CPD: SARS-CoV-2 Infection/ Cocid-19 Outcomes

Continuing Professional Development CPD CPD

AUTHORS:

Mary Kelly, FFNMRCSI, RANP, RNP, Msc, BSc Cancer Nursing, BSc Adult

Nursing: Mary is an Advanced Nurse Practitioner in Haematology at the Midlands Regional Hospital, Tullamore. Mary has worked in Haematology Nursing for the past 24 years. She has worked in all Haematology nursing care settings both in the UK and Ireland at St Marys and St Bartholomew’s Hospitals, London, Blackrock Clinic and Midland Regional Hospitals. Mary manages CLL patients as part of her clinical caseload.

Orlaith Cormican RGN, Bsc, MHsc, Post Graduate Certificate in Cancer Care

and Haematology: Orlaith is a Clinical Nurse Specialist in Haematology at the Midlands Regional Hospital. Orlaith has worked in cancer care and haematology since 2013. She is currently completing a PhD via the HRB SPHeRE programme. Her areas of interest include chronic haematological malignancies and quality of life in this area. Orlaith works with CLL patients on a daily basis. Mary Kelly Orlaith Cormican

60 Second Summary

Chronic Lymphocytic Leukuemia also known as CLL is a cancer that affects the blood and bone marrow. CLL affects the white blood cells called lymphocytes. It accounts for 2.4% of cancer diagnose in Ireland every year, affects men more than women and is more common in those over the age of 70. CLL comprises over 40% of all leukaemias, affects older patients and may be asymptomatic for much of its course. It is often detected only through routine blood counts and only picked up if the individual presents to clinical services. Approximately 10% of individuals with CLL report a family history of the condition or a related lymphoproliferative disorder, but the genes which account for increased susceptibility have not been identified. The course of the disease generally follows a period of “watch and wait”, followed by treatment with periods of relapse and remission. It remains an incurable disease however there are a number of novel treatments that have become available which have changed the course of the disease, improving patient’s response to treatments and overall quality of life. COVID19 has had a significant impact on CLL patients, many of them being immunodeficient due to the nature of the disease or the multiple lines of treatment received. As such treatments for this high risk group are welcomed. This CPD article will particularly focus on and examine the evidence on the treatment of CLL with Bruton's tyrosine kinase inhibitors (BTKi’s) particularly in the newly diagnosed CLL setting.

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice? 2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area. 3. PLAN - If I have identified a knowledge gap - will this article satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result?Have I identified further learning needs? 5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the 4 previous steps, log and record your findings. Published by HPN. Copies can be downloaded from www.irishpharmacytraining.ie

Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. Abbvie has no editorial oversight of the CPD programmes included in these modules.

Chronic Lymphocytic Leukemia (CLL): An overview of its management and treatment with Bruton's tyrosine kinase Inhibitors

What is it?

CLL is the most common leukaemia in the western world (AlSawaf et al., 2020). CLL is more common in males and is generally associated with those over the age of 70 (NCRI, 2022). All leukaemia’s in Ireland account for 2.4% of all malignant disorders and there are over 500 new diagnoses of CLL made in Ireland every year. The cause of CLL is unknown. Risk factors include family history of haematological malignancy, increasing age and working in farming or hairdressing (Slager et al., 2014). CLL is characterised by the clonal proliferation and accumulation of neoplastic B-lymphocytes in the blood, bone marrow lymph nodes and spleen (Al-Sawaf et al., 2020). B cell receptor signalling leading to activation of various intracellular signalling pathways plays an important role in the survival of CLL cells (Stevenson & CaligarisCappio, 2004). These pathways are now being successfully exploited as therapeutic targets (Jain & Rai, 2012).

Background and Overview

The majority of CLL cases are diagnosed through blood counts, differential counts, a blood smear and immunophenotyping. In CLL, CD5 + B cells undergo malignant transformation. They are activated by the acquisition of mutations leading to monoclonal B cell lymphocytosis (MBL). MBL is defined as an asymptomatic condition where the absolute monoclonal B cell count is <5 x 10 9/L. It occurs in 4-5% of healthy adults and is a proposed precursor of CLL. Most cases of CLL are preceded by MBL while only 1-2% with MBL can develop CLL every year (Jain & Rai, 2012). In CLL, further accumulation of genetic abnormalities and subsequent oncogenic transformation of monoclonal B cells occurs (Burger, 2020). The diagnosis of CLL requires the presence of ≥5000 B-lymphocytes/μL in the peripheral blood for duration of at least 3 months. The clonality of the circulating B cells needs is confirmed by flow cytometry. Furthermore, there may be evidence of lymphadenopathy or organomegaly by physical or CT exam (Hallek, 2019). CLL and small lymphocytic lymphoma (SLL) are different clinical presentations of the same pathological disease and commonly referred to as CLL(Patel & Pagel, 2021). The term CLL is used when the disease manifests primarily in the blood, whereas SLL is used when involvement is primarily nodal (Rai KR, Stilgenbauer, 2021). Patients with CLL commonly develop complications associated with an intrinsic immune dysfunction resulting in immunodeficiency and autoimmune disorders. Ten per cent of patients will present with autoimmune haemolytic anaemia (Christi, M, 2020). Infection, anaemia and thrombocytopenia are the most common disease related complications. The increased risk of severe infections in CLL patients is primarily related to the disease and treatment related immunodeficiency, mainly bacterial and herpes virus family. Tumour lysis syndrome (TLS) and secondary cancers are less common but also potentially life threatening. CLL remains an incurable disease but there continues to be progress made in therapeutics, with the emergence of newer therapies improving overall survival (OS) and being well tolerated by patients enabling them to maintain a good quality of life for many years (Sharma & Rai, 2019). For those patients who are relatively asymptomatic, they may follow the “watch and wait” protocol followed up by clinical observation without receiving any therapies (Milne et

Table 1

Stage Characteristics

Stage

Low Risk Low Risk (Stage 0) (Stage 0)

Intermediate Risk Intermediate Risk (Stages I & II) (Stages I & II)

Characteristics  Abnormal increase in the number of lymphocytes in the blood and marrow  No enlargement of the lymph nodes, spleen, or liver and with near normal red blood cell and platelet counts.

 Abnormal increase in the number of lymphocytes in the blood and marrow  No enlargement of the lymph nodes, spleen, or liver and with near normal red blood cell and platelet counts.  Abnormal increase in the number of lymphocytes in the circulating  Abnormal increase in the number of lymphocytes in the circulating blood and the marrow  blood and the marrow Enlarged lymph nodes  Enlarged lymph nodes OR  OR Abnormal increase in the number of lymphocytes in the circulating  Abnormal increase in the number of lymphocytes in the circulating blood and the marrow  blood and the marrow Enlarged spleen and/or liver  Enlarged spleen and/or liver  The red blood cell or platelets counts are normal or only slightly low.  The red blood cell or platelets counts are normal or only slightly low.

High Risk High Risk (Stages III & IV) (Stages III & IV)

 Abnormal increase in the number of lymphocytes in the circulating  Abnormal increase in the number of lymphocytes in the circulating blood and the marrow  blood and the marrow Anemia (hemoglobin <11g/dL)  Anemia (hemoglobin <11g/dL) OR  OR Abnormal increase in the number of lymphocytes in the circulating  Abnormal increase in the number of lymphocytes in the circulating blood and the marrow  blood and the marrow Thrombocytopenia (platelet counts <100,000/uL)   Thrombocytopenia (platelet counts <100,000/uL)   Enlarged Lymph nodes, liver or spleen.  Enlarged Lymph nodes, liver or spleen.

al., 2020). Treatment is usually commenced at disease progression or when the patient starts to develop symptoms associated with CLL (Milne et al., 2020). The majority of patients with a diagnosis of CLL will have more than one comorbidity at diagnosis, which may influence treatment selection (Kabel C, 2021). In addition, treatment can be patient- dependent, considering compliance, convenience, financial toxicity and duration of therapy (Murphy, 2021).

Diagnosis, Staging and Prognosis

CLL has a widely variable disease course, influencing prognosis. Some patients die rapidly, within 2-3 years of diagnosis, due to CLL complications. Most patients live 5-10 years, with an initial course that is relatively benign, followed by a terminal, progressive and resistant phase lasting 1-2 years (Christi, M, 2020). Significant morbidity from both the disease and complication of therapy may exist in the later phase (Rai & Barrientos, 2014). Table 2 A patient’s prognosis is dependent on disease stage; in addition to the presence or absence of high-risk markers (See Table 1 and 2). The Rai staging system classifies CLL into three separate risk groups. The Binet staging system classifies CLL into three stages (Table 1).

Prognostic indicators

Cytogenetics may detect abnormalities on the chromosomes, which are associated with CLL. Samples are from the blood or bone marrow. FISH analysis may identify abnormalities associated with chromosomes 11, 12 13 and 17: deletion 13q, deletion 11q, trisomy 12, and deletion 17p. Deletion 13q remains the most favourable prognostic group, with deletion 17p being the least favourable (Puiggros et al., 2014). Furthermore, genomic abnormalities associated with TP53 mutation tend to be characterised as high risk and associated with adverse outcomes.

Score

0 1 2-3 Risk Category

Low Intermediate High 5 year cumulative risk to start treatment 8.4% 28.4% 61.2%

Table 1

The IGHV mutation status is also a useful prognostic and treatment indicator; mutated IGHV tends to be less aggressive and especially when combined with additional prognostic factors such as favourable cytogenetics (Puiggros et al., 2014). Condoluci et al., (2020) developed an International Prognostic score for early stage CLL (IPS-E). The IPS –E aims to predict time to first treatment (TTFT) in patients with early asymptomatic CLL at the time of diagnosis. The CLL-IPI-E combines genetic, biochemical and clinical parameters to categorise patients into risk groups (Table 2). The following three covariates were consistently and independently correlated with TTFT, Unmutated IGHV, absolute lymphocyte count >10x 109/L and presence of palpable lymph nodes. Each covariate is assigned 1 point each and scoring is used to classify risk. Importantly, del (17p) and TP53 mutations were not prognostic for TTFT but are important in predicting treatment response and guiding treatment choice once indicated (Rai KR, Stilgenbauer, 2021).

Treatment and Management

The clinical course of CLL is extremely varied. Clinical trials in early stage CLL have failed to show survival benefit and therefore by international guidelines treatment is not recommended in this cohort. Ongoing randomised trials are evaluating the use of modern therapies in early stage disease and prognostic markers associated with poor clinical outcomes. However, until treatment benefit proves more as beneficial, treating in this setting is reserved for patients enrolled in these clinical trials (Rai KR, Stilgenbauer, 2021). Indications for treatment outlined by the International working group CLL (IWCLL) criteria include progressive lymphadenopathy, organomeagly, deteriorating blood counts and constitutional symptoms (Hallek et al, 2018). In addition the presence of progressive lymphocytosis, a doubling time of < 6 months, Hb less than 100g/L or a platelet count of < 100 x 109/L or treatment resistant autoimmune cytopenias are indications to commence treatment (Milne et al, 2020). Lymphocytosis itself, even if extreme, is not a strict indication for treatment if patients have no symptoms and adequate bone marrow function. However, extreme lymphocytosis (>200,000/ micro/L) is associated with an increased risk of hyperviscosity and may serve as an indication for treatment in an otherwise asymptomatic CLL patient (Rai KR, Stilgenbauer, 2021).

Treatment selection

There is no single standard front line therapy regime for all patients with symptomatic or advanced CLL (Rai III-IV, Binet C) or patients with progressive cytopenias. Several initial

Table 2

Chemo Drugs Monclonal Antibodies Kinase inhibitors PI3K Inhibitors

B-cell lymphoma-2 (BCL-2) inhibitors

Fludarabine Rituximab Ibrutinib Idelalisib Venetoclax Chlorambucil Obinutuzumab Acalabrutinib Bedamustine Cyclophosphamide

Common Side Effects

Hair loss

Mouth sores

Loss of appetite

Nausea and vomiting

Low blood counts Chest pain

Heart racing

Swelling of the face and tongue

Cough

Trouble breathing

Feeling dizzy, lightheaded, or faint Diarrhoea

Nausea

Constipation

Fatigue,

shortness of breath

Swelling of the feet and hands, body aches,

Rash

Low blood counts

Atrial Fibrillation Diarrhoea

Fever

Fatigue

Nausea

Cough

Pneumonia

Low blood counts

Pneumonitis Tumour Lysis Syndrome

Low blood counts

Diarrhoea

Nausea

Respiratory infections

Thrombocytopenia

Fatigue

treatments options exist, with varying rates of complete response, time to progression and associated toxicities (See Table 3). Patient’s treatment is individualised based on the patient, tumour characteristics and goals of therapy At least 90% of patients have one or more co-morbidities, therefore an MDT approach involving patients and outlining the potential benefits and risks of a particular treatment is important when considering treatment (Thurmes et al., 2008). Optimising health related quality of life (HRQoL) and managing adverse events are also important considerations in the decision to treat and choice of therapy (Patel & Pagel, 2021). Frey et al., (2016) reports disease severity as a predictor of poor HRQoL. In addition, toxicities associated with long-term targeted treatments have been shown to affect adherence, thus the emergence of limited duration therapies where appropriate is welcome. Treatment options for CLL include CIT, targeted therapies, radiation therapy and supportive care. Over the past two decades, a dramatic increase in our understanding of the pathogenesis of CLL has led to the development of small molecule inhibitors for CLL targeting the B cell receptor pathway and the apoptotic regulator BCL2 (Milne et al, 2020). These targeted therapies, enable patients to be treated with a chemotherapy free regime. Similar to management in most malignancies, the most suitable treatment for a patient is selected based on genetic features of the disease itself (Milne et al, 2020). Molecular assessment prior to every line of treatment is essential to avoid ineffective treatments.

When planning treatment it is also important to consider the current pandemic. Nevertheless, in those patients with active CLL, treatment should not be withheld, because data suggests that the outcome of patients with COVID-19 is better if their cancer is under control. In patients requiring intervention, BTKi’s may represent the preferred therapeutic option (Roschewski et al., 2020).

Chemo immunotherapy (CIT)

For many years Fludarabine, cyclophosphamide and Rituximab (FCR) were the gold standard treatment for CLL. FCR yielded high overall response rates of up to 95% with some patients remaining in remission for over a decade. Table 3

Although FCR is not an effective option for patients with TP53 and del (17q) mutations, for patients with mutated IGHV trials showed that time limited FCR can provide functional cure and therefore despite its diminishing role FCR may still be considered in this patient group. Bendamustine and rituximab and Obinutuzumab plus chlorambucil are also regimes that are active in CLL. These regimes are also options for older patients with cardiovascular comorbidities where BTK inhibitor therapy could increase the risk of cardiovascular events. CIT may be considered in patients where a time-limited treatment is preferable. Newer treatment options with fixed duration combinations for example Ibrutinib and ventoclax will further challenge the role of chemoimmunotherapy in the near future.

Targeted Treatments Bruton Tyrosine Kinase (BTK) Inhibitors- Ibrutinib, Acalabrutinib

The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and CLL. BTK's pivotal role in signalling through the B-cell surface receptors and results in activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion. These BTKi work by forming a covalent bond with a cysteine residue (Cys-481) in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. Potent, small-molecule inhibitors of BTK developed to treat CLL include, Ibrutinib and Acalabrutinib.

Ibrutinib

Ibrutinib was the first available oral small molecule inhibitor that binds to BTK preventing its kinase activity. This affects multiple signalling pathways and disrupts the interaction between CLL cells and the microenvironment leading to further apoptosis (Milne et al, 2020). Ibrutinib is indicated for the treatment of CLL and SLL with or without del (17p) (SPC, 2021). Clinical trials demonstrated the clinical benefit of Ibrutinib in a variety of clinical settings (Ghia et al., 2021). The Resonate trial showed improved PFS, OS and ORR for Ibrutinib versus ofatumumab in previously treated patients (Byrd et al., 2014). Resonate 2 showed ibrutinib superiority in PFS, OS and ORR in treatment naïve patients when compared to Chlorambucil. Further Resonate-2 analysis revealed 61% of patients were alive and progression free at 6.5 years and 6.5 year OS was 78%. Adverse events of clinical interest over time for patients on Ibrutinib included hypertension, atrial fibrillation and less commonly major haemorrhage (Ghia, P, Owen, C et al., 2021). The iLLUMINATE trial compared Ibrutinib plus obinutuzumab versus chlorambucil and obinutuzumab. The results showed significantly

improved PFS (Moreno et al., 2019). Ibrutinib is taken orally at the same time each day. Ibrutinib is generally well tolerated; though there are some common side effects (Table 3).

Acalabrutinib

Acalabrutinib is a highly selective, potent BTK inhibitor (Ghia et al, 2020). In the phase II study that evaluated. Acalabrutinib in relapsed/refractory CLL, Acalabrutinib resulted in an overall response rate (ORR) of 93% in patients with Del (17p) and 90% of those with complex karyotype.

Elevate trial

The Elevate trial was the first trial of Acalabrutinib versus Ibrutinib in previously treated CLL. Patients were randomised to Acalabrutinib 100mg orally twice daily or Ibrutinib 420mg orally once daily and continued until disease progression or unacceptable toxicity. The primary endpoint was non-inferiority and secondary endpoints included incidence of Atrial fibrillation, grade >/ three infections, Richter’s transformation (RT) and (OS). At a median follow up of 40.9 months, Acalabrutinib was non-inferior to Ibrutinib, with a medium PFS of 38.4 months in both arms. Acalabrutinib demonstrated lower frequencies of adverse events (AE). Cardiovascular events were less common with Acalabrutinib, 9.4% vs 16% for atrial fibrillation (AF) and 9.4% vs 23.2% for hypertension.

ELEVATE-TN Trial

In this randomised, controlled, phase 3 trial the efficacy of Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatmentnaïve CLL patients was compared. At a median follow up of 28.3 months median PFS was longer with Acalabrutinib – obinutuzumab (A-O) and Acalabrutinib monotherapy compared with obinutuzumab-chlorambucil (O-C). Estimated PFS at 24 months was 93% with A-0, 87% for patients on Acalabrutinib monotherapy and 47% in the O-C arm. Patients on A-O and Acalabrutinib tolerated treatment well and had a manageable safety profile, with 79% of patients remaining on therapy after a median follow up of 28.3 months. Sharman et al., (2020) concluded that Acalabrutinib with or without obinutuzumab is efficacious and a well tolerated treatment for patients with treatment – naïve CLL.

ASCEND trial

Acalabrutinib proves to be an effective treatment for patients with relapsed/refractory (R/R) disease. The study demonstrated a statistically significant and clinically meaningful PFS with Acalabrutinib compared with Idelalisib plus Rituximab (I-R) or Bendamustine plus Rituximab (B-R). The benefit of Acalabrutinib was seen across all patient subgroups including those with del (17p) or TP53. In addition, a tolerable safety profile was demonstrated. Acalabrutinib is licenced to treat adults with mantle cell lymphoma (MCL) who have received at least one prior treatment for their cancer, or adults with CLL or SLL.

Based on the above studies and committee appraisal, in April of last year NICE, (2021) recommended the use of Acalabrutinib as a monotherapy for adult patients with: • 17p deletion or TP53 mutation, or

• No 17p deletion or TP53 mutation, (FCR), or (B-R) is unsuitable.

• Previously treated CLL patients

Administration

Acalabrutinib is a self-administered oral capsule taken twice daily, 12 hourly. Patients are advised to swallow the capsule whole with a glass of water, with or without food. Prior to commencing BTK treatment a detailed history of past medical history, drug allergies and current medications is obtained. The prescriber assesses the patient’s ability to self-administer and will involve family members /carers in education sessions where appropriate. It is important to check for food and drug interactions when prescribing Ibrutinib and Acalabrutinib. Grapefruit and Seville oranges are contraindicated in patients on Ibrutinib and with Acalabrutinib concomitant use of CYP3A inhibitors or inducers should be avoided. Patients on gastric reducing agents require specific advice due to the potential for drug interaction.

BTK inhibitors and Fixed duration treatment

Drug combinations with fixed duration regimens such as Ibrutinib in combination with venetoclax are producing promising progression free survival data and improved patient benefits including limited treatment duration with a shorter period for side effects, outpatient based therapy and reduced financial burden on patients and carers (DePace, 2021).

Supportive Care in CLL

CLL is generally associated with a gradual decrease in antibody-mediated immunity and the development of hypogammaglobulinaemia. Hypogammaglobulinemia is a condition caused by low serum immunoglobulin or antibody levels. Immunoglobulins have the ability to recognize antigens to trigger a biological response and eradicate infectious sources (Huq M, Bhatnagar NK, 2021). Hypogammaglobulinemia is the most common primary immunodeficiency and encompasses a majority of immune-compromised patients. Hypogammaglobulinemia affects up to 85% of all patients with CLL and may affect all immunoglobulin subclasses (IgG, IgA, and IgM). Lower immunoglobulin levels correlate with increased risk for severe and recurrent infections and severity increases with disease progresson. This can be exacerbated by the different treatments a patient receives and the lymphocytopenia associated with same (Hamblin & Hamblin, 2008). It is important to implement strategies to reduce risk; including vaccination, antibiotic prophylaxis, early pre-emptive antimicrobial therapy and immunoglobulin replacement therapies. Furthermore, intravenous immunoglobulins may benefit this population. The dose is generally calculated at 0.4/kg and given intravenously every 4 weeks.

Patient Management/Education

Patients with CLL require strong psychosocial support due to oftenvarying treatments dependent on their disease. Most medications come with a side effect profile and it is vital that patients are educated about this as well as the symptoms associated with disease. It is well documented that adherence to medications is critical to treatment success (Gast & Mathes, 2019). As we move to more oral based regimes it is imperative we impress on our patients the need for adherence with medications and ensure we ask about adherence at every consultation (Usherwood, 2017). The specialist nurse plays a role in educating the patient and their family about the common side effects seen often in many treatments as well as the risks of developing an oncological emergency such as tumour lysis syndrome or neutropenic sepsis. Some specific targeted therapies have rare side effects such as tumour lysis syndrome associated with venetoclax. Nurses need to empower patients with the correct resources to identify these potential complications rapidly and to escalate if necessary.

CLL and COVID

In 2020, the emergence of COVID brought new difficulties for those diagnosed with CLL. CLL generally associated with the older age group is also be linked with immunodeficiency (Montserrat, 2020). This categorises those with a CLL diagnosis as being at risk of severe disease (Montserrat, 2020). With this immunodeficiency it is likely that even with the COVID19 vaccine patients with a diagnosis of CLL will have an impaired or inadequate response with limited antibodies produced (Roeker et al., 2021). However it does appear that response rates and antibody titres do improve with subsequent doses of the vaccine (Herishanu et al., 2022). Due to the limited response in CLL patients, a primary dose followed by a fourth dose 3 months later is recommended (HSE, 2022). Patients are encouraged to inform their healthcare provide should they test positive for COVID19. The proceeding patient care is assessed based on individualised risk, severity of treatment and current treatments available. The use of treatments e.g. sotrivimab, redensivir and paxlovid will be considered based on each individual patient.

The Future of CLL

Small molecule inhibitors have revolutionised CLL treatment. It is anticipated that they will be used in the majority of patients, early after diagnosis and with curative intent. They are generally well tolerated and enable patients to maintain a good quality of life. Given the success of newer agents such as venetoclax in the clinical setting thus far, it is likely that BCL-2 inhibition will take on an increasingly important role in the treatment of CLL going forward.

References available on request

Worse Scores but Similar Patterns of Disease Activity: Interpreting Outcomes in women with axial spondyloarthropathy

Written by Sinead Maguire, Department of Rheumatology, St James’s Hospital Dublin/School of Medicine, Trinity College Dublin; Dr Fiona Wilson, Associate Professor, Physiotherapy, Trinity College Dublin; Phil Gallagher, Department of Rheumatology, St Vincent’s University Hospital & Finbar D O’Shea, Consultant Rheumatologist, St James’s Hospital Dublin/School of Medicine, Trinity College Dublin

Axial spondyloarthropathy (axSpA) is an autoinflammatory arthritis predominantly involving the axial spine.1 The defining feature is inflammatory sacroiliitis, which can be detected on X-ray in radiographic axial spondyloarthropathy (r-axSpA), or on magnetic resonance imaging (MRI) in non-radiographic axial spondyloarthropathy (nr-axSpA).2 This causes symptoms of inflammatory back pain such as nocturnal pain and prolonged early morning stiffness (EMS). Several articular and extra-articular manifestations (psoriasis, inflammatory colitis, and uveitis) are recognized, which can aid in clinical identification of axSpA. Onset is typically in the third decade, with a higher incidence in Caucasians and an association with human leucocyte antigen (HLA)-B27.3 There has been a considerable shift in the sex distribution of axSpA over time. Historically described as strongly malepredominant disease with male to female sex ratios reported as high as 10:1,4 more recent studies have reported ratios closer to 2–3:1.5 One of the major factors contributing to this dramatic shift is the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, which recognized not only r-axSpA, also called ankylosing spondylitis (AS), but also nr-axSpA.6 While initially believed to represent an early stage of disease, longitudinal studies have demonstrated that only 10–40% of nr-axSpA will advance to r-axSpA over time.7 As women with axSpA are more likely to have non-radiographic disease,8 the formal recognition of nr-axSpA allowed these women not only to have a diagnosis of their condition but also to be eligible for treatment previously reserved for r-axSpA only. Despite the evolution of classification and epidemiology of axSpA, much of what is known about axSpA is based on research into men with AS.9 As a result, there remains a considerable underrepresentation of axSpA in women in published research. Combined with the underrecognition of the disease in women,10 there is a significant need for increased awareness and focused research on the sex-specific impact and disease manifestations of axSpA.11 Previous research into women with axSpA has demonstrated significantly worse quality of life, functional ability, and disease activity, as well as a poorer response to treatment compared to men.9 Detailed analysis and characterization of axSpA in women is the first step in optimizing management and outcomes in this significant proportion of the population. The aim of this study is to carry out a focused analysis of disease activity, reporting of disease, and impact of disease in women compared to men with axSpA. This sex-based analysis goes beyond summary comparisons, to capture how axSpA affects women, examine the relationship between functional ability and spinal mobility, and highlight directions for future research.

METHOD

Study population

The Ankylosing Spondylitis Registry of Ireland (ASRI) is a large, observational, national registry of patients with axSpA in Ireland. Currently, the ASRI contains data on 887 patients recruited from 12 rheumatology centres nationally, representing all geographic regions of Ireland. This study includes data on all axSpA patients captured within the ASRI since enrolment began in 2013. To be considered for enrolment in the ASRI, participants must have been diagnosed with axSpA by a rheumatologist and must meet the 2009 ASAS classification criteria for axSpA. This enabled capture of both radiographic and nonradiographic disease. Additional eligibility criteria included: age over 18 years, fluency in English, and presence of full capacity to consent to participation. Once identified, eligible patients were invited to participate in the ASRI. To limit the possibility of selection bias, investigators recruited as many patients as possible from each centre, including participants across the spectrum of disease severity, socioeconomic status, and geographic regions in the country. Prior to enrolment, trained investigators discussed what participation in the ASRI would involve, the purpose of the ASRI, and how the collected information would be used and protected. Participants were encouraged to ask questions of the investigator prior to signing a written consent form. Ethical approval for the ASRI was obtained from local hospital ethics committees from all participating centres, including the Joint Research Ethics Committee for St James’ and Tallaght University Hospital. Trained investigators at each centre were responsible for local oversight of data collection. All data were collected and stored in compliance with national data protection legislation.

Outcomes and assessment

Enrolment consisted of a single clinical visit involving a structured interview, a series of questionnaires to capture patient-reported outcomes (PROs), a focused clinical examination, and chart review. This captured information on baseline demographics (age, sex, ethnicity), details of disease history (age at symptom onset, delay to diagnosis, disease duration), pattern of disease (articular and extra-articular manifestations), and treatments [non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biological agents]. Information on imaging (conventional radiographs, MRI) and serology (inflammatory markers, HLA-B27) was also captured via a medical records review.

Multiple PROs were recorded for each participant. These outcome measures are validated for use in axSpA and capture information on numerous aspects of participants’ daily living.12 PROs captured via self-administered questionnaires were the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI),13 Bath Ankylosing Spondylitis Function Index (BASFI),14 Health Assessment Questionnaire (HAQ),15 and Ankylosing Spondylitis Quality of Life questionnaire (ASQoL).16 Focused clinical examination to assess spinal mobility allowed for calculation of the Bath Ankylosing Spondylitis Metrology Index (BASMI).17 Responses were recorded along a numerical rating system of a visual analogue score. For all outcome measures, higher scores indicated a greater level of impairment or severity.

Statistical analysis

Data were extracted from the ASRI and cleaned for analysis. A series of descriptive comparison analyses was carried out on all participants captured in the ASRI, stratified on the basis of sex. Participants

who did not have sex recorded were excluded from the analysis. A Shapiro–Wilk test was used to assess normality of distribution for all included variables. Differences between continuous variables in the two groups were tested for significance using an independent two-tailed t-test or a Mann–Whitney U-test. A chi-squared test for independence was used to assess statistical significance in differences in categorical variables between sexes. Focused analysis of the BASDAI involved comparison of mean total score and mean component scores between sexes. In addition to statistical testing for significance of differences, components were ranked by average scores within each sex, with average component scores plotted in a spider chart for visualization of results. For the correlation analysis, data from patients with both BASFI and BASMI scores were included. Variables were assessed with a Shapiro–Wilk test for normal distribution, in addition to visual inspection of a scatterplot to determine the presence of a monotonic relationship between the two variables. Once established, a Spearman’s rankorder correlation was run between the two PROs. Records were then split by sex and a Spearman’s rank-order correlation was undertaken to assess the strength of correlation of scores within each sex. An alpha level of p < 0.05 was deemed significant. SPSS version 26 (IBM Corp., Armonk, NY, USA) was used to carry out all statistical analyses in this study.

Results

At the time of data extraction, 886 participants were enrolled in the ASRI. The patient population comprised 232 females (26.2%) and 644 males (72.6%), with a mean ± sd age of 45.9 ± 12.6 years (range 18–85 years), mean disease duration of 19.4 ± 12.3 years, and mean delay to diagnosis of 8 ± 8.5 years. Mean scores for the ASRI population were: ASQoL 6.47 [95% confidence interval (CI) 6.07, 6.95], HAQ 0.53 (95% CI 0.55, 0.6), BASDAI 4.02 (95% CI 3.81, 4.19), BASFI 3.67 (95% CI 3.47, 3.89), and BASMI 4 (3.85, 4.17). The majority of the population was Caucasian (90.2%), with a high prevalence of HLA-B27 positivity (88.7%). No significant differences between sexes were noted in delay to diagnosis (females vs males: 7.42 vs 8.18; 95% CI −2.03, 0.52; p = 0.24) or age at symptom onset (25.9 vs 26.6; 95% CI −2.49, 1.02; p = 0.41). r-axSpA was more commonly encountered in males than females (78.1% vs 70.7%, p = 0.02), while nr-axSpA was significantly more prevalent in females (21.9% vs 29.3%, p = 0.02). In terms of articular manifestations, females had a significantly higher

There was a statistically significant, strong positive prevalence of dactylitis (9.9% vs 5%, p = 0.01) and a trend correlation between BASMI and BASFI scores in towards an increased prevalence axSpA patients [rs(678) = 0.568, p < 0.01], based on of peripheral arthritis (36.2% vs 28.3%, p = 0.08). For extracalculations by a Spearman’s rank-order correlation. articular manifestations (EAMs), females reported a significantly higher prevalence of both uveitis (40.5% vs 35.7%, p = 0.01) and colitis (17.2% vs 7.9, p < 0.01) compared to males. Females with axSpA recorded significantly higher ASQoL (7.51 vs 6.12; 95% CI 0.56, 2.22; p < 0.01) and BASDAI (4.57 vs 3.83; 95% CI 0.37, 1.10; p < 0.01) scores compared to males. They also recorded trends towards worse mean HAQ (0.59 vs 0.51; 95% CI −0.002, 0.16; p = 0.05) and BASFI scores (3.85 vs 3.63; 95% CI −0.22, 0.66; p = 0.32), but these differences were not significant. Spinal mobility, as captured in the BASMI, was significantly less impaired in females than in males (3.58 vs 4.16; 95% CI −0.94, −0.22; p < 0.01).

This analysis of real-world data from a large axSpA patients captured in the ASRI outlines nificant burden of disease in women with is reflected by worse PROs, with a higher prevalence articular and extra-articular manifestations women compared to men with axSpA. The contained within this study provides valuable into the impact of axSpA and how this varies men and women.

Overall, women with axSpA reported worse disease activity and greater impairment quality of life compared to men, captured average BASDAI and ASQoL scores. There non-significant trends towards worse HAQ representing greater impairment of function. women recorded significantly better spinal captured via the BASMI, with a lower 10.00 8.00 6.00 4.00 2.00

I F B A S F I B A S r = 0.619s

Ranking by severity 1 – most severe Fatigue Spinal pain 2 Spinal pain Fatigue 3 EMS EMS 4 Discomfort Discomfort 5 Other pain Other pain 6 – least severe EMS duration EMS duration EMS, early morning stiffness. *Indicates statistically significant difference between sexes (p < 0.05) Figure 1. Mean Bath Ankylosing Disease Activity Index (BASDAI) scores plotted by sex. EMS, stiffness.

.00

.00 2.00 4.00 6.00 8.00 10.00

BASMI

10.00

8.00

6.00

4.00

2.00

.00

.00 2.00 4.00

BASMI

6.00

r = 0.572s

8.00 10.00 Figure 1. Mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) component scores plotted by sex. EMS, early morning stiffness

BASDAI analysis

Females with axSpA reported worse mean total BASDAI (4.6 vs 3.83; 95% CI 0.37, 1.10; p < 0.01), compared to males. Within the BASDAI, females scored significantly worse than males across all components (Fatigue: 5.56 vs 4.51, p < 0.01; Spinal pain: 5.51 vs 4.63, p < 0.01; Other pain: 3.82 vs 3.19, p = 0.01; Discomfort: 4.05 vs 3.29, p < 0.01; EMS: 4.55 vs 3.94, p = 0.01), with the exception of duration of EMS, which demonstrated a nonsignificant trend towards higher average scores in females (3.54 vs 3.12, p = 0.07) (Table 2). Ranking of the BASDAI components by mean scores in order of overall severity revealed identical ranking in both sexes for four of the six components of the BASDAI, with the only variation observed in the component ranked as the most severe. For males this was spinal pain, while for females it was fatigue. Plotting of average component scores for each sex revealed a similar pattern in disease activity (Figure 1).

Spinal mobility and function

Data on both BASMI and BASFI scores were available for 680 patients, and were included in the analysis. Variables were not normally distributed, as assessed by the Shapiro–Wilk test (p < 0.01). The relationship between the two measures was monotonic (as the BASFI score increases, so too does the BASMI score), as determined by visual inspection of the scatterplot. There was a statistically significant, strong positive correlation between BASMI and BASFI scores in axSpA patients [rs(678) = 0.568, p < 0.01], based on calculations by a Spearman’s rank-order correlation. A Spearman’s rank-order correlation analysis following splitting of records by sex showed that the correlation became stronger when assessed within each sex [females rs(144) = 0.619, p < 0.01; males rs(509) = 0.572, p < 0.01] and had a slightly stronger association with in females (Figure 2).

Discussion

This analysis of real-world data from a large cohort of axSpA patients captured in the ASRI outlines the significant burden of disease in women with axSpA. This is reflected by worse PROs, with a higher prevalence of articular and extra-articular manifestations noted in women compared to men with axSpA. The analysis contained within this study provides valuable insight into the impact of axSpA and how this varies between men and women.

Overall, women with axSpA reported significantly worse disease activity and greater impairment of their quality of life compared to men, captured via worse average BASDAI and ASQoL scores. There were also non-significant trends towards worse HAQ and BASFI, representing greater impairment of function. However, women recorded significantly better spinal mobility, captured via the BASMI, with a lower proportion classified as r-axSpA than males with axSpA, although the majority of the ASRI population had radiographic disease. These findings are supported by studies in other large international axSpA cohorts, which reported similar differences between sexes.8, 18–21

Women with axSpA recorded significantly worse total BASDAI scores compared to men, consistent with results from other large axSpA cohorts.8, 19, 20 Further focused analysis of the individual components of the BASDAI demonstrated that this was due to worse scores across all six components of the BASDAI in women, and not driven by higher scores in any single component. Ranking of mean component scores in order of severity between sexes revealed identical ranking of four of the six BASDAI components. The main difference observed in this ranking was the symptom ranked as the most severe within each sex, which was spinal pain in men and fatigue in women. However, when examining the mean scores for these two components within each sex, minimal difference was noted. This suggests that despite differences in total scores, the overall pattern of disease activity, as captured by the BASDAI, is strikingly similar in men and women.

The question of why women record worse PROs, including the BASDAI, still remains. The findings of our analysis demonstrated that women with axSpA had a significantly higher burden of a number of both articular and extra-articular manifestations. This could explain the higher average scores across a number of items within the BASDAI, with a greater burden of inflammatory symptoms potentially contributing to the increased severity of fatigue observed in women with axSpA. Of interest, a previous study examined the topography of pain reporting in axSpA and reporting

Women with axial spondyloarthropathy Women with axial spondyloarthropathy

EMS Duration

Fatigue

6

5

4

3

2

1

0

Females

Spinal Pain Males

Figure 2. Correlation between Bath Spondylitis Functional Index (BASFI) Ankylosing Spondylitis Metrology (BASMI) in (A) females and (B)

EMS Other Pain

Figure 2. Correlation between Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) in (A) females and (B) males

of symptoms in the BASDAI.22 This revealed that the level of pain corresponded to BASDAI total scores in men, while in women the level of pain was linked to assessment of peripheral and axial symptoms when considered separately. These findings led to the recommendation of sex-specific approaches when considering the results of the BASDAI.

The elegance of the BASDAI is in the simplicity of the design, allowing both ease of use for patients and ease of interpretation for clinicians. It is one of the most commonly used outcome measures in clinical practice for monitoring disease activity in axSpA. For this reason, it is essential to ensure that the wealth of information captured by this tool is interpreted in a way that adequately reflects the clinical picture in both men and women with axSpA. It has been well established that men with axSpA tend to have greater limitation of spinal mobility, as captured in the BASMI,23, 24 although this finding seems contradictory to the worse outcomes observed in women with the disease. It stands to reason that level of function would have a strong positive correlation with spinal mobility in axSpA; in clinical terms, patients with greater limitation of spinal mobility tend to have an increased level of functional impairment and vice versa. The results of this analysis by sex indicate that this correlation is more significant if compared separately within each sex, and is notably stronger in females. Men with axSpA have previously been shown to have a higher prevalence of radiographic disease and a worse severity of radiographic disease over time.21, 25, 26 It would be expected that this would result in greater impact on functional ability; however, males in the ASRI demonstrated a non-significant trend towards better BASFI scores compared to females. The stronger correlation noted in women with axSpA in our study indicates that as the level of spinal mobility worsens, a larger change is observed in deterioration of functional ability compared to men. In practical terms, deterioration of spinal mobility appears to have less of an impact on restriction of function in men compared to women with axSpA. Why this variation occurs is not immediately apparent; however, research and advances in motion capture technology may offer further insights.27 Previous studies have proposed that the higher prevalence of centralized sensitization20 and fibromyalgia28 in women could be significant contributors to the differences detected in patient outcomes, as both can lead to chronic widespread pain (CWP).29, 30 Although these issues are more common in women in the general population, they are clinical diagnoses of exclusion.31, 32 The importance of thorough investigation of CWP was highlighted in an Israeli study of known fibromyalgia patients, which found that 10.2% met ASAS criteria for axSpA while up to 25% had imaging findings suggestive of inflammatory disease.33 In patients with a known underlying axSpA, distinguishing between disease activity and CWP can be quite difficult.34, 35 To further complicate this diagnostic dilemma, symptoms of inflammatory pain can vary by sex, with women more likely to describe widespread pain while men report back pain.36 However, it is crucial to ensure adequate treatment of axSpA prior to attributing symptoms to CWP. Recent increased use of the Ankylosing Spondylitis Disease Activity Score (ASDAS) has demonstrated less variation between sexes37, 38 when assessing disease activity in axSpA. A meta-analysis examining the performance of the ASDAS and BASDAI concluded that the ASDAS may not be sensitive enough in the detection of active peripheral disease.39 As peripheral involvement is more common in females with axSpA,5 this introduces a significant sex bias. The ASDAS has proven to be a remarkable tool in detecting disease activity and even in predicting response to biological therapies in males with axSpA.40 However, given the known variation in patterns of disease activity between axSpA in women and men, it may be time to reconsider our evaluation of disease activity in females with axSpA. As suggested by the experience with the ASDAS, differences in reporting of disease activity could be due to the methods used to capture this information. Tools such as the BASDAI and BASFI were developed and validated for AS in predominantly male cohorts.13, 41 The development of sex-specific scores indicative of active disease could help to better compare scores between men and women. In addition, evaluation of outcome measures regarding their ability to capture the burden of articular and extra-articular manifestations in both sexes may provide further insights into the variation in outcomes observed between sexes.

Despite the higher prevalence of several disease manifestations and worse PROs in women with axSpA, medication use was statistically similar between the sexes. This pattern of medication use is not unique to the ASRI, with similarities in the frequency of use of DMARDs and biological therapy in men and women observed in other large cohort studies.8, 18 A 2020 publication examining medication use before and after the recognition of nr-axSpA found no change in use of DMARDs or biologics between males and females.42 This raises the question: Are women with axSpA less likely to be offered treatment? If so, why? Could it be that women’s symptoms are less likely to be considered inflammatory and thus less responsive to treatment? Most importantly, are women with axSpA being undertreated? The most obvious but least understood cause for variations between men and women is hormonal differences.43 Oestrogens have been shown to inhibit production of tumour necrosis factor-α and decrease differentiation of Th17 cells,44 which has significant effects on the inflammatory pathway. However, studies examining the effect of female sex hormone supplementation have failed to show any effect on outcomes in axSpA.45 In addition, we must consider the significant hormonal shifts that the female body undergoes over the course of a lifetime and how they affect disease activity. These include menstruation, pregnancy, and menopause, as data suggest that the overall effects of hormones are concentration dependent.46 Studies on pregnancy in axSpA vary widely, but a high prevalence of active disease during pregnancy, peaking in the second trimester, has been reported.47 Research on menstrual variation in disease activity is incredibly limited; however, one study reported an inverse relationship between oestrogen level and erythrocyte sedimentation rate.48 Further research into the effect of sex hormones in axSpA has the potential to offer significant insight into observed variations in outcomes between sexes and could potentially lead to improved management of axSpA in women. This study has several potential limitations. Data for the analysis contained within this study were cross-sectional in nature owing to the current design of the ASRI. As such, it was not possible to comment on disease progression over time or treatment response. Plans to collect longitudinal data for the ASRI are in place and will further enrich this valuable epidemiological resource. At the time of analysis, ASDAS results were not available for a large proportion of the ASRI population, preventing comparative analysis of the performance of the ASDAS and the BASDAI in our population. This has been studied in detail in numerous axSpA populations previously, and thus sex-specific patterns in reporting of the ASDAS are well established. As fluency in English was required for participation, it is possible that this resulted in exclusion of certain smaller populations from enrolment in the ASRI; however, English fluency in Ireland is 97.5% so this is unlikely.49 Ireland does not have centralized medical records, so it was not feasible to report the percentage of axSpA patients in Ireland captured within the ASRI. However, recruitment was from all major geographic regions of the country and included all levels of the socioeconomic spectrum to reflect the true population as accurately as possible and limit selection bias.

Conclusion

In this large registry-based study of axSpA, women had a higher prevalence of a number of articular and extra-articular manifestations compared to men. They also reported significantly worse disease activity and quality of life. However, the overall pattern of symptom severity as captured by the BASDAI was similar in men and women. Despite better mean spinal mobility overall compared to men with axSpA, limitation of spinal mobility in women with axSpA corresponded to a greater impairment in functional ability. These results suggest that further evaluation of the tools and outcome measures currently used to monitor disease activity are needed to accurately assess the burden of axSpA in women. In addition, further studies are required to examine the impact of significant hormonal changes on disease activity and disease progression in women with axSpA.

References available on request

Osteoporosis: The Silent Disease

It is estimated that up to 300,000 people in Ireland have osteoporosis. Although more common in females who have gone through the menopause, it can also affect men and even children.

It is commonly known as the “Silent Disease”, and is characterised by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased risk of fractures.

Osteoporosis is the most common metabolic bone disease in Ireland and increases the risk of 'fragility fractures'. These fractures occur mainly at the hip, vertebrae, and distal forearm and are associated with significant morbidity, mortality, and reduced quality of life, attributed not only to the fracture itself but also to the high prevalence of comorbidities in this patient population. According to the Irish Osteoporosis Society (IOS), 20% of people aged 60 and above who sustain a hip fracture will die within 6 to 12 months, due to secondary complications and 50% of people over the age of 60 who sustain a fractured hip will lose their independence. Only 15% of people in Ireland are diagnosed with bone loss, leaving an estimated 280,000 people undiagnosed.

Causes of Osteoporosis

According to Theresa Lowry Lehnen, Clinical Nurse Specialist and Associate Lecturer South East Technological University, osteoporosis is multifactorial in origin. “It occurs when there is an imbalance between new bone formation and old bone resorption,” she explains.

Interview with Theresa Lowry Lehnen (GPN, RNP, PhD) Clinical Nurse Specialist and Associate Lecturer South East Technological University (SETU)

“Bone turnover is regulated by the interaction between osteoblasts and osteoclasts. Osteoblasts form new bone and osteoclasts are responsible for bone resorption. Both types of cell are under hormonal regulation. Up to 90 percent of peak bone mass is acquired by age 18 in females and age 20 in males. The amount of bone mass in the skeleton can keep increasing until a person

Modifiable and Non-modifiable Risk Factors for Osteoporosis Modifiable and Non-modifiable Risk Factors for Osteoporosis

Modifiable Risk Factors

Sex hormones: The reduction of oestrogen levels in women at menopause is a strong risk factors for developing osteoporosis. Men have a gradual reduction in testosterone levels as they age. Treatments for prostate cancer that reduce testosterone levels in men and treatments for breast cancer that reduce oestrogen levels in women accelerate bone loss. Endocrine: Too much thyroid hormone can cause bone loss. This can occur in hyperthyroidism or if too much thyroid hormone medication is used to treat an underactive thyroid. Osteoporosis has also been associated with overactive parathyroid and adrenal glands and hypogonadism. Medication use: Long-term use of certain medications, such as glucocorticoids and some anticonvulsants can lead to loss of bone density and fractures. Depo-Provera contraceptive has been proven to cause bone loss, particularly high risk if given during adolescence when bone is being laid down.

Lifestyle factors: An inactive lifestyle can lead to weakened bones and increased risk of osteoporosis.

Cigarette smoking and excessive consumption of alcohol

increases the risk of bone loss and fractures. Poor diet increases the risk for osteoporosis. Low calcium and Vitamin D intake contributes to diminished bone density, early bone loss and an increased risk of fractures.

Eating disorders, severely restricting food intake, low BMI and being underweight weakens bone in both men and women.

Non-modifiable Risk Factors

Sex: Women are much more likely to develop osteoporosis than men. Women have less bone tissue and lose bone faster than men because of the changes that occur with menopause Age: The risk of developing osteoporosis as bones become thinner and weaker increases with age.

Body size: People who have small body frames tend to have a higher risk of developing osteoporosis because they have less bone mass to draw from as they age Ethnicity: White and Asian women are at highest risk. African American and Hispanic women have a lower but significant risk. Genetic: A family history of osteoporosis is a very strong risk factor. People whose parents have a history of fractures also seem to have reduced bone mass and may be at greater risk for fractures.

reaches their late 20’s, at which point, bones have reached their maximum strength and density, known as peak bone mass. As people age the rate of bone resorption by osteoclast cells exceeds the rate of bone formation, so bone weakens.” Theresa adds that the greatest cause of osteoporosis is oestrogen deficiency which results in increased bone turnover in which resorption exceeds formation. “Corticosteroids can also induce osteoporosis in which trabecular bone is particularly affected from suppression of osteoblastic activity,” she says.

Diagnosis

Osteoporosis can be diagnosed by: 1. The presence of a fragility fracture

2. Measurement of bone mineral density (BMD) 3 Bone biopsy: Bone biopsy is a diagnostic procedure restricted to untypical, unclear and complicated cases in evidencebased guidelines on diagnosis and treatment of osteoporosis.

Bone Biopsy is not routinely used and should never be undertaken without consultation with a specialist in osteoporosis and metabolic bone disease.

Theresa continues, “Most fractures occurring after 50 years of age are osteoporotic. All persons presenting with a fragility fracture after 50 years

of age or menopause should be considered as possibly osteoporotic. A detailed history of the fracture occurrence, physical examination and evaluation for other fractures is carried out while noting any presence of back pain, kyphosis, and height loss. Baseline laboratory tests include: Full blood count: Serum chemistry levels: Liver function tests: Thyroid-stimulating hormone level: 25-Hydroxyvitamin D level: Serum protein electrophoresis: 24-hour urine calcium/creatinine: Testosterone (total and/or free) and luteinizing hormone/folliclestimulating hormone. “Additional testing should include measurement of bone mineral density (BMD) and if there is height loss and/or back pain, imaging of the spine. On average BMD is lower in women than in men, because women have smaller bones and smaller trabeculae. Women, as they also go through the menopause lose more bone in their lifetime than men; 50% in females Vs 35-40% in males.”

Osteopenia is the early stage of osteoporosis and places a person at risk of developing osteoporosis. The Irish Osteoporosis Society divides osteopenia into three categories: 1. Mild Osteopenia is a T-score of -1 to -1.49 and usually requires lifestyle changes; however, causes should be investigated and addressed.

2. Moderate Osteopenia is a

T-score of -1.5 to -1.9 which usually requires lifestyle changes. Causes should be found and addressed and the person may require medication, depending on the cause, or if they have had a fragility fracture. 3. Marked Osteopenia is a T-score of -2 to -2.49 which requires lifestyle changes. Causes should be found and addressed and the person may require medication, depending on the cause, or if they have had a fragility fracture.

Treatment

Osteoporosis is treatable and fractures are preventable. “The primary goal of osteoporosis therapy is to reduce the risk of fracture,” she says. “A comprehensive osteoporosis treatment program includes a focus on proper nutrition, exercise, and safety issues to prevent falls that may result in fractures. In addition, medication to slow or stop bone loss, increase bone density, and reduce fracture risk may be prescribed. “The treatment selected for each individual is based on their risk of fracture or re-fracture, causes of osteoporosis, age, DXA scan results and medical history. Assessment of bone markers before and at three and six months after the commencement of treatment will give an earlier indication of the response to treatment.”

Calcium and Vitamin D supplements

Calcium and vitamin D are essential for the prevention and treatment of osteoporosis. “Bone is a major store of calcium and phosphate. Every cell in the body requires calcium. Vitamin D helps to regulate cell growth and the immune system and is essential for the absorption of calcium. It increases the body’s ability to absorb calcium by 30-80%. Vitamin D is the only vitamin required by the body that does not have to be consumed through food or supplements as it is manufactured through the skin, when exposed to sunlight,” adds Theresa. “Supplements are generally only recommended when the daily amounts of calcium and Vitamin D from dietary sources are not being met.

HRT – Hormone Replacement Therapy

Oestrogen replacement for women going through the menopause can help to maintain bone density and reduce fracture rates while they are on the treatment. “There is a direct relationship between the lack of oestrogen after menopause and the development of osteoporosis. Early menopause before age 45 and any long phases in which the woman has low hormone levels and no or infrequent menstrual periods can cause loss of bone mass. Oestrogen therapy and oestrogen with progesterone hormone therapy are approved for the prevention of osteoporosis in postmenopausal women provided there are no contraindications. HRT is not suitable for people who have a history of breast cancer in their family, particularly in early menopausal patients or patients who have had a history of deep vein thrombosis,” she says.

Selective Estrogen Receptor Modulators (SERMs)

Theresa continues, “SERMs, brand name Evista® work in a similar manner to oestrogen on bone, by preventing bone loss in postmenopausal women who do not have hot flushes and provided there are no other contraindications. It is used for the prevention and treatment of osteoporosis in postmenopausal women and to reduce risk of invasive breast cancer in postmenopausal women at high risk or with osteoporosis. Evista helps to maintain bone density and reduce fracture rates, specifically at the spine. It is administered as a 60mg tablet once daily. Evista can be taken with or without food or drink and at the same time as calcium and vitamin D supplements. Appropriate weight bearing exercise is also necessary.”

Monoclonal Antibody

Denosumab, brand name Prolia, is a monoclonal antibody which binds to RANK Ligand, inhibiting the maturation of osteoclasts, therefore protecting the bone from degradation. “Prolia is indicated for the treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Prolia reduces the risk of vertebral, non-vertebral and hip fractures. Prolia is also indicated for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. It is the first choice of drug for those at high risk of hip fracture or who have had a hip fracture over the age of 75 with T scores < −2.5 at femoral neck or with a humeral fracture. The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months into the

Babies

Children Recommended Daily Allowances of Calcium and Vitamin D

Age (years) Calcium (mg/day) Vitamin D (µg/day)

0-1 N/A 5 (as supplement)

1-3 800 10

4-6 800 0-10

7-10

Males & Females 11-14 800

1200 0-10

0-15

15-18

Males & Females 19-64 1200

800 0-15

0-10

65+ 800 10

Pregnancy 1200 10

Lactation 1200 10

thigh, abdomen or upper arm. Patients must be adequately supplemented with calcium and vitamin D.”

Bisphosphonates “Parathyroid Hormone – (PTH)

brand name preotac is a bone forming agent that stimulates the formation of new bone administered as a daily 100mcg dose, subcutaneous injection in the thigh or abdomen for 24 months. It can only be prescribed by a Consultant, as it is a ‘high tech’ drug for severe osteoporosis. It is contraindicated in patients with cancer. Patients need to have follow up tests done at 1, 3 and 6 months, for elevated serum or urinary calcium. The patient should then have a repeat DXA scan and a new treatment plan should be implemented at the end of the course of treatment.

“Parathyroid hormone -

(PTH) teriparatide, brand name Forsteo is a recombinant human parathyroid hormone 1-34 and a bone forming agent that stimulates the formation of new bone. Foresto is a ‘high tech’ medication that can only be prescribed by a Consultant. It is given as a daily 20mcg, subcutaneous injection in the thigh or abdomen for 24 months. The patient should then have a repeat DXA scan and a new treatment plan should be implemented at the end of the course of treatment. PTH is usually recommended for those with severe osteoporosis or fractures and those who cannot tolerate other medications. Forsteo can help with the pain of vertebral fractures and the reduction of vertebral and nonvertebral fractures in women.”

Theresa reflects that other treatments for osteoporosis can include Kyphoplasty and Vertebroplasty: “Kyphoplasty is a surgical treatment involving a balloon being placed into the fractured vertebrae, followed by “bone cement” being injected into the balloon. Vertebroplasty is a non-surgical treatment involving a needle with “bone cement” inserted into the fractured body of the vertebrae under imaging guidance. The decision to perform these techniques is made by a multi-disciplinary team to ensure that this is the correct approach to managing the collapse. “Many of the consequences of osteoporosis, particularly vertebral fractures, are associated with severe pain. Patients with established osteoporosis should be treated for pain relief and physiotherapy offered for the secondary effects of osteoporosis. Pharmaceutical and non- pharmaceutical measures can be used to alleviate pain. Patients should be advised of all the options, and encouraged to try different approaches until they find what works best for them.

“Prevention of osteoporosis should ideally start in utero. Childhood and teenage years, are critical periods for developing a strong healthy bone, especially before puberty, between the ages of 8 and 12 years. If good peak bone strength is achieved in early childhood, the risk of osteoporosis in later life is reduced.”

References available on request

Rheumatology News

Calls to Increase Number of Orthopaedic Consultants

The HSE needs to almost double the number of Orthopaedic Consultant posts to reach the recommendation of a major health report published in 2003, almost two decades ago, and meet current and projected demand. The Hanly Report, published when Bertie Ahern was still Taoiseach and Micheál Martin was Minister for Health, made it clear that Ireland needed at least 4 Orthopaedic Consultants per 100,000 population to provide a minimum standard of care.

Today, in 2022, there are just 2.4 Orthopaedic Consultants per 100,000 population. In contrast, in the UK and New Zealand, there are more than 6 Orthopaedic Consultants per 100,000 people. The HSE has estimated that the number of Orthopaedic Consultants will need to almost double to around 230 posts by 2028 to address current shortfalls and meet increased patient demand. Ms Eimear Conroy, Consultant Orthopaedic Surgeon at University Hospital Kerry, said that the chronic lack of orthopaedic consultants, available hospital beds, and theatre operating space are the main causes of the unacceptable delays in providing care. This is resulting in very serious consequences for patients. There are currently over 11,700 patients nationally waiting for Orthopaedic surgery and 76,000 waiting for an orthopaedic outpatient appointment. This represents an increase of 24,700 (48%) over the past 7 years, and of 7,300 (11%) since the beginning of the pandemic. In Kerry alone, Ms Conroy said, there are more than 2,000 people waiting for an orthopaedic outpatient appointment. “Having someone wait for more than eighteen months to be seen so that we can provide them with a solution is heart-breaking,” said Ms Conroy. “Excessive wait times can lead to the development of chronic pain. If a patient with a rotator cuff injury hasn't used their arm properly for a year, they'll have a huge amount of dysfunction, making recovery from any intervention extremely difficult. People in these situations definitely have worse outcomes, on top of a standard nine to 12-month recovery.” Pandemic backlog, triaging, and consultant numbers

Professor Alan Irvine, President of the IHCA, said: “When the Hanly Report was published almost twenty years ago, its author said that failure to implement its recommendations was “not an option.” Professor Alan Irvine, President of the IHCA

“In 2022, the results of that failure are clear. Sick patients are waiting longer, outcomes are worsening, and we are still no closer to ensuring a minimum standard of timely orthopaedic care due to the severe shortage of Orthopaedic surgeons and the hospital facilities they need. Given the backlog of care caused by the pandemic and the continuing Government policy which discriminates against new Consultants contracted since 2012, this problem is simply going to get worse. “The solution to this problem is clear and very well communicated by hospital Consultants across Ireland: we must quickly appoint additional permanent Consultants and address the long-standing issues of pay inequity and poor working conditions. The longer this Government reneges on its commitments to Consultants and dithers on a resolution, the more frustrated and ill hundreds of thousands of Irish patients will become. “This should not be an issue in twenty-first-century Ireland. The UK and New Zealand, the latter with a population similar to ours, are able to appoint a sufficient number of Orthopaedic Consultants. Other developed countries consistently provide timely, effective care to patients, as well as reasonable, efficient, and empathetic working environments for their doctors and other healthcare staff.

Serum MicroRNA Signatures as Diagnostic Tools that Distinguish Rheumatoid and Psoriatic Arthritis

Written by Professor Ursula Fearon and Órla Tynan, Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin

Professor Ursula Fearon Órla Tynan

Inflammatory Arthritis (IA) constitutes a diverse range of autoimmune conditions sharing characteristic features including soft tissue swelling, joint inflammation and subsequent bone and cartilage destruction of a debilitating nature. Unfortunately, the prevalence of IA in Ireland is 1-2%, of which Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) encompass two of the most common forms. While common pathogenic mechanisms are involved in driving inflammation in both arthropathies there are significant differences, including the presence/absence of autoantibodies, synovial vascularity, presence of skin psoriasis, immune cell infiltrates, molecular signalling, the pattern of periarticular inflammation, bone erosion and new bone formation at the entheseal complex of peripheral and spinal joints. These differences may explain distinct clinical manifestations of the two diseases, and more importantly, explain different responses to specific therapies impacting on disease outcomes and prognoses. While there are common treatments that are utilised as first line treatment for RA and PsA, including methotrexate and tumor necrosis factor inhibitors (TNFi), their response to other biologic therapies differs, with Rituximab and anti-IL-6R only utilised for treatment of RA, while anti-IL-17A and antiIL-12/IL23 are utilised for PsA. Furthermore, the multifaceted nature of synovial inflammation, joint destruction, enthesitis, axial disease, and skin manifestations often makes diagnosis, prediction of disease progression and prediction of response difficult. However, currently there are few biomarkers that distinguish disease pathotype or response to therapy. Thus there is a need for the identification of noninvasive, convenient, and reliable biomarkers for the diagnosis and prediction of treatment response outcomes in autoimmune disease.

‘MicroRNA (miRNA)’ which are small endogenous regulatory RNA molecules have emerged as potential therapeutic targets and biomarkers in autoimmunity. MiRNA bind to complementary sequences on messenger RNA (mRNA), and they function generally by suppressing the translation of target proteins (Figure 1A). In the context of Inflammatory Arthritis, their effects generally down regulate proteins involved in keeping the immune response in-check, thus once unchecked this allows for an uncontrolled immune response which leads to cartilage

“This study has demonstrated the potential for serum miRNAs to be instrumental in a diagnostic capacity in a clinical setting”

degradation and bone erosions. Over the last 10 years numerous studies have demonstrated that altered miRNA expression in Inflammatory Arthritis influences immune cell regulation, enhances pro-inflammatory signaling pathways, and leads to the overproduction of proinflammatory proteins that are critical to driving the pathogenic mechanisms involved in joint destruction and subsequent joint disability. However, more recent studies have identified that, in addition to their localization within the cell, miRNAs are also present in extracellular fluids such as serum, plasma, and synovial fluid, and through the circulation can be transported to specific cell types or tissues to carry out their function. Interestingly, it is now known that circulatory miRNAs are more stable than cellular miRNAs and are emerging as potential non-invasive biomarkers for disease. Therefore, in this study we examined the expression profile of miRNAs, specifically focusing on a defined immunology miRNA panel, to identify a potential circulatory miRNA signature that could distinguish RA from PsA, in addition to evaluating the potential implication for disease pathogenesis. To do this we utilised the clinically amenable FirePlex Biofluids miRNA assay. While previous approaches employed to detect circulating miRNA relied on laborious isolation techniques and required high sample volume to obtain sufficient miRNA and thus limited the potential use in the clinical setting, the FirePlex platform allows for miRNA detection in very small volumes of blood (~20μl) that can be measured by automated flow cytometric analysis, thus allows for robust, reproducible results that can easily be assessed in clinical labs on hospital sites. We obtained serum samples from patients with active RA and PsA, in addition to healthy controls (HC) and performed an immunological miRNA analysis using the FirePlex miRNA Immunology-V2 panel (FirePlex Bioworks Inc.). We identified a miRNA signature of seven miRNA (miR-126-3p, miR-29b-3p, miR-22-3p, miR-223-3p, miR320a, let-7g-5e, and let-7g-5p) that were significantly elevated in RA serum compared to both PsA patients and HC. Further computational bioinformatic analysis demonstrated that the miRNA expression distribution was associated with a dominant skew towards 3 specific miRNA in RA vs PsA: miR-29b-3p, miR-223p and miR-223-3p. In contrast, we identified three miRNA that were significantly elevated in PsA compared to RA which included miR-203a-3p, miR-185-5p, and miR-151a-5p. To examine sensitivity/specificity of miRNA to either RA or PsA we performed Receiver Operating Characteristic (ROC) curves, that demonstrated high sensitivity and specificity of each miRNA signature to either that of RA or PsA.

As highlighted above, miRNA regulate their function by targeting different proteins. Therefore, we next utilised computational analysis (DIANA miRPATH tool) to identify the specific genes and inflammatory pathways targeted by the identified miRNA signatures, followed by STRING software analysis which allowed the identification of target gene interactions. Functional pathway analysis of the RA miRNA signature (miR29b-3p, miR-22-3p and miR223-3p) showed significant association with pathways that regulate key pathogenic mechanisms involved in synovial inflammation. Specifically, the miRNA signature was involved in mediating a diverse number of cellular processes including metabolism, cell growth, invasion, and proliferation, all of which contribute to the uncontrolled proliferation and activation of stromal cells within the inflamed joint, particularly for RA which is known to have a more aggressive synovial invasive layer compared to that of PsA. While few studies have examined these miRNA in RA, studies have shown that increased levels have been associated with RA disease activity and development of RA in susceptible individuals demonstrating positivity for ACPA antibodies. Furthermore, the RA miRNA have also been associated with regulation of matrix metalloproteinases, invasive signalling pathways, and chondrocyte dysfunction, key mechanisms associated with cartilage breakdown. Interestingly, the miRNA signature associated with PsA regulate angiogenic function and specific signalling pathways associated with blood vessel migration, leukocyte adhesion and trans-endothelial cell migration, a feature more pronounced in PsA. Indeed, many of the pathways associated with the PsA miRNA are also associated with cancer, and specifically involved in driving angiogenic processes. In particular, studies have shown that miR-151a-5p is associated with the Notch signalling pathway, which we know is increased in the PsA joint and in psoriasis skin lesions and is critically involved in the regulation of the pathogenic dysfunctional blood vessel pattern observed in PsA. Furthermore, miR-185-5p is associated with high levels of the VEGF receptor, which activates the Notch signalling pathway in endothelial cells that line the blood vessels. The PsA miRNA were also associated with the Hippo signalling pathway which again target genes associated with angiogenic growth factor regulation and cellular adhesion. Interestingly, the distinct synovial blood vessel pattern observed in the PsA joint (elongated, tortuous and dilated) is similar to the dysfunctional blood vessel patterns observed in malignant tumors. This is in stark contrast to RA where the blood vessel pattern is defined by straight, regular branching synovial vessels. The implications for these different blood vessel patterns are still unclear but must be involved in differential recruitment of immune cells to the joint, in addition to differential levels of nutrients entering the synovial cavity. In summary, this study has demonstrated the potential for serum miRNAs to be instrumental in a diagnostic capacity in a clinical setting. The benefit of a serum miRNA signature as a biomarker utilising this method is that it is a minimally invasive approach requiring a minimal amount of blood that would be sufficient for diagnosis using the FirePlex assay. This assay has clinical potential as it is a highly reproducible test which requires only minimal serum that can simultaneously detect a panel of selected miRNAs, without the need for laborious RNA purification and amplification steps which can lead to lack of reproducibility in the clinical setting. This platform would also be an efficient, convenient, and cost-effective approach. The serum miRNA signatures identified in this study discriminated RA from PsA, and importantly from that of healthy subjects (Figure 1B). However, further investigations are required in larger multicentre patient cohorts for validation. If they prove to be consistent, it would be interesting to examine in future approaches if the circulatory miRNA signatures could be useful not only in the monitoring of disease progression but also as pharmacodynamic biomarkers of treatment response. In conclusion these findings are valuable, and the identification of reliable biomarkers that may facilitate pathotype diagnosis would facilitate interventions with more targeted therapeutic approaches, thus alleviating symptoms, and potentially inducing earlier disease remission whilst ultimately enhancing patient quality of life. Acknowledgements: These studies would be impossible to perform without patient involvement, therefore we would like to thank all patients who contributed to this study.

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miR-29b-3p, miR-203 miR-22-3p, miR-185p miR-223-3p, miR-151a5p