and follow-up ≥6 months to recognize misdiagnosed IBD because of mimic causes. Results: 158 patients (63 males, age 54 years±19) performed a colonoscopy with a final diagnosis of NIC associated with drug-exposition (74), food allergies (26), recent/active gastrointestinal infections (20), ischemic colitis (14), segmental colitis associated diverticulosis (SCAD) (10), obstructed defecation syndrome (ODS) (8) and microscopic colitis (6). Frequencies of endoscopic features and colon distribution were: Drug exposition (hyperemia, erosions/ulcers, 88%; right colon, 70%), recent infection (erosions, 60%; left colon/rectum, 88%), food allergies (red spots/erosions, 67%; all the colon), ischemic colitis (ulcers, 86%; right or left colon), SCAD (hyperemia/edema, 75%; always left colon), ODS (hyperemia, erosions, and loss of vascularity, 90%; always rectum), microscopic colitis (edema and hyperemia; all the colon). Conclusion: Drug-exposition is the most frequent cause of out-patient NIC. In an appropriate diagnostic context, red spots, hyperemia, and erosions are associated with drug expositions, recent infections, and food allergies. Ulcers are more frequent with ischemic colitis or drug-exposition.

Objectives To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it.Methods Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018–2023). Maternal and infant information were collected in a web-based database.Results We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress.Conclusions Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures.

IntroductionJAK-inhibitors (JAK-i) represent an effective treatment in Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA). Oral glucocorticoids (OGC) are commonly used in combination with JAK-i to reach therapeutic target. We aimed to assess, in a real-life setting, the reduction of OGC dose during JAK-i treatment in active RA and PsA patients. MethodsWe prospectively enrolled 103 patients (88 RA, 15 PsA) treated with JAK-i: 24% bio-naïve (b-naïve), 76% bDMARD-insufficient responders (bDMARD-IR) and 40% difficult to treat (D2T), defined as failure of ≥2 bDMARDs with different mechanism of action. Disease activity (DAS28 and DAPSA, VAS-pain, GH) and OGC dose was collected at baseline and after 3, 6 and 12 months (T3, T6, T12) of treatment.ResultsIn all the cohort and in b-naïve patients we reported a reduction of OGC dose at all time-points; bDMARD-IR patients were able to reduce OGC dose at T3 and T12; D2T ones only at T3. We reported an improvement of disease activity and withdrawal of OGC as early as three months of therapy, at all time-points, regardless of line of bDMARD treatment. ConclusionChronic OGC may cause detrimental bone, metabolic, cardiovascular side effects and infections; therefore JAK-i steroid-sparing effect may be beneficial for patients in long-term treatment.

Objective. A monocentric cross-sectional study recruiting rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients residing in the Lazio region, Italy, to assess factors related to diagnostic delay and treatment accessibility. Methods. Clinical/serological data, including the time between symptom onset, diagnosis, and the beginning of treatment, were collected. Residence, referral to a rheumatologic center, physician who made the diagnosis, and previous misdiagnosis were also evaluated. Results. A higher diagnostic delay (p=0.003), and time between symptom onset and the start of I-line therapy (p=0.006) were observed in PsA compared to RA. A delayed start of II-line therapy was observed in RA compared to PsA (p=0.0007). Higher diagnostic delay (p=0.02), and time between symptom onset and the start of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (p=0.02) were observed among residents of small-medium cities for both groups. Patients who have been diagnosed by another physician rather than a rheumatologist had a longer diagnostic delay (p=0.034) and a delayed start of I-line therapy (p=0.019). Patients who received a different previous diagnosis experienced greater diagnostic delay (p=0.03 and p=0.003) and time of start of csDMARDs (p=0.05 and p=0.01) compared with those receiving RA or PsA as the first diagnosis. PsA had a delay in starting targeted synthetic disease-modifying anti-rheumatic drugs (p=0.0004) compared to RA. Seronegative RA had delayed diagnosis (p=0.02) and beginning of therapies (p=0.03; p=0.04) compared to seropositive ones. Conclusions. According to our results, greater diagnostic delay was found in PsA compared to RA, in patients living in small-medium cities, in those who did not receive the diagnosis from a rheumatologist, in those who were previously misdiagnosed, and in seronegative RA.

Background: Enteropathic spondyloarthritides (eSpAs) are chronic inflammatory joint diseases associated with inflammatory bowel disease (IBD). Limited data are available on the prevalence since arthritis in IBD patients may be underestimated because medications may hide disease activity with a possible diagnostic delay. Objectives: We aimed to evaluate diagnostic delay in eSpA and explore associated demographic, clinical, and radiographic characteristics. Design: Single-centre cross-sectional study conducted on consecutive out-patients referred to the combined Gi-Rhe clinic (November 2018–October 2019). Methods: We analysed eSpA patients for diagnostic delay, disease activity, inflammatory markers, conventional radiography (CR) and magnetic resonance images (MRI) of sacroiliac joints/spine. Results: A total of 190 eSpA patients [118 peripheral SpA, 72 axial (Ax) SpA including 44 non-radiographic (nr)-axSpA] were enrolled. axSpA patients had a higher prevalence of men sex, HLA-B27 positivity, uveitis and pancolitis compared with peripheral eSpA. Median diagnostic delay in eSpA was 48 months (IQR 6–77) with no difference between axial and peripheral patients. Radiographic-axial SpA (r-axSpA) patients displayed a higher diagnostic delay compared with nr-axSpA (median/IQR 36/17–129 versus 31/10–57 months, p = 0.03) and were older, with longer disease duration, low education status and high rate of employment than patients with nr-axSpA. r-axSpA patients with sclerosis, syndesmophytes and bridge at CR had higher diagnostic delay than those without lesions. Men showed higher prevalence of spine damage lesions than women as sclerosis, squaring, syndesmophytes and bridges. Longer disease duration was detected in patients with radiographic damage as bridge and sacroiliitis grade 3. On MRI, sacroiliac bone oedema was associated with reduced diagnostic delay, whereas bone erosions were associated with higher diagnostic delay compared with that in patients without these lesions. Patients with psoriasis displayed a higher diagnostic delay compared to those without skin involvement. Conclusion: Diagnostic delay was higher in r-axSpA compared with nr-axSpA despite the same treatment. Demographic, clinical features and radiological lesions were associated with diagnostic delay.

Objective Evaluate spondyloarthritis (SpA) incidence in inflammatory bowel diseases (IBD) between patients treated with biological disease-modifying antirheumatic drugs (bDMARDs) and conventional DMARDs (cDMARDs) and define risk factors associated with SpA development.Methods Retrospective cohort study was conducted on patients with Crohn’s disease (CD) or ulcerative colitis (UC) and divided into two cohorts: cDMARDs or bDMARDs/targeted synthetic (ts) DMARDs treated patients. Rheumatological assessment was performed in patients presenting musculoskeletal symptoms. Multivariate analysis and Kaplan-Meier curves were used to evaluate the adjusted SpA risk development.Results 507 patients were included in the study. 176 patients with CD received bDMARDs, 112 cDMARDs and 106 new SpA diagnosies were formulated. Females (OR 1.7 (95% CI 1.1 to 3), adjusted p=0.04), non-stricturing/non-penetrating phenotype (OR 2 (95% CI 1.1 to 3.4), adjusted p=0.01), psoriasis (OR 2.1 (95% CI 1 to 4.6), adjusted p=0.04) and non-infectious uveitis (OR 6.8 (95% CI 1.4 to 33.4), adjusted p=0.01) were associated with increased SpA risk development, while bDMARDs usage was protective (OR 0.4 (95% CI 0.2 to 0.8), adjusted p=0.01), statistically higher than cDMARDs throughout the entire follow-up (effect size 0.47). 98 patients with UC received b-tsDMARDs, 121 cDMARDs and 56 new SpA diagnoses were formulated. Females (OR 2.1 (95% CI 1 to 4.3), adjusted p=0.02) and psoriasis (OR 2.7 (95% CI 1 to 6.8), adjusted p=0.03) were associated with increased SpA risk development, while bDMARDs were protective for SpA development for up to 12 months of treatment compared with cDMARDs (p=0.03).Conclusions bDMARDs treatment had an impact in reducing SpA development and clinical associated risk factors to transition from IBD to IBD-SpA emerged.

Paola Triggianese, Paola Conigliaro, Erica De Martino, Benedetta Monosi, Maria Sole Chimenti Department of Systems Medicine, Rheumatology, Allergology and Clinical Immunology, University of Rome Tor Vergata, Rome, ItalyCorrespondence: Maria Sole Chimenti, Rheumatology, Allergology and Immunology, University of Rome Tor Vergata, Via Montpellier 1, Rome, Italy, Tel +39 6 20900358, Email maria.sole.chimenti@unroma2.itAbstract: Complement system (CS) dysregulation is a key factor in the pathogenesis of different autoimmune diseases playing a central role in many immune innate and adaptive processes. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by ta breach of self-tolerance leading to a synovitis and extra-articular manifestations. The CS is activated in RA and seems not only to mediate direct tissue damage but also play a role in the initiation of RA pathogenetic mechanisms through interactions with citrullinated proteins. Interstitial lung disease (ILD) represents the most common extra-articular manifestation that can lead to progressive fibrosis. In this review, we focused on the evidence of CS dysregulation in RA and in ILD, and highlighted the role of the CS in both the innate and adaptive immune responses in the development of diseases, by using idiopathic pulmonary fibrosis as a model of lung disease. As a proof of concept, we dissected the evidence that several treatments used to treat RA and ILD such as glucocorticoids, pirfenidone, disease modifying antirheumatic drugs, targeted biologics such as tumor necrosis factor (TNF)-inhibitors, rituximab, tocilizumab, and nintedanib may act indirectly on the CS, suggesting that the CS might represent a potential therapeutic target in these complex diseases.Keywords: complement system, rheumatoid arthritis, interstitial lung disease, target therapies

Introduction: Long non-coding RNA H19 (lncH19) is highly expressed in colorectal cancer (CRC) and plays critical roles in tumor development, proliferation, metastasis, and drug resistance. Indeed, the expression of lncH19 usually affects the outcomes of chemo-, endocrine, and targeted therapies. ITF2357 (givinostat) is a histone deacetylase inhibitor (HDACi) that revealed a significant anti-tumor action by inducing apoptosis in different tumor models, including leukemia, melanoma, and glioblastoma. However, no data are present in the literature regarding the use of this compound for CRC treatment. Here, we investigate the role of lncH19 in ITF2357-induced apoptosis in CRC cells.Methods: The HCT-116 CRC cell line was stably silenced for H19 to investigate the role of this lncRNA in ITF2357-induced cell death. Cell viability assays and flow cytometric analyses were performed to assess the anti-proliferative and pro-apoptotic effects of ITF2357 in CRC cell lines that are silenced or not for lncH19. RT-PCR and Western blot were used to study the effects of ITF2357 on autophagy and apoptosis markers. Finally, bioinformatics analyses were used to identify miRNAs targeting pro-apoptotic factors that can be sponged by lncH19.Results: ITF2357 increased the expression levels of H19 and reduced HCT-116 cell viability, inducing apoptosis, as demonstrated by the increase in annexin-V positivity, caspase 3 cleavage, and poly (ADP-ribose) polymerase (PARP-1) degradation. Interestingly, the apoptotic effect of ITF2357 was much less evident in lncH19-silenced cells. We showed that lncH19 plays a functional role in the pro-apoptotic activity of the drug by stabilizing TP53 and its transcriptional targets, NOXA and PUMA. ITF2357 also induced autophagy in CRC cells, which was interpreted as a pro-survival response not correlated with lncH19 expression. Furthermore, ITF2357 induced apoptosis in 5-fluorouracil-resistant HCT-116 cells that express high levels of lncH19.Conclusion: This study shows that lncH19 expression contributes to ITF2357-induced apoptosis by stabilizing TP53. Overall, we suggest that lncH19 expression may be exploited to favor HDACi-induced cell death and overcome 5-fluorouracil chemoresistance.

Background/Aims: Endoscopic submucosal dissection (ESD) has been proposed for removal of gastrointestinal subepithelial tumors (GI-SETs), but data are still scanty. This study aimed to report a case series from a western country. Patients and Methods: Data of patients with upper GI-SETs suitable for ESD removal observed in 4 centers were retrospectively reviewed. Before endoscopic procedure, the lesion was characterized by endosonographic evaluation, histology, and CT scan. The en bloc resection and the R0 resection rates were calculated, as well as incidence of complications, and the 1-year follow-up was reported. Results: Data of 84 patients with esophageal (N = 13), gastric (N = 61), and duodenal (N = 10) GI-SETs were collected. The mean diameter of lesions was 26 mm (range: 12–110 mm). There were 17 gastrointestinal stromal tumors, 12 neuroendocrine tumors, 35 leiomyomas, 18 lipomas, and 2 hamartomas. En bloc and R0 resection were achieved in 83 (98.8%) and in 80 (95.2%) patients, respectively. Overall, a complication occurred in 11 (13.1%) patients, including bleeding (N = 7) and perforation (N = 4). Endoscopic approach was successful in all bleedings, but 1 patient who required radiological embolization, and in 2 perforations, while surgery was performed in the other patients. Overall, a surgical approach was eventually needed in 5 (5.9%), including 3 in whom R0 resection failed and 2 with perforation. Conclusions: Our study found that ESD may be an effective and safe alternative to surgical intervention for both benign and localized malignant GI-SETs.