A multi-national survey to identify clinicians' perspectives concerning Proton Pump inhibitors in patients with systemic sclerosis.

OBJECTIVES: Proton Pump Inhibitors (PPIs) are widely used in SSc for gastroesophageal reflux disease (GERD). However, there is little evidence to support their empirical use and long-term safety has been questioned. Our objective was to better describe clinicians' attitudes toward PPIs prescription and use in SSc patients. METHODS: Clinicians involved in the care of SSc patients were invited through international physician networks and social media to participate in an online survey. RESULTS: Responses from 227 clinicians from 36 countries were evaluable. The majority 'agreed' (41.4 %) or 'strongly agreed' (45.4 %) that GERD is a major cause of morbidity in SSc. Lifestyle modifications are seldom (16 %) considered effective. Only half 'agreed' (43 %) or 'strongly agreed' (11 %) there is solid evidence supporting PPIs efficacy in SSc. The most common reasons for PPIs prescription were symptomatic GERD unresponsive to lifestyle modification (95 %), objective evidence of GERD (82 %), and hoarseness or respiratory symptoms (71 %). There are variable concerns about PPIs long-term safety in SSc. The three highest (mean) reasons (0-10, here 10 is 'very concerned') were: small intestinal bacterial overgrowth (5.5), osteoporosis (5.4), and drug interactions (5.2). There are significant differences in attitudes towards surgery for refractory GERD, and concerns about potential complications. PPIs may have a putative role for disease modification (e.g., ILD and calcinosis), and the role of immunosuppression is uncertain for GI (gastrointestinal) disease in SSc. CONCLUSION: PPIs are frequently prescribed in SSc. Side effects are a recognized concern, especially regarding long-term therapy. There is significant variation in attitudes towards surgical intervention. Future research and practical treatment recommendation for PPIs in SSc are urgently needed.

Patients' unmet needs and treatment preferences concerning digital ulcers in systemic sclerosis.

INTRODUCTION: Digital ulcers (DUs) significantly impact on quality of life and function in patients with systemic sclerosis (SSc). The aim of our survey was to explore patients' perspectives and their unmet needs concerning SSc-DUs. MATERIALS: SSc patients were invited through international patient associations and social media to participate in an online survey. RESULTS: 358 responses were obtained from 34 countries: US (65.6%), UK (11.5%) and Canada (4.5%). Recurrent DUs are common: >10 DUs (46.1%), 5-10 DUs (21.5%), 1-5 DUs (28.5%), 1 DU (3.9%). Fingertip DUs were most frequent (84.9%), followed by those overlying the interphalangeal joints (50.8%). The impact of DUs in patients is broad, from broad-ranging emotional impacts to impact on activities of daily living, and personal relationships. Half (51.7%) of respondents reported that they received wound/ulcer care, most often provided by non-specialist wound care clinics (63.8%). There was significant variation in local (wound) DU care, in particular the use of debridement and pain management. DU-related education was only provided to one-third of patients. One-quarter (24.6%) were 'very satisfied' or 'satisfied' that the provided DU treatment(s) relieved their DU symptoms. Pain, limited hand function, and ulcer duration/chronicity were the main reasons for patients to consider changing DU treatment. CONCLUSIONS: Our data show that there is a large variation in DU treatment between countries. Patient access to specialist wound-care services is limited and only a small proportion of patients had their DU needs met. Moreover, patient education is often neglected. Evidence-based treatment pathways are urgently needed for DU management.

The management of cardiovascular risk in psoriatic disease: A bridge over troubled water.

Evidence that psoriatic disease is burdened by an excess cardiovascular (CV) risk has accrued, however many questions remain unanswered. Although an interplay between traditional risk factors inflammation, disease activity and pharmacological therapies, as observed in rheumatoid arthritis (RA), may account for this increased risk, metabolic comorbidities rather than inflammation seem to have a leading role in psoriatic disease. Therefore, specific approaches, risk factors targeting and the importance of traditional risk factors and inflammation management need to be considered. The purpose of this review article is to discuss current data on CV risk in psoriatic disease, and to outline similarities and differences with RA in the light of international recommendations. Arguments in favour of developing specific guidance for CV prevention in psoriatic disease are discussed.

A systematic literature review of randomised controlled trials evaluating colchicine for cardiovascular prevention: There is an elephant in the room.

OBJECTIVES: To review randomised controlled trials (RCT) investigating colchicine (COL) for cardiovascular (CV) prevention in patients at high to very high CV risk aiming to extract data that could be useful in rheumatology practice. METHODS: A systematic search of multiple databases according to the PICO framework was performed from inception to April 3, 2023. Three researchers independently screened abstracts/titles and reviewed full texts reviewed. Data extraction was performed using a pilot-tested data extraction form. RESULTS: A total of 14,096 references were retrieved by the search and 30 articles, describing 28 RCTs, were included in the review (Total number of patients 16,795, of which 8,463 randomised to COL; dose 0.5-2 mg/day, treatment duration 1day-29 months). Only one of the 28 RCTs provided clear information on whether patients with rheumatic diseases (more specifically gout) were enrolled in the study cohorts and previous use of COL was an exclusion criterion only in 14 (50 %) RCTs. Previous therapy with glucocorticoids and/or non-steroidal anti-inflammatory drugs and/or immune suppressive therapies was an exclusion criterion only in 9 (32 %) RCTs. CONCLUSION: Our results highlight the need to redefine the eligibility criteria as well as the reporting of results in future RCTs in order to minimise bias or previous exposure to COL and also obtain data that could be useful in rheumatology practice.

A Multinational Survey Investigating the Unmet Needs and Patient Perspectives Concerning Proton Pump Inhibitors in Systemic Sclerosis.

OBJECTIVE: Proton pump inhibitors (PPIs) are widely prescribed to treat gastroesophageal reflux disease (GERD) in Systemic Sclerosis (SSc). However, not all patients adequately respond to the treatment, and there are frequent concerns about the safety of long-term use of PPIs. Our aim was to identify the main problems/complaints of SSc patients on PPIs, as well as understand their unmet needs. METHODS: SSc patients treated with PPIs were invited through international patient associations and social media to participate in an online survey. RESULTS: We gathered 301 valid responses from 14 countries (United Kingdom 19.3% and United States 70.4%). Multiple PPIs use (two: 30% and three: 21% in series) was common. The majority (89%) reported improvement in gastrointestinal symptoms from receiving PPIs. Side effects attributed to receiving PPIs were uncommon (19%); however, most (79%) were potentially concerned. Around half (58%) had received lifestyle information, and most (85%) had searched online for information about PPIs. Only in the minority (12%) had a surgical approach been discussed; however, half (46%) indicated that they would be willing to undergo surgery to resolve their GERD symptoms but had important concerns. CONCLUSION: Despite the frequent use of PPIs in patients with SSc, there is significant heterogeneity in prescription, and combination therapy (PPIs plus other medication for acid reflux) is not uncommon (approximately 40%). Patients have significant concerns about PPIs side effects. Education about PPIs is often neglected, and patients very frequently use online sources to obtain information on drug treatment. A surgical approach is infrequently discussed, and patients fear this potential therapeutic approach.

Human Leukocyte Antigen B*27-Negative Spondyloarthritis: Clinical, Serological, and Radiological Features of a Single-Center Cohort.

The strong genetic association between HLA-B*27 and spondyloarthritis (SpA) accounts for about 90% of the susceptibility to axial SpA (axSpA), and the presence of HLA-B*27 is helpful in classifying patients according to the Assessment of SpondyloArthritis International Society (ASAS) classification criteria. However, over the years, other HLA-B alleles have been associated with an increased risk of developing SpA; on this basis, the aim of our study was to describe the demographic, clinical, and radiological characteristics of a cohort of SpA patients who were negative for HLA-B*27. We identified 85 patients with a clinical diagnosis of SpA displaying HLA-B alleles other than HLA-B*27; HLA-B*51 emerged as the most prevalent allele (N = 33, 39%), regardless of the fulfilment of either the axial or the peripheral ASAS criteria. The second most prevalent allele in the full cohort (N = 16, 19%) and in the patients fulfilling either the axial or the peripheral criteria was HLA-B*35. The third most prevalent allele in the full cohort was HLA-B*18 (N = 12, 15%), which was also the second most prevalent allele in the patients fulfilling neither of the two sets of criteria. Overall, the clinical picture was similar across the subgroups fulfilling the different sets of ASAS criteria; however, the patients not fulfilling any ASAS criteria had a higher likelihood of having arthritis compared to the patients fulfilling the axial criteria, whereas the Bath Ankylosing Spondylitis Functional Index was significantly higher in those patients fulfilling the axial criteria compared to those who did not fulfill any criteria. Our results indicate that other HLA alleles, beyond HLA-B*27, could be useful in facilitating SpA diagnosis, particularly in patients with a clinical picture which is consistent with SpA but does not fulfill the ASAS classification criteria.

Untangling the relationship between bempedoic acid and gout: results from a systematic literature review.

Background: Bempedoic acid (BA) is a small-molecule first-in-class of inhibitor of ATP citrate lyase that significantly lowers low-density lipoproteins cholesterol (LDL-c) in statin-intolerant and inadequate responders. Increased serum uric acid (SUA) levels and gout incidence have been described in BA-treated patients. The aim of this systematic review was to investigate the safety of BA regarding SUA levels and gout in randomised controlled trials (RCTs). Methods: A search on 7 databases was performed from inception to May 4, 2023. RCTs of BA monotherapy or combination with other lipid-lowering treatment (LLT) in patients with increased LDL-c were included. Dual data extraction was performed with disagreements resolved through consensus. Due to the methodological purpose of this review risk-of-bias assessment of studies was not performed. Results: 6 Phase 3 RCTs (N = 17,975 patients of which 9,635 received BA) 9 Phase 2 RCTs (N = 362 patients of which 170 received BA) and an open-label extension of a Phase 3 RCT were included. Gout and/or hyperuricemia were not mentioned as exclusion criteria, previous/current use of urate-lowering therapies (ULT) and/or colchicine and/or dietary patterns were not reported. Phase 3 RCTs: 2 studies specified the number of patients experiencing hyperuricemia over the study period (BA: 4.9%-11%; placebo: 1.9%-5.6%) and the effect size was significant only in 1 study (OR = 2.0, 95% CI 1.8-2.3). Four RCTs reported a higher incidence of gout in the BA arm however, when we calculated the effect size, it was small and often not significant. Two studies reported 0 cases of gout. The paucity of information about SUA levels at baseline and/or at the end of follow-up do not allow us to quantify the effect sizes for BA-induced SUA elevation. Data on gout from Phase 2 RCTs is scant. Conclusions: Data from phase 2 and 3 RCTs do not allow for confirming a clear association between BA and gout. It is conceivable that a careful assessment of SUA levels/history of gout at baseline and the concomitant use of urate-lowering agents may be instrumental to minimise the risk of new-onset gout/gout flares in patients treated with BA.

Unfolding dermatologic spectrum of Behçet's disease in Italy: real-life data from the International AIDA Network Behçet's disease Registry.

Behçet's disease (BD) is a heterogeneous multifactorial autoinflammatory disease characterized by a plethora of clinical manifestations. Cutaneous lesions are considered hallmarks of the disease. However, their evolution over time and a thorough description are scarcely reported in non-endemic regions. The aim of this study was to detail BD skin manifestations and their evolution over time in Italy, as well as the dermatological prognostic impact of specific cutaneous features in long-standing disease. Data were collected in a double fashion, both retrospectively and prospectively, from the AutoInflammatory Disease Alliance (AIDA) international registry dedicated to BD, between January 2022 and December 2022. A total of 458 Italian patients were included. When assessing skin manifestations course, the constant or sporadic presence or absence of cutaneous involvement between onset and follow-up was considered. Oral ulcers (OU) (88.4%) and genital ulcers (GU) (52.6%), followed by skin involvement (53.7%) represented the most common presenting mucocutaneous manifestations at disease onset. Up to the time of enrolment into the AIDA registry, 411 (93.8%) patients had suffered from OU and 252 (57.9%) from GU; pseudofolliculitis (PF) accounted for the most common skin manifestation (170 patients, 37.1%), followed by erythema nodosum (EN) (102 patients, 22.3%), skin ulcers (9 patients, 2%) and pyoderma gangrenosum (4 patients, 0.9%). A prospective follow-up visit was reported in 261/458 patients; 24/148 (16.2%) subjects with skin involvement as early as BD onset maintained cutaneous lesions for the entire period of observation, while 120 (44.1%) patients suffered from sporadic skin involvement. Conversely, 94/113 (83.2%) with no skin involvement at disease onset did not develop skin lesions thereafter. At follow-up visits, cutaneous involvement was observed in 52 (20%) patients, with a statistically significant association between PF and constant skin involvement (p = 0.031). BD in Italy is characterized by a wide spectrum of clinical presentations and skin manifestations in line with what is described in endemic countries. Patients with skin disease at the onset are likely to present persistent cutaneous involvement thereafter; mucocutaneous lesions observed at the onset, especially PF, could represent a warning sign for future persistent skin involvement requiring closer dermatological care.

Surgical management of digital ulcers in systemic sclerosis: A systematic literature review.

BACKGROUND: There is a strong rationale to develop locally-acting surgical treatments for digital ulcers (DUs) in patients with systemic sclerosis (SSc). Our aim was to examine the safety and efficacy of local surgical management for SSc-DU. METHODS: A systematic literature review was carried out until to August 2022 using 7 different databases. Original research studies concerning adult patients with SSc-DUs, and local surgical treatments were analysed using the PICO framework. We included randomized controlled trials, prospective/retrospective studies, and case series (minimum of 3 patients) References were independently screened by two reviewers including assessment of the risk of bias using validated tools. RESULTS: Out of 899, 13eligible articles were included. Autologous fat (adipose tissue AT) grafting was the surgical modality most identified (7 studies, 1 randomized controlled double blinded trial and 6 prospective open-label single arm studies). The healing rate (HR) with autologous fat grafting (4 studies) was 66-100 %. Three studies reported autologous adipose-derived stromal vascular fraction grafting: HR of 32-60 %. Bone marrow derived cell transplantation in a single study showed 100 % healing rate over 4-24 weeks. Surgical sympathectomy was examined in 3 studies, prospective without comparator with a median healing rate of 81 %. Two surgical studies (of direct microsurgical revascularisation and microsurgical arteriolysis) showed 100 % healing of ulcers, with no complications. CONCLUSION: Several surgical approaches for SSc-DUs have demonstrated some degree of safety and effectiveness for DU healing. However, there are significant methodological issues. Future studies are warranted to rigorously investigate surgical interventions for SSc-DUs.

Non-surgical local treatments of digital ulcers in systemic sclerosis: a systematic literature review.

INTRODUCTION: Digital ulcers (DUs) are difficult to treat in patients with systemic sclerosis (SSc) and systemic (i.e., pharmacological) therapy is currently considered the 'standard of care'. Our aim was to examine the safety and efficacy of local, non-surgical treatment for SSc-DUs. METHODS: A systematic literature review (SLR) of original research articles up to August, 29 2022 was performed according to the PICO framework. References were independently screened by two reviewers and risk of bias was assed using validated tools. Due to study heterogeneity narrative summaries are used to present data. RESULTS: Among 899 retrieved references, 14 articles were included (2 randomised trials (RTs), and 12 observational (OBS) studies). The most frequently studied procedure (5 studies) was botulin A toxin (hand or single finger) injection with a reported healing rate (HR) of 71%-100%. Amniotic and hydrocolloid membranes were examined in one study each and associated with a good HR. Tadalafil 2% cream was studied in a single study with a reduction in the number of DUs. Vitamin E gel was associated with a reduction in ulcer healing time. Low-level light therapy, hydrodissection and corticosteroid injection, extracorporeal shock wave (ESW) and photobiomodulation were evaluated in a single study each and showed a positive trend. Dimethyl sulfoxide was associated with significant local toxicity. CONCLUSIONS: A range of non-surgical, local treatments for SSc-DUs have been explored and showed efficacy to some extent. We have identified methodological flaws that should be avoided in the design of future studies to explore locally-acting treatments for SSc-DUs.

SpA plus IBD or IBD plus SpA: Does commutative property apply?

The term spondyloarthritis (SpA) encompasses a group of interrelated disorders characterised by the involvement of the musculoskeletal system as well as extra-articular manifestations like acute anterior uveitis, psoriasis and inflammatory bowel diseases (IBD). Likewise, IBD may present with various extra-intestinal manifestations among which those involving the musculoskeletal system, namely peripheral and axial SpA are the most common. The identification of patients with both SpA and IBD is of paramount importance in clinical practice since the coexistence of these two entities has been associated with great disability and decreased quality of life. In order to achieve an early diagnosis of IBD-SpA it is instrumental that rheumatologists seek for gastrointestinal symptoms in SpA patients and likewise that gastroenterologists seek for inflammatory musculoskeletal symptoms in patients with IBD. This narrative review aims at critically appraising the available evidence about SpA occurring in IBD patients versus IBD occurring in patients with SpA and at highlighting similarities and differences between the two scenarios.

Pathogenesis of rheumatoid arthritis: one year in review 2023.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by local and systemic inflammation. The complex interplay between immune cells and soluble mediators leads to the induction and perpetuation of aberrant inflammatory and autoimmune responses. The research carried out in the last year in the field of RA enabled the identification of new mechanisms involved in the pathogenesis of the disease and therefore unmasked new potential therapeutic targets. In this review article we summarised the new insights into RA pathogenesis from original research articles published in the last year.

Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review.

OBJECTIVE: To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines. METHODS: A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data. RESULTS: Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs. CONCLUSION: There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need.

Points to consider: EULAR-UEMS standards for the training of European rheumatologists.

BACKGROUND: Postgraduate rheumatology training programmes are already established at a national level in most European countries. However, previous work has highlighted a substantial level of heterogeneity in the organisation and, in part, content of programmes. OBJECTIVE: To define competences and standards of knowledge, skills and professional behaviours required for the training of rheumatologists. METHODS: A European Alliance of Associations for Rheumatology (EULAR) task force (TF) of 23 experts, including two members of the European Union of Medical Specialists (UEMS) section of rheumatology, was convened. The mapping phase consisted of the retrieval of key documents on specialty training in rheumatology and other related specialties across a broad set of international sources. The content of these documents was extracted and represented the foundation for the document draft that underwent several rounds of online discussion within the TF, and afterwards was also distributed to a broad group of stakeholders for collecting feedback. The list of generated competences was voted on during the TF meetings, while the level of agreement (LoA) with each statement was established by anonymous online voting. RESULTS: A total of 132 international training curricula were retrieved and extracted. In addition to the TF members, 253 stakeholders commented and voted on the competences through an online anonymous survey. The TF developed (1) an overarching framework indicating the areas that should be addressed during training, (2) 7 domains defining broad areas that rheumatology trainees should master by the end of the training programme, (3) 8 core themes defining the nuances of each domain and (4) 28 competences that trainees should acquire to cover each of the areas outlined in the overarching framework. A high LoA was achieved for all competences. CONCLUSION: These points to consider for EULAR-UEMS standards for the training of European rheumatologists are now defined. Their dissemination and use can hopefully contribute to harmonising training across European countries.

The Interplay between Cardiovascular Risk, Cardiovascular Events, and Disease Activity in Primary Sjögren's Syndrome: Is Uric Acid the Missing Link?

(1) Background: Uric acid is a well-known cardiovascular (CV) risk factor in the general population but its role in the setting of rheumatic diseases other than gout is unclear. (2) Methods: This is a retrospective study investigating a cohort of 105 pSS patients recording clinical, serological, and CV-related variables including adherence to the Mediterranean diet. (3) Results: We observed a strong relationship between disease activity, interstitial lung disease (ILD), and CV events. The association between ILD and CV events was dependent on higher SUA levels but independent of other traditional CV risk factors. All three cases of previous non-fatal stroke were reported by females aged <65 years, with higher SUA levels, and two of them also had pSS-ILD. Forty (38%) patients had a 10-year risk of fatal and non-fatal CV disease events beyond the cut-off recommended for their age, and using the correction factor of 1.5 currently applied only to rheumatoid arthritis, we could better identify patient subsets characterized by different CV risk profiles including different SUA levels. (4) Conclusions: This study is the first to investigate in depth the role of SUA in the CV scenario of pSS. Our findings underpin the importance of assessing SUA levels in pSS in addition to the other traditional CV risk factors and to consider applying the correction factor for CV risk assessment tools to achieve a better stratification of CV risk.