One-pot synthesis of 5-amino-2,5-dihydro-1-benzoxepines: access to pharmacologically active heterocyclic scaffolds

A one-pot multibond-forming process involving a thermally mediated Overman rearrangement and a ring closing metathesis reaction of allylic trichloroacetimidates bearing a 2-allyloxyaryl group has been developed for the synthesis of 5-amino-substituted 2,5-dihydro-1-benzoxepines. Chemoselective reduction and functionalization of these compounds allowed access to a range of pharmacologically active 5-amino-2,3,4,5-tetrahydro-1-benzoxepine scaffolds

The development of one-pot tandem reactions for the synthesis of polycyclic y-lactams

A novel tandem process has been developed for the stereoselective synthesis of bicyclic γ-lactams. Treatment of an allylic alcohol with trichloroacetonitrile, in the presence of DBU, affords the corresponding allylic trichloroacetimidate. This is then subjected to a tandem Overman rearrangement/RCM/Kharasch cyclisation, forming the desired bicyclic lactam in high yield and high enantiomeric excess. Overall, the one-pot tandem process involves three mechanistically distinct processes catalysed by palladium(II) (step 1) and Grubbs 1st generation catalyst (steps 2 and 3). The use of a thermal Overman rearrangement in tandem with the Grubbs catalysed RCM/Kharasch cyclisation was also investigated. Furthermore, a microwave-assisted tandem process was developed which resulted in the accelerated synthesis of the desired bicyclic γ-lactams. A two-step tandem process was then developed for the synthesis of bicyclic allylic amides, a closely related core unit to that found in a number of important commercially available drugs. Finally, progress has been made towards the total synthesis of (±)-deethylibophyllidine, which will utilise a tandem RCM/Kharasch cyclisation to construct the C and D rings of the natural product

From Psoriasis to Psoriatic Arthritis: Insights from Imaging on the Transition to Psoriatic Arthritis and Implications for Arthritis Prevention

Purpose of Review: To describe the recent advances in the field towards the prevention and early recognition of Psoriatic Arthritis (PsA). Recent Findings: Defining the preclinical phase of PsA remains challenging since up to 50% of subjects with psoriasis have subclinical imaging enthesopathy, but many of these do not progress to PsA. Nevertheless, there is evidence that subjects with subclinical imaging enthesopathy are at increased risk of developing PsA. In recent years, it has been shown that both PsA and anti-citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA) are characterized by a subclinical phase of non-specific or brief duration arthralgia with shared imaging features accounting for joint symptomatology. Sonographically determined tenosynovitis and enthesitis are the key imaging features present in non-specific PsO arthralgia that are at risk of future PsA development. Furthermore, the early phases of PsA are complicated by factors including body mass index (BMI), which is a risk factor for PsA, but BMI is also associated with imaging abnormalities on enthesopathy. Fully disentangling these clinical and imaging factors will be important for enrichment for imminent PsA so that disease prevention strategies can be investigated. Summary: Psoriasis patients with arthralgia have a higher prevalence of tenosynovitis and imaging enthesopathy is at higher risk of transitioning to overt PsA

Transition phase towards psoriatic arthritis: Clinical and ultrasonographic characterisation of psoriatic arthralgia

Objective Non-specific musculoskeletal pain is common in subjects destined to develop psoriatic arthritis (PsA). We evaluated psoriatic patients with arthralgia (PsOAr) compared with psoriasis alone (PsO) and healthy controls (HCs) using ultrasonography (US) to investigate the anatomical basis for joint symptoms in PsOAr and the link between these imaging findings and subsequent PsA transition. Methods A cross-sectional prevalence analysis of clinical and US abnormalities (including inflammatory and structural lesions) in PsOAr (n=61), PsO (n=57) and HCs (n=57) was performed, with subsequent prospective follow-up for PsA development. Results Tenosynovitis was the only significant sonographic feature that differed between PsOAr and PsO (29.5% vs 5.3%, p<0.001), although synovitis and enthesitis were numerically more frequent in PsOAr. Five patients in PsOAr and one in PsO group developed PsA, with an incidence rate of 109.2/1000 person-years in PsOAr vs 13.4/1000 person-years in PsO (p=0.03). Visual Analogue Scale pain, Health Assessment Questionnaire, joint tenderness and US active enthesitis were baseline variables associated with PsA development. Conclusion Tenosynovitis was associated with arthralgia in subjects with psoriasis. Baseline US evidence of enthesitis was associated with clinical PsA development in the longitudinal analysis. These findings are relevant for enriching for subjects at risk of imminent PsA development

Clinical Examination, Ultrasound and MRI Imaging of The Painful Elbow in Psoriatic Arthritis and Rheumatoid Arthritis: Which is Better, Ultrasound or MR, for Imaging Enthesitis?

Introduction: The purpose of the current study was to examine the painful elbow, and in particular enthesitis, in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) using clinical examination, ultrasonography (US) and magnetic resonance imaging (MRI). Methods: Patients with elbow pain (11 with PsA and 9 with RA) were recruited. Clinical examination, US and MRI studies were performed on the same day. For enthesitis, the common extensor and flexor insertions and the triceps insertion were imaged (20 patients, giving a total of 60 sites with comparative data). Imaging was performed with the radiologists blinded to the diagnosis and clinical findings. US was used to assess ‘inflammatory activity’ (Power Doppler signal, oedema, tendon thickening and bursal swelling) and ‘damage’ (erosions, cortical roughening and enthesophytes). MRI was used to assess ‘inflammation’ (fluid in paratenon, peri-entheseal soft-tissue oedema, entheseal enhancement with gadolinium, entheseal oedema and bone oedema) and ‘damage’ (erosion, cortical roughening and enthesophyte). Results: Complete scan data were not available for all patients as one patient could not tolerate the MRI examination. No significant differences in imaging scores were found between PsA and RA. Analysis of damage scores revealed complete agreement between US and MRI data in 43/55 (78%) comparisons; in 10/55 (18%) cases the US data were abnormal but the MRI data normal; in 2/55 (4%) cases, the MRI data were abnormal and the US data normal. Analysis of the inflammation scores revealed complete agreement between US and MRI data in 33/55 (60%) comparisons; in 3/55 (5%) cases US data were abnormal but MRI data normal; in 19/55 (35%) cases the MRI data were abnormal and the US data normal. There was a poor relationship between assessments based on clinical examination and imaging studies. Readers could not accurately identify the disease from imaging findings. Conclusion: Based on our results, at the elbow, US and MR have different roles in assessing enthesitis, with US apparently the better diagnostic tool for assessing damage and MR the better tool for assessing inflammation. In this study enthesitis and synovitis in the painful elbow were found equally in cases of established RA and PsA

The problem in differentiation between psoriatic-related polyenthesitis and fibromyalgia

The recognition of the primacy of enthesitis in animal models of spondyloarthritis and the prevalence of clinically occult enthesopathy in psoriatic subjects and of persistent joint pain in PsA subjects who have ostensibly good reduction of joint swelling under biological therapy has highlighted the potential impact of polyenthesitis in psoriatic disease. In daily practice, the formal demonstration of enthesitis is challenging for the following reasons: the relatively avascular nature of enthesis, often leading to the absence of overt clinical inflammatory signs; the frequent lack of elevation of inflammatory markers; and finally, the limitations of current imaging techniques to provide supportive evidence for inflammation in these areas. Consequently, enthesitis may present as widespread pain indistinguishable from FM or may emerge as the dominant feature after successful biological therapy for suppression of synovitis. The unmet needs in the differentiation between FM and enthesitis in psoriatic disease patients are highlighted and critically evaluated in this article

Psoriatic Dactylitis: Current Perspectives and New Insights in Ultrasonography and Magnetic Resonance Imaging

Dactylitis, one of the most typical features of psoriatic arthritis (PsA), is the diffuse swelling of the digits and is determined by the involvement of different anatomic structures, including: the subcutaneous fibrous tissue “accessory pulley” system; flexor tendons, with their related structures; the articular synovium; the small enthesis of the hands. Dactylitis is currently considered both a marker of disease activity and severe prognosis and its importance in PsA is emphasized by the inclusion in the classification criteria of PsA. This review focuses on the role of imaging in the management of PsA patients with dactylitis in clinical practice and in a research setting. Furthermore, imaging could be a valuable tool to assist in unravelling some of the underlying mechanisms of the onset and chronicization of dactylitis in PsA patients

Preparation of amino-substituted indenes and 1,4-dihydronaphthalenes using a one-pot multireaction approach: total synthesis of oxybenzo[c]phenanthridine alkaloids

Allylic trichloroacetimidates bearing a 2-vinyl or 2-allylaryl group have been designed as substrates for a one-pot, two-step multi-bond-forming process leading to the general preparation of aminoindenes and amino-substituted 1,4-dihydronaphthalenes. The synthetic utility of the privileged structures formed from this one-pot process was demonstrated with the total synthesis of four oxybenzo[c]phenanthridine alkaloids, oxychelerythrine, oxysanguinarine, oxynitidine, and oxyavicine. An intramolecular biaryl Heck coupling reaction, catalyzed using the Hermann–Beller palladacycle was used to effect the key step during the synthesis of the natural products

EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19

OBJECTIVES: Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies. METHODS: PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting. RESULTS: Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates. CONCLUSIONS: Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19

2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19

OBJECTIVES: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19. METHODS: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting. RESULTS: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy CONCLUSIONS: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19