From bench to bedside- is there a role of IL-17 drugs in rheumatoid arthritis?

INTRODUCTION: IL-17 has been described as a pro-inflammatory cytokine that is relevant in the seronegative spondylarthritides with IL-17 targeted therapies being licensed for their treatment.There is evidence to demonstrate that IL-17 is found in RA joints and contributes to the pro-inflammatory cascade. This results in synovial hyperplasia and osteoclastogenesis thus causing joint destruction and bony erosions. AREAS COVERED: This review article summarizes trials that have studied the use of IL-17 targeted therapies in RA patients who have failed conventional synthetic disease-modifying therapy (C-DMARDS) and biologic DMARDS. EXPERT OPINION: The trials that have studied IL-17 inhibitors in RA patients have only shown a modest improvement in disease activity. In several trials, the primary endpoint was not achieved whilst in others, when comparing with existing licensed biologics for RA, did not demonstrate any superiority.Tissue Necrosis Factor-alpha (TNF-α) likely plays more of a pivotal role in the pathogenesis of RA with IL-17 having a synergistic effect. Therefore, in our opinion, IL-17 inhibitors as an independent therapy for RA are less likely to provide a cost-effective benefit. There may be scope to potentially combine it with TNF-α-inhibitors (TNF-i), but this requires further research especially with the potential concerns related to increased immunosuppression.

Development and testing of a bespoke cultural intervention to support healthcare professionals with patients from a diverse background.

OBJECTIVE: Development and test of a culturally sensitive intervention for rheumatology healthcare professionals (HCPs). METHODS: Using a before and after study design, fifteen HCPs were recruited to undertake the bespoke intervention from four NHS sites across England, in areas serving a diverse population. The intervention was evaluated using the validated outcomes: [1] Patient Reported Physician Cultural Competency (PRPCC); and [2] Patient Enablement Instrument (PEI), measuring patients' perceptions of their overall healthcare delivery. Additionally, HCPs completed the Capability COM-B questionnaire (C), Opportunity (O) and Motivation (M) to perform Behaviour (B), measuring behaviour change. RESULTS: 200 patients were recruited before HCPs undertook the intervention (cohort 1), and 200 were recruited after (cohort 2) from fifteen HCPs, after exclusions 178 patients remained in cohort 1 and 186 in cohort 2. Patients identifying as White in both recruited cohorts were 60% compared with 29% and 33% of patients (cohorts 1 and 2 respectively) who identified as of South Asian origin. After the intervention, the COM-B scores indicated HCPs felt more skilled and equipped for consultations. No significant differences were noted in the average overall cultural competency score between the two cohorts in White patients (57.3 vs 56.8, p= 0.8), however, in the South Asian cohort, there was a statistically significant improvement in mean scores (64.1 vs 56.7, p= 0.014). Overall, the enablement score also showed a statistically significant improvement following intervention (7.3 vs 4.3, p< 0.001) in the White patients; and in the South Asian patients (8.0 vs 2.2, p< 0.001). CONCLUSION: This novel study provides evidence for improving cultural competency and patient enablement in rheumatology settings.

Clinical efficacy of JAK inhibitors on enthesitis in spondyloarthropathy: A scoping literature review.

BACKGROUND: Enthesitis is a key feature of spondyloarthropathy (SpA). In recent years, JAK inhibitors have emerged as efficacious drugs in the landscape of advanced therapies for patients with SpA. METHOD: The aim of this scoping literature review was to search the published literature for studies on JAK inhibitors and their effects on enthesitis in patients with SpA and evaluate the data and summarise the findings. The clinical trials reviewed used the Leeds Enthesitis Index, Spondyloarthritis Research Consortium of Canada Enthesitis Index, and Maastrich Ankylosing Spondylitis Enthesitis Score as outcome measures. RESULTS: Tofacitinib, upadacitinib, and filgotinib had numerically greater reductions in the enthesitis scores when compared with placebo. CONCLUSION: While the JAK inhibitors are therapeutic options for enthesitis in SpA, head-to-head studies are needed to compare the JAK inhibitors against the biological drugs (targeting TNF, IL-17, and IL-12/23) as well as studies showing the effects of JAK inhibitors on enthesitis imaging.

Ethnic differences in cellular and humoral immune responses to SARS-CoV-2 vaccination in UK healthcare workers: a cross-sectional analysis.

Background: Few studies have compared SARS-CoV-2 vaccine immunogenicity by ethnic group. We sought to establish whether cellular and humoral immune responses to SARS-CoV-2 vaccination differ according to ethnicity in UK Healthcare workers (HCWs). Methods: In this cross-sectional analysis, we used baseline data from two immunological cohort studies conducted in HCWs in Leicester, UK. Blood samples were collected between March 3, and September 16, 2021. We excluded HCW who had not received two doses of SARS-CoV-2 vaccine at the time of sampling and those who had serological evidence of previous SARS-CoV-2 infection. Outcome measures were SARS-CoV-2 spike-specific total antibody titre, neutralising antibody titre and ELISpot count. We compared our outcome measures by ethnic group using univariable (t tests and rank-sum tests depending on distribution) and multivariable (linear regression for antibody titres and negative binomial regression for ELISpot counts) tests. Multivariable analyses were adjusted for age, sex, vaccine type, length of interval between vaccine doses and time between vaccine administration and sample collection and expressed as adjusted geometric mean ratios (aGMRs) or adjusted incidence rate ratios (aIRRs). To assess differences in the early immune response to vaccination we also conducted analyses in a subcohort who provided samples between 14 and 50 days after their second dose of vaccine. Findings: The total number of HCWs in each analysis were 401 for anti-spike antibody titres, 345 for neutralising antibody titres and 191 for ELISpot. Overall, 25.4% (19.7% South Asian and 5.7% Black/Mixed/Other) were from ethnic minority groups. In analyses including the whole cohort, neutralising antibody titres were higher in South Asian HCWs than White HCWs (aGMR 1.47, 95% CI [1.06-2.06], P = 0.02) as were T cell responses to SARS-CoV-2 S1 peptides (aIRR 1.75, 95% CI [1.05-2.89], P = 0.03). In a subcohort sampled between 14 and 50 days after second vaccine dose, SARS-CoV-2 spike-specific antibody and neutralising antibody geometric mean titre (GMT) was higher in South Asian HCWs compared to White HCWs (9616 binding antibody units (BAU)/ml, 95% CI [7178-12,852] vs 5888 BAU/ml [5023-6902], P = 0.008 and 2851 95% CI [1811-4487] vs 1199 [984-1462], P < 0.001 respectively), increments which persisted after adjustment (aGMR 1.26, 95% CI [1.01-1.58], P = 0.04 and aGMR 2.01, 95% CI [1.34-3.01], P = 0.001). SARS-CoV-2 ELISpot responses to S1 and whole spike peptides (S1 + S2 response) were higher in HCWs from South Asian ethnic groups than those from White groups (S1: aIRR 2.33, 95% CI [1.09-4.94], P = 0.03; spike: aIRR, 2.04, 95% CI [1.02-4.08]). Interpretation: This study provides evidence that, in an infection naïve cohort, humoral and cellular immune responses to SARS-CoV-2 vaccination are stronger in South Asian HCWs than White HCWs. These differences are most clearly seen in the early period following vaccination. Further research is required to understand the underlying mechanisms, whether differences persist with further exposure to vaccine or virus, and the potential impact on vaccine effectiveness. Funding: DIRECT and BELIEVE have received funding from UK Research and Innovation (UKRI) through the COVID-19 National Core Studies Immunity (NCSi) programme (MC_PC_20060).

An update on the considerations for patients with rheumatic disease being treated with rituximab during the COVID-19 pandemic and the potential drug treatment strategies.

INTRODUCTION: Over the last two decades, rituximab has become an increasingly popular drug in the treatment of a wide range of rheumatic diseases. However, with the advent of the COVID-19 pandemic, clinicians face challenges in weighing risk against benefit in its use. AREAS COVERED: A review of existing data was performed to examine the relationship between rituximab use, morbidity and mortality from COVID-19, and vaccine efficacy in patients with rheumatic diseases, aiming to guide clinicians in continued use of the medication and consider the direction of future research. A literature review was performed through a search of the PubMed database, using the terms ((SARS-CoV-2) OR (COVID-19)) AND (rituximab) AND (rheumatic), which generated an initial 55 results, with relevant articles then selected for inclusion. EXPERT OPINION: In order to safeguard patients with an ongoing need for rituximab therapy, vaccination remains the primary concern. A target of performing booster doses 6 months after last rituximab dose is a reasonable estimate, which may be made more precise by use of B cell counts, although primary immunization should not be delayed. In those patients who remain seronegative, the use of newer antivirals and broadly neutralizing antibody infusions may help provide further safeguards.

Cannabinoids in rheumatology: Friend, foe or a bystander?

OBJECTIVES: Cannabinoids have gained popularity recently with special emphasis on their use for chronic pain. Although NICE guidelines advise against their usage for management of chronic pain, almost all rheumatologists encounter a few patients in their daily practice who either use them or are curious about them. We reviewed the mechanism of action of cannabinoids, current knowledge about their role in rheumatology and potential drug interactions with common drugs used in Rheumatology. We attempted to answer the question "If cannabinoids are friend, foe or just a mere bystander?" METHODS: We adhered to a search strategy for writing narrative reviews as per available guidelines. We searched PubMed with the search terms "Cannabinoids", "Rheumatology" and "Chronic pain" for published articles and retrieved 613 articles. The abstracts and titles of these articles were screened to identify relevant studies focusing on mechanism of actions, adverse effects and drug interactions. We also availed the services of a musculoskeletal librarian. RESULTS: Despite the NHS guidelines against the usage of cannabinoids and associated significant stigma, cannabinoids are increasingly used for the management of pain in rheumatology without prescription. Cannabinoids act through two major receptors CB1 and CB2, which are important modulators of the stress response with potential analgesic effects. Their role in various rheumatological diseases including Rheumatoid arthritis, Osteoarthritis and Fibromyalgia have been explored with some benefits. However, in addition to the adverse effects, cannabinoids also have some potential interactions with common drugs used in rheumatology, which many users are unaware of. CONCLUSION: While the current studies and patient reported outcomes suggest cannabinoids to be a "friend" of rheumatology, their adverse events and drug interactions prove to be a "Foe". We were unable to arrive at a definite answer for our question posed, however on the balance of probabilities we can conclude cannabinoids to be a "foe". Under these circumstances, a disease and drug focussed research is need of the hour to answer the unresolved question.

Lifestyle modification and inflammation in people with axial spondyloarthropathy-A scoping review.

INTRODUCTION: People with axial spondyloarthritis (AS) have an inflammatory profile, increasing the risk of hypertension, type 2 diabetes, obesity, and dyslipidaemia. Consequently, AS is linked with co-morbidities such as cardiovascular disease (CVD). Physical inactivity, diet, smoking, alcohol consumption, and obesity influence inflammation, but knowledge of the interaction between these with inflammation, disease activity, and CVD risk in AS is dominated by cross-sectional research. METHODS: A review of the literature was conducted between July 2020 and December 2021. The focus of the scoping review is to summarise longitudinal and randomised control trials in humans to investigate how tracking or modifying lifestyle influences inflammation and disease burden in patients with AS. KEY MESSAGES: (1) Lifestyle modifications, especially increased physical activity (PA), exercise, and smoking cessation, are critical in managing AS. (2) Smoking is negatively associated with patient reported outcome measures with AS, plus pharmaceutical treatment adherence, but links with structural radiographic progression are inconclusive. (3) Paucity of data warrant structured studies measuring inflammatory cytokine responses to lifestyle modification in AS. CONCLUSION: Increased PA, exercise, and smoking cessation should be supported at every given opportunity to improve health outcomes in patients with AS. The link between smoking and radiographic progression needs further investigation. Studies investigating the longitudinal effect of body weight, alcohol, and psychosocial factors on disease activity and physical function in patients with AS are needed. Given the link between inflammation and AS, future studies should also incorporate markers of chronic inflammation beyond the standard C-reactive protein and erythrocyte sedimentation rate measurements.

Testing the Water: Osteoporosis Management in Primary Care.

INTRODUCTION: Osteoporosis is a common bone condition in the United Kingdom (UK). The risk of osteoporosis and fragility fractures increases with age, and with the ageing population in the UK, the incidence is growing. It is imperative that General Practitioners (GPs) correctly diagnose and manage their patients with osteoporosis. To improve the awareness, a treatment pathway was developed in secondary care to guide local GPs. The aim of this study was to investigate whether patients at a GP practice with a population of 14,000 have been appropriately identified, coded as osteoporosis, treated, and have followed the recommended treatment pathway. METHODS: This retrospective study identified three patient groups through a search of the practice IT system, using the words 'osteoporosis', 'fragility fracture', 'Quality and Outcomes Framework', and names of all medications that are used to treat osteoporosis. Group 1 consisted of patients currently on the practice osteoporosis register. Group 2 consisted of patients with a coding of 'osteoporosis' or 'fragility fracture', but not currently on osteoporosis treatment. Group 3 consisted of patients currently on osteoporosis treatment with no coding for 'osteoporosis' or 'fragility fracture'. RESULTS: In Group 1, 62% were found to be following the local treatment pathway in the first cycle of the study, and 70% in the second cycle. In Group 2, 45% were found to be following the local treatment pathway in the first cycle of the study, and 43% in the second cycle. In Group 3, 86% were found to be following the local treatment pathway in the first cycle of the study, and 96% in the second cycle. The completed study cycle shows an improvement of adherence of the pathway, from 75% in the first cycle to 81% in the second cycle. The first cycle of the study was presented at the GP practice meeting, which improved the awareness of the treatment pathway. CONCLUSION: This study illustrates that there is a need for improvement in the diagnosis and management of osteoporosis in primary care. This can be achieved by improving awareness through continuing medical education about following the appropriate pathway to enhance the management of osteoporosis. Resources need to be allocated for prioritising osteoporosis care to prevent falls and fragility fractures, which have devastating effects on individual patients and the healthcare system.

Are There Any Ethnic Differences in the Response to Baricitinib for the Treatment of Rheumatoid Arthritis?

Introduction Baricitinib is an oral synthetic Janus Kinase inhibitor that inhibits JAK1 and JAK2, and the new kid on the block in the treatment of rheumatoid arthritis (RA). To date, there are no studies comparing the clinical benefit of baricitinib in RA between different ethnicities. Ethnicity plays a role in the effectiveness of therapeutic agents. Given the large multi-ethnic population of Leicestershire in the United Kingdom and the range of new therapeutics in RA, we reviewed our cohort of patients with RA to see whether there is any difference in baricitinib Disease Activity Score 28 (DAS28) response between the Asian and White cohorts. Methods This was a retrospective study. The patients included were those under the care of rheumatology at University Hospitals of Leicester (UHL) with a diagnosis of RA and either receiving baricitinib or had received it in the past. Data was collected using the UHL information technology systems, clinic letters and pharmacy records. In addition to ethnicity, we reviewed patient age, gender, concurrent disease-modifying anti-rheumatic drugs (DMARDs) used, previous biologics used, baseline and post-treatment DAS28, dropout from therapy, baseline biochemical assays (anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) status) and radiographic findings. An independent t-test was used to compare continuous data, and Pearson's chi-squared test was used to compare categorical data. Results A total of 120 patients were included in the analysis, and data were analysed with Portable Format for Analytics (PFA). There was no statistically significant difference in the mean DAS28 at baseline (Asian: 5.17 versus White: 4.65; p-value = 0.107) and post-treatment (Asian: 2.8 versus White: 3.3; p-value = 0.404). Comparing both ethnicities, there was no statistically significant difference in previous biologics used, anti-CCP and RF titres, and radiographic findings of erosions. Conclusion This is the first study of its kind, and it found no significant difference in baricitinib response between the Asian and White cohorts. Our study had certain limitations, and future studies will be needed to evaluate this subject further. Such data is important as it can contribute to a body of evidence that may in the future help inform clinical decision-making.

Is There a Correlation Between Patient-Reported Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Score and MRI Findings in Axial Spondyloarthropathy in Routine Clinical Practice?

Background The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is the patient-reported outcome (PRO) that is routinely used in clinical practice to monitor and measure disease activity in axial spondyloarthropathy (axSpA). BASDAI scores greater than four are thought to indicate active disease and require better control. Magnetic resonance imaging (MRI) is the most objective measure of disease activity in axSpA with its ability to pick up active inflammation both in the spine and sacroiliac joints. Previous studies have shown conflicting correlations between BASDAI and MRI, and therefore, there is the question of whether BASDAI is the best tool to monitor disease activity when it is subjective and potentially influenced by other patient factors. We, therefore, conducted a retrospective study to investigate the correlation between BASDAI and MRI in axSpA patients. Methodology Data were collected by retrospective analysis of axSpA patients attending University of Leicester (UHL) axSpA services. BASDAI scores were done within a year and closest to the time of MRI spine + sacroiliac joints were collected. The results prior to the initiation of biologic therapy were used. Data of one hundred and forty-nine patients were collected on their MRI results and BASDAI scores. Data were analysed using Statistical Package for the Social Sciences (SPSS) software and Pearson's chi-squared applied to assess the correlation between BASDAI and MRI findings. Results Out of one hundred and forty-nine patients, 61.7% had active sacroiliitis on their MRI, 57.7% had chronic sacroiliitis, 53% had active spinal inflammation, and 17.4% had other MRI findings of active disease. There was a significant correlation between active sacroiliitis and BASDAI (p=0.014), but similar results were not found with other radiological features. A significant correlation was also found with males having higher BASDAI scores compared to females (p=0.027). Conclusion This study demonstrates a statistically significant correlation between BASDAI and active sacroiliitis with those having higher scores more likely to have active disease on their MRI.

Reactive arthritis: a clinical review.

Reactive arthritis (ReA) is a form of inflammatory arthritis triggered by a remote antecedent infection, usually in the genitourinary or gastrointestinal tract. It is part of the spondyloarthropathy (SpA) spectrum, an umbrella term for a group of distinct conditions with shared clinical features. Typically, it presents with an asymmetric oligoarthritis of the lower limb joints, and patients may also have sacroiliitis, enthesitis and dactylitis. Other features often seen include anterior uveitis, urethritis and skin manifestations such as pustular lesions on the plantar areas. Although ReA was characterised initially as a sterile arthritis, the detection of metabolically active Chlamydia species in the joint fluid of some affected patients has generated further questions on the pathophysiology of this condition. There are no formal diagnostic criteria, and the diagnosis is mainly clinical. HLA-B27 can support the diagnosis in the correct clinical context, and serves as a prognostic indicator. The majority of patients have a self-limiting course, but some develop chronic SpA and require immunomodulatory therapy.

Patient Empowerment: Apni Jung (Our Fight) against Rheumatoid Arthritis for South Asian Population.

Covid-19 has affected many populations in the UK, and ethnic minority communities in particular. People from ethnic minority communities living with long-term chronic diseases have shown to be less engaging with self-management and report having poor medication adherence. The main reason to this problem is the way information is delivered to non-English speaking patients. This editorial discusses an innovation to over this barriers in rheumatology practice.

An Ethnic Variation in the Acceptance of Biological Disease-Modifying Therapies: A University Hospital Experience.

Ethnic variations in the outcomes of rheumatological diseases are well documented. While physiological differences may account for these disparities, attitude to treatment is also likely to be a significant modifiable contributor. We sought to determine if an ethnic variation exists in the uptake of biological disease-modifying anti-rheumatic drugs (DMARD) among a multi-ethnic cohort when offered in-person through a healthcare system free at the point of access. We conducted a retrospective cross-sectional study of patients seen in a biologic therapy counselling clinic between December 2016 and April 2017. Clinic letters from consultations were reviewed, and data including ethnicity, language spoken, and decision to accept or reject the therapy were extracted. We chose to measure uptake over adherence, as we believe it is an earlier, more direct marker of attitudes to joint saving medications. Ninety-one cases were included in the analysis. Over 13.2% (12/91) of the cohort declined a biologic treatment when it was offered as the standard of care for joint disease. Non-Caucasian patients accepted treatment less often than Caucasian (White British) patients (OR 0.265, CI 0.73-0.959, p = 0.043), as did those who did not speak English as a first language (OR 0.094, CI 0.18-0.497, p = 0.005). Age, sex, and diagnosis were well matched between those who accepted and declined therapy. We demonstrate a disparity in the uptake of biologic therapies between the White British population and patients from other ethnicities. The reasons for this are likely multifactorial and could be related to socio-economic factors, language barriers, and cultural differences. Addressing this discrepancy is a crucial first step to tackling preventable disparities in the outcomes of rheumatological disease between different ethnicities.

Promising Treatment Options for Axial Spondyloarthritis: An Overview of Experimental Pharmacological Agents.

Axial spondyloarthritis (axSpA) is a chronic inflammatory condition that predominantly affects the axial skeleton. All patients receive conservative management measures which include physiotherapy, patient education and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Those with significant active disease will require escalation of their treatment with the use of biologics. Currently, there are five approved TNF inhibitors and two approved IL-17 inhibitors for use in axSpA. However, despite this up to 40% of patients do not respond or are intolerant to current available treatment. This leaves a significant number of patients with uncontrolled disease and unmet need for additional therapies. Though many drug classes have been trialed for axSpA they show poor efficacy; however, over the last few years there are three which demonstrate much greater promise as novel therapies for axSpA, these include dual neutralization of IL-17A and IL-17F, Janus kinase (JAK) inhibitors, and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors. This article reviews the evidence for these novel emerging therapeutic options for axSpA.