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Hydroxychloroquine (HCQ), the controversial immunosuppressive therapy that made headlines earlier in the coronavirus disease 2019 (COVID-19) pandemic when it was floated as potential treatment option, has been a topic of interest for rheumatologists concerned about potential cardiovascular (CV) safety and risks associated with the drug. A recent study published in 

however, found no association between hydroxychloroquine therapy and heart failure in patients with rheumatoid arthritis (RA) and other rheumatic diseases, such as systemic lupus erythematous (SLE).

HCQ, a popular disease-modifying anti-rheumatic drug (DMARD), lists cardiotoxicity as a rare, yet potentially life threatening, side effect. In this population-based study, investigators examined the relationship between this therapy and the risk of developing heart failure (HF) in patients with RA. This is of particular concern to rheumatologists because “the inflammatory burden characteristic of RA has been linked to the increase risk of CV disease, including HF. HF development in RA patients is multifactorial, with contribution from cardiovascular risk factors and RA disease-related factors. The relationship between HCQ and HF has been controversial, with one argument suggesting a cardioprotective effect of HCQ, while the counterargument supports a cardiotoxic role.”

Using data from the Rochester Epidemiology Project to perform the nested case-control study, investigators pulled cases of patients with RA who developed HF after diagnosis in Olmsted County, Minnesota, between 1980-2013. All patients were 18 years of age or older and fulfilled the American College of Rheumatology (ACR) classification criteria. Patients with HF were marked as “HF cases,” while those without HF were labeled as “non-HF controls.” Both groups were matched 1:1 for age, sex, and year of RA diagnosis. In order to calculate HCQ duration and cumulative dose, start/stop date data and dosage changes were collected from medical records and reviewed. Medical records also allowed investigators to dig deeper to discover potential CV risk factors, including age, smoking, hypertension, diabetes, and dyslipidemia. A patient’s glomerular filtration rate (GFR) was calculated from creatinine values obtained around the same time as the HF diagnosis within ±90 days.

Beginning with a cohort of 1078 patients with RA, the study focused on 143 RA HF cases (mean age 65.8 years, 62% female) and another 143 non-HF controls (mean age 64.5, 62% female). Both groups were matched for similar demographics and RA characteristics, with a multimorbidity of hypertension and diabetes mellitus being the most prevalent in the HF cases. A total of 71 HF cases and 69 non-HF controls used HCQ at some point prior to their HF diagnosis or index date. The age-adjusted logistic models confirmed that HCQ usage prior to index date did not increase a patient’s risk of developing HF.

Standard doses of HCQ for patients with RA ranged from 200 to 400 mg daily. The median (IQR) cumulative dose for patients prior to their index date/HF diagnosis was 371 g and 203 g, respectively. A cumulative dose of at least 300 g was similar for both HF cases and non-HF controls (55% and 54%, respectively). Investigators found that neither HCQ cumulative dose (<300 g or ≥300 g) was associated with HF. Additionally, taking HCQ prior to the index was not associated with an increased chance of developing HF.

The biggest limitation of this study was that it was a retrospective, and therefore could only use information attained in medical records to draw conclusions. However, investigators assure, “availability of complete medical records from all healthcare providers in the area and standardized case ascertainment likely minimized this bias.” Additionally, there were no follow-ups for patients after HCQ discontinuation and information on biological markers for HF and other cardiovascular statistics were not available. Further, cases of hypertension and diabetes mellitus were higher for patients with HF, which could lead to an imbalance of baseline characteristics. Investigators do not believe this is statistically significant, however, given the outcome of the study.

Although the results of the study are promising, more research is needed in order to understand the impact and safety of higher cumulative doses to determine whether HCQ can lead to the development of HF and cardiotoxicity in patients with RA and other rheumatic diseases. This information can help investigators further categorize and identify high-risk patients that may need cardiovascular screening before HCQ therapy is introduced.

Sorour AA, Kurmann RD, Shahin YE, et al. Use of Hydroxychloroquine And Risk of Heart Failure in Patients With Rheumatoid Arthritis [published online ahead of print, 2021 Jan 15]. 

. 2021;jrheum.201180. doi:10.3899/jrheum.201180

Articles

A recent study published in The Journal of Rheumatology found no association between hydroxychloroquine therapy and heart failure in patients with rheumatoid arthritis (RA) and other rheumatic diseases, such as systemic lupus erythematous (SLE). 

Study Results Determine No Link Between Hydroxychloroquine and Heart Failure in Patients With Rheumatoid Arthritis 

Adherence rates for patients with rheumatoid arthritis (RA) taking methotrexate (MTX) can be improved with simple techniques including drug education and messaging. Simple reminders about the benefits of treatment and warnings of adverse reactions associated with non-adherence, in conjunction with motivational interviewing (MI), cumulatively halved non-adherence rates in a UK study published in the Oxford

MTX is the “cornerstone” therapy for patients with RA, but a drug will never be able to reach its full potential if it is not taken consistently, meaning that improving adherence rates is a priority in order for patients to obtain the best results possible.

But it goes beyond individual health benefits, investigators explain. “Given that failure to respond to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) is part of the eligibility criteria for biologic therapies in the UK, and given the cost differential of MTX compared with biologic drugs, there is a health economic argument to optimize adherence to MTX in order to reduce health costs,” the research team wrote.

Investigators created a team consisting of 2 rheumatologists, an academic clinical lecturer in rheumatology, a health psychologist, and a senior specialist nurse. The group developed an anonymous self-report questionnaire to capture patients’ non-adherence information. The data were collected for 3 months prior to the official start of the study, monthly for the subsequent 2 years, and then sporadically during the third year. In order to test adherence to MTX, investigators utilized both the questionnaire, as well as a biochemical assay to measure MTX serum levels (tested before and 2.8 years after introducing the changes).

The first step in understanding the potential barriers to adherence was to create a process map. This outlined the pathway from prescribing MTX to establishing therapy. Next, staff members were required to take mandatory MI trainings to learn the “patient-centered consultation technique designed to elicit the patient’s own goals and plans for behavior change.” Physicians were able to schedule 1:1 drug education consultations for patients with whom they had concerns regarding non-adherence. An “agenda-setting tool” was developed but was later discarded as patients did not find it to be a helpful strategy for encouraging adherence. Additionally, patients were informed of the risks and benefits of the treatment and learned strategies to improve adherence. These educational points were placed in doctors’ offices to reinforce these messages. Colleagues held weekly meetings to discuss data and feedback as a means to continue long-term momentum.

Blood samples were taken from 20 patients already receiving oral MTX in October 2016 and 21 patients in June 2019. Samples were tested for MTX levels and patients were asked about their MTX usage (day and dose). Reasons for non-adherence included forgetting and stopping treatment due to illness. Physicians were able to use this information to support adherence by teaching patients how to set reminders on their phones and assuring them that they did not need to stop treatment unless they were prescribed antibiotics.

The interventions continued to focus on MI training, consistent information delivery, and messaging, as well as the deployment of a summary bookmark. Between June and August 2016, self-reported non-adherence to MTX was 24.7%. After the introduction of the new methods, between April 2018 and August 2019, non-adherence rates dropped to an average of 7.4%. Reinforcing the key areas (benefits, alcohol guidance, and importance of adhering to the medication) improved from 64% (September 2016) to 94% (January 2018). Non-adherence measured via the biochemical assay was reduced from 56% (September 2016) to only 17% (June 2019). Remission rates improved from 13% in 2014/15 to 37% in 2017/18, which resulted in saving £30,000 per year. This number was estimated by comparing the actual new biologic starters with the expected numbers.

The biggest limitation was the lack of a prescribing database before investigators introduced intervention techniques, as they could not accurately correlate improved adherence with increased persistence on MTX. However, data did show that there had been fewer new patients on biologic drugs than had been expected. Another weakness was that although non-adherence generally means poorer response to treatment, this data can only relate to patients initially starting MTX treatment. As investigators had no prescribing database at the beginning of the study, they could not make similar connections for patients already established on MTX.

Moreover, the study advised patients that they should limit alcohol intake to 6 units per week as liver function may be compromised as a result of MTX treatment and excessive alcohol intake. However, as the population anonymously screened for adherence was not the same at each point, investigators could not say with certainty that this constraint played a role in the decrease. This means that they would not be able to suggest that these recommendations be implemented at other centers moving forward.

Despite the limitations of the study, non-adherence rates were significantly reduced in patients observed throughout the 3 years, indicating that the methods developed and deployed were successful. “The Hawthorne effect of behavior modification as a result of being observed is likely to have played a role in improving adherence rates, and one of the most important culture changes in the department was that clinicians asked about adherence more often,” investigators hypothesized. “We see this as a positive benefit, as the results show that improved adherence correlated with improved remission rates over the same time periods.” They added, “By using a combination of personalized and population-level approaches and maintaining momentum through regular meetings, we were able to demonstrate long-term sustained improvements.“

Barton A, Jani M, Bundy C, et al. Translating research into clinical practice: quality improvement to halve non-adherence to methotrexate. 

. 2021;60(1):125-131. doi:10.1093/rheumatology/keaa214

Despite the limitations of the study, non-adherence rates were significantly reduced in patients observed throughout the 3 years, indicating that the methods developed and deployed were successful. 

Methotrexate Adherence Rates Improve After Implementation of New Strategies

The US Food and Drug Administration (FDA) has approved voclosporin (LUPKYNIS, Aurinia Pharmaceuticals) for the treatment of 

 nephritis (LN), a condition that is associated with kidney damage, kidney failure, cardiac events, and death. Voclosporin, the first FDA-approved oral therapy for this condition, has shown significantly improved renal response rates when compared with standard therapies.

Currently, 200,000-300,000 people in the United States are living with LN, a serious complication of systemic lupus erythematosus (SLE), with the disease disproportionately affecting Black, Asian, and Hispanic individuals. Voclosporin, in combination with an existing immunosuppressive therapy regimen, works to safely and effectively treat adult patients with LN.

The development of voclosporin stemmed from Aurinia’s existing clinical studies in LN: the AURORA Phase 3 study and the AURA-LV Phase 2 study. Over the course of 52 weeks, patients receiving voclosporin had vastly improved outcomes when taken in combination with standard-of-care therapy (SoC), mycophenolate mofetil (MMF), and low dose steroids.

For both Phase 2 and 3 studies, 533 patients with LN were given voclosporin 23.7 mg or a placebo twice a day in conjunction with SoC and a MMF target dose of 2 g daily. For the first 2 days, patients received intravenous (IV) methylprednisolone (up to 1 g), with a taper of oral corticosteroids after that. Oral prednisone dosage was 20 mg/day for patients weighing <45 kg and 25 mg/day for patients ≥45 kg. By week 16, their target goal was a dose of 2.5 mg/day. Patients (Class III, IV or V) were required to have baseline eGFR >45 mL/min/1.73 m

The phase 3 study demonstrated that voclosporin was twice as effective at achieving a complete renal response than the SoC group. Patients also obtained a 50% reduction in urine protein creatinine ratio (UPCR), the measurement used to monitor protein in the kidneys, twice as fast with more achieving a complete renal response by 24 weeks when compared with SoC. Early intervention and kidney response (marked by UPCR) have been historically linked to better outcomes and prevention of kidney damage. The study found that patients receiving voclosporin had improved response rates across all classes of LN.

3%) included a decrease in glomerular filtration rate, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, abdominal pain, dyspepsia, alopecia, renal impairment, mouth ulceration, fatigue, tremor, acute kidney injury, and decreased appetite.

Aurinia Pharmaceuticals has recently launched Aurinia Alliance, a support program, to help patients and physicians learn more about voclosporin, including how to navigate insurance and medication costs.

Up until this point, treating patients with LN has been incredibly challenging as the limited therapies available have been shown to be highly toxic and not significantly effective. “The [voclosporin] approval marks a turning point for the lupus nephritis community – patients, caregivers, families, and healthcare professionals – all of whom we thank for their partnership in the development of this innovative novel treatment," Peter Greenleaf, president and chief executive officer of Aurinia Pharmaceuticals, said in a 

. "We are thrilled to bring [voclosporin] to the people impacted by this devastating condition.”

Voclosporin (LUPKYNIS), in combination with an existing immunosuppressive therapy regimen, works to safely and effectively treat adult patients with lupus nephritis. 


FDA Approves First Oral Therapy Voclosporin for Lupus Nephritis

Scientific breakthroughs in immunology have fueled a renaissance in the treatment of diseases like rheumatoid arthritis (RA) and psoriatic arthritis (PsA). The practice of rheumatology has been transformed from providing symptomatic therapy as patients’ disease progressed unabated, to modifying the underlying pathophysiology to provide not only symptom relief but also the potential to prevent disability for patients.

Over the course of my career in rheumatology, I have witnessed and been privileged to contribute to the growing understanding of immune system dysfunction in rheumatic diseases, and more broadly in immune-mediated diseases. For example, development of therapies that inhibit the pro-inflammatory cytokine tumor necrosis factor (TNF) alpha revolutionized the way we treat rheumatic diseases like RA and PsA. Despite these advances, however, most patients do not achieve lasting remission. Additionally, unmet needs and limited treatment options in other rheumatic diseases, such as systemic lupus erythematosus (SLE), lupus, Sjogren’s syndrome, and scleroderma, also persist.

PsA has been a particular challenge because it is a heterogeneous disease characterized by inflammation not just in the joints, but also in the skin (psoriasis), as well as soft tissues (enthesitis and dactylitis).

 An ideal treatment for PsA should provide lasting efficacy for multiple disease domains with a tolerable safety profile. Because PsA is particularly variable from patient to patient, and as of yet we cannot predict the efficacy of a given therapy for a specific patient, it is beneficial for the physician to have therapies targeting multiple different mechanisms. If a patient is not in remission on his or her current therapy, the physician needs alternative therapies to treat the patient.

Treating Rheumatic Disease in New Ways: The Pathway Approach

Recent advances in technology have provided new insights into how the immune system works in health and disease.For example, we can examine the behavior of a single cell and now have the computational power to combine the information from thousands of cells to enhance our understanding of biology. In addition, advances in genetics have permitted identification of more disease-associated genes, tantalizing clues to disease pathogenesis. We are harnessing these new methods to identify additional pathways that are central to driving disease. Every new pathway discovered unlocks novel targets for the development of future therapies for patients with immune-mediated diseases.

As we start to focus on key pathways in disease, it becomes clear that many pathways are shared across different diseases. In the past, this was determined empirically. For example, we learned that certain immune-mediated diseases, such as RA, PsA, ankylosing spondylitis and inflammatory bowel disease could be treated by inhibiting TNF alpha, but others, such as systemic lupus erythematosus (SLE), could not.

 Our advances in studying the immune system should allow us to predict with greater certainty the relevance of particular pathways in immune-mediated diseases.

Focusing on key pathways allows us to move away from defining diseases by organ and anatomical region. Just as the paradigm shifted from targeting specific tumors based on their tissue of origin to targeting biological hallmarks of cancer growth and persistence, we are zeroing in on the underlying mechanisms driving immune-mediated diseases, targeting the pathways implicated in diseases like psoriasis and PsA. By marrying unmet need to the mechanisms, we can expand the reach of drugs targeting relevant pathways to all patients who may benefit. In essence, this is a shift from the “one drug, one disease” mindset of the past to a “one drug, many diseases” approach.

As we continue to build upon our understanding of the molecular mechanisms of immune-mediated diseases, we expand our ability to develop smarter, more targeted therapeutic strategies addressing chronic inflammation across multiple disorders.

We are at another pivotal moment in immunology. By understanding key pathways that drive immune-mediated diseases, we can develop more potent and specific therapies. This will help us not only increase the number of patients achieving remission in diseases like RA and PsA but will also help develop better therapies for patients who currently have limited therapeutic options, including patients with SLE, Sjögren's syndrome, and scleroderma.

Today, patients living with immune-mediated disease show great fortitude as they see improvements in treatment options but still wait patiently for science to progress even further. Their expectation should be a future in which these patients can live disease- and symptom-free and enjoy a normal quality of life, without pain and disability. It is this aspiration and resilience that motivates and inspires all of us in our relentless pursuit of new and better medicines. We are a large community of people thinking about the same problems from different perspectives, mobilizing multiple facets of expertise in medicine, biology, genetics, and technology and driven by a mission to restore the balance of the immune system to create a lifetime of vibrant health for the millions of people living with immune disease. These are indeed exciting times.

Alyssa Johnsen, MD, PhD, is Vice President and Rheumatology Disease Area Leader for the Immunology Therapeutic Area at Janssen Research & Development, LLC. In this role, Alyssa is responsible for driving scientific leadership in rheumatology and related immune-mediated conditions, overseeing innovative compounds across multiple phases of development.

Alyssa received her bachelor’s degree in chemistry at Duke University and her PhD in immunology and MD at Case Western Reserve University. She completed residency training in internal medicine at the Massachusetts General Hospital and a fellowship in Rheumatology at the Brigham and Women’s Hospital.

1. McInnes IB. Psoriatic arthritis: embracing pathogenetic and clinical heterogeneity?. 

2. Li P, Zheng Y, Chen X. Drugs for Autoimmune Inflammatory Diseases: From Small Molecule Compounds to Anti-TNF Biologics. 

. 2017;8:460. Published 2017 Jul 12. doi:10.3389/fphar.2017.00460

Alyssa Johnsen, MD, PhD, shares her insight on the importance of understanding key pathways that drive immune-mediated diseases, which can help rheumatologists develop more potent and specific therapies for patients with rheumatic disease. 

If Remission Is Our Goal, Rheumatology Must Embrace the Importance of Studying New Mechanisms 

Zoledronic acid is associated with a 25% increased risk of atrial fibrillation during its first year of use for osteoporosis compared to treatment with denosumab, shows a US study published in 

As Randomized placebo-controlled trials of the bisphosphonate zoledronic acid in osteoporosis have produced conflicting results on whether zoledronic acid is associated with an increased risk of atrial fibrillation, investigators in Boston, MA, set out to examine the association in practice. They used real-world data to compare the incidence of atrial fibrillation in patients during the first year of zoledronic acid use with the incidence in patients who took denosumab, a monoclonal antibody to receptor activator of NF-κB ligand (RANKL) which has no known risk of atrial fibrillation.

They examined data on privately insured Americans aged ≥ 50 years with no known arrhythmia or advanced kidney disease, who were initiated on zoledronic acid between January 1, 2010, and June 30, 2019, for osteoporosis or malignant bone disease. These patients were 1:1 propensity score (PS)-matched with patients initiated on denosumab during the same time period.

“Based on 16,235 pairs of zoledronic acid and denosumab initiators (for osteoporosis), we found a greater risk (HR 1.25, 95% CI 1.04-1.50) of atrial fibrillation with zoledronic acid vs denosumab: an absolute risk difference of 3.69 events per 1000 person-years,” said Seoyoung Kim, MD, ScD, Associate Professor of Medicine and Director of the Program in Rheumatologic, Immunologic, and Musculoskeletal Pharmaco Epidemiology at Brigham and Women's Hospital/Harvard Medical School. “We, however, found no difference in the risk of stroke or transient ischemic attack (TIA), or risk of non-vertebral fracture between the two drug groups.”

The mean age of patients in the osteoporosis cohort was 71 years and 93% were women. During the first year of use, zoledronic acid was associated with an incident rate of 18.6 cases of atrial fibrillation per 1000 person-year, whereas denosumab was associated with 14.9 cases per 1000 person-years. A similar level of increased risk of atrial fibrillation for zoledronic acid vs denosumab was also found in the 7732 malignancy-related bone disease pairs (HR 1.19; 95% CI 1.00 to 1.43; p = 0.06) but was not statistically significant in this group.

Many previous studies examined the risk of atrial fibrillation among all kinds of bisphosphonate users, but the inclusion of just IV zoledronic acid initiators and a single active comparative treatment, ie, denosumab, was a strength of the study. Kim emphasized, “this type of approach, use of active comparator, is a strength as it can reduce confounding bias in observational studies.”

It has previously been proposed that an effect on calcium might be responsible for the association of increased risk of atrial fibrillation with zoledronic acid, but the findings of this study throw doubt on that hypothesis. “Since both zoledronic acid and denosumab can affect serum calcium levels, it is unclear why zoledronic acid would lead to more atrial fibrillation events,” Kim explained.

She stressed, “While further studies are needed to better understand the mechanism for atrial fibrillation among zoledronic acid users, clinicians should be aware of a modestly increased risk of atrial fibrillation upon initiating the treatment with zoledronic acid. This potential harm should be discussed with patients when making a treatment decision – particularly among patients at high risk for atrial fibrillation.”

Ultimately, patients with osteoporosis do get more benefits than harm from osteoporosis treatments. Kim warned, “While wise decision making is obviously needed for individual patients, in general, many patients with osteoporosis or at high risk for osteoporosis are not getting appropriate treatment. Untreated osteoporosis leads to substantial morbidity and mortality in many patients.”

D'Silva KM, Cromer SJ, Yu EW, Fischer M, Kim SC. Risk of Incident Atrial Fibrillation With Zoledronic Acid Versus Denosumab: A Propensity Score-Matched Cohort Study [published online ahead of print, 2020 Nov 2]. 

. 2020;10.1002/jbmr.4174. doi:10.1002/jbmr.4174

“Based on 16,235 pairs of zoledronic acid and denosumab initiators (for osteoporosis), we found a greater risk (HR 1.25, 95% CI 1.04-1.50) of atrial fibrillation with zoledronic acid vs denosumab: an absolute risk difference of 3.69 events per 1000 person-years,” said Seoyoung Kim, MD, ScD.




Zoledronic Acid Associated With Higher Risk for Atrial Fibrillation Than Denosumab

After realizing that the current approach to managing elderly patients with rheumatoid arthritis and multimorbidity was not working because “their needs are more than just those for the sum of individual diseases,” investigators set out to create an Elderly Multimorbidity Clinic (EMC) in hopes of improving care and quality of life. According to a pilot study, published in 

, the difficulty in treating this population group is in part due to the “pathophysiology, symptoms, and management of rheumatoid arthritis and other disease might interact and alter the course of each disease, amplifying their effect on overall functioning and health.”

The head rheumatologist of the EMC, Marloes van Onna, MD, PhD, explained, “Single-disease oriented care organization is often inefficient in patients with multimorbidity and becomes burdensome for patients [as well as] physicians because of poor healthcare planning. Patients can become confused about who is responsible for particular aspects of their health issues. Physicians may not recognize that a patient has interrelated problems, resulting in more investigations, unnecessary referral to other healthcare providers, or polypharmacy. Polypharmacy leads to an increase in morbidity, hospital admissions, health-related costs, and mortality.”

Multimorbidity is incredibly common in patients with rheumatoid arthritis. According to the study, multimorbidity is present in 2 out of 3 people diagnosed with rheumatoid arthritis and “is associated with greater functional impairment, a negative impact on rheumatoid arthritis disease course, and a shorter life span.” Elderly patients are at an even greater disadvantage, as they are more prone to acquire any number of geriatric syndromes (GS) in addition to their rheumatoid arthritis diagnosis.

Investigators aimed to improve the quality of care by creating effective management plans using the goals of both the patient and physician. During the course of the EMC program, 75% of patients accomplished at least 1 of their goals. Unfortunately, no sustained benefits were observed because of low follow-up.

Patients with rheumatoid arthritis (≥ 55 years) were considered and interviewed for the year-long EMC pilot conducted at the Maastricht University Medical Center, The Netherlands, between April 2018 and March 2019. The study was evaluated using a quantitative-qualitative approach. The patient’s ability to formulate personal goals was considered during the selection process.

Once the 20 patients were chosen, they each met with a rheumatologist and internist-geriatrician in order to create personal goals and review their current medication schedules. They then developed an action plan based on these aspects. The subsequent appointments followed the same structure. Clinic visits were excluded from the study if the rheumatologist felt the intervention offered no benefit, if the patient was unable to create any personal goals, if the patient exhibited severe cognitive decline, and if the patient failed to provide informed consent.

Baseline characteristics were collected, including age, sex, marital status, smoking status, alcohol use, presence of polypharmacy, comorbidities, and hospitalizations and outpatient visits over the last 6 months. Of the patients involved in the pilot study, the mean age was 76.8±7.7 years and 70% of participants were female.

After the completion of the study, the rheumatologist and internist-geriatrician conducted interviews with the patients in order to ascertain their satisfaction with the pilot study, as well as evaluate whether patients reached their goals and how they perceived the care they received.

Only 12 (60%) patients attended the first follow-up and only 3 (15%) attended the second. Some patients indicated that the caregiver burden was too high, while others had achieved their predetermined goals and believed that there would be no benefit in coming in attending the follow-up appointment. One patient was wrongly referred to the study.

Personal goals developed by participants included a reduction of physical symptoms not caused by rheumatoid arthritis (8/20), less pain (15/20), medication remediation (9/20), and social goals (6/20). Investigators were able to track goals in the 12 (60%) of patients that were able to attend at least one follow-up appointment. Of the 12 remaining patients, 75% were able to achieve 1 or more of their goals. 6 out of 8 patients who had indicated medication remediation as a goal had initially accomplished this, but medications were eventually changed back. In addition to work done in the clinic, doctors referred patients to specialists like cardiologists, physiotherapists, occupational therapists, and pedorthists.

Investigators discovered several challenges during the course of the program. First, the referral strategy was difficult as rheumatologists were unable to adequately select patients due to lack of clear criteria and underperforming referral instruments. The next issue faced was that while patients enjoyed the care provided at the clinic, the effects on health and wellbeing were not easily demonstrated. Additionally, “the personal goals that were formulated were often not related to rheumatoid arthritis but to common geriatric complaints (eg, less vertigo) or social issues (eg, going out with friends again).” Further, although the medication remediation was initially successful, long-term analysis showed that the medication was “often changed back because of regaining complains or new complaints.”

When asked if van Onna was surprised by the results, she explained, “Yes and no. We expected that the medication review would be one of the more successful parts of the initiative. We did not expect that it would be so difficult to select the correct patient for this outpatient clinic, as we only selected patients with rheumatoid arthritis and complex multimorbidity…We tested 5 referral instruments (1 published referral tool, 2 frailty instruments, and the perspective of the rheumatologist or patient), but none of these instruments proved to be accurate enough.”

Although the study was successful in some ways (eg, patient satisfaction and the level of comprehensive care), the study “could not demonstrate an improvement in the delivery of health care (high loss to follow-up) or improvement of the health status of the patient,” investigators concluded. In the future, the research team hopes to develop a better system to select patients who would benefit from this type of program and ensure that the care provided would not increase resource use and caregiver burden. Van Onna added that “as soon as we know what patient might benefit from these care interventions, the care intervention itself can hopefully become efficient and effective.”

van Moerbeke A, Magdelijns F, Cleutjens F, Boonen A, van Onna M. Development and Evaluation of a Clinic for Elderly Patients with Rheumatoid Arthritis and Multimorbidity: A Pilot Study [published online ahead of print, 2020 Dec 31]. 

. 2020;10.1002/acr2.11213. doi:10.1002/acr2.11213

Investigators aimed to improve the quality of care by creating effective management plans using the goals of both the patient and physician. During the course of the Elderly Multimorbidity Clinic (EMC) program, 75% of patients accomplished at least 1 of their goals. Unfortunately, no sustained benefits were observed because of low follow-up.

Elderly Multimorbidity Clinic Model Offers No Sustained Benefit for Patients With Rheumatoid Arthritis

Secukinumab (Cosentyx, Novartis) improved the signs and symptoms of axial disease in patients with axial psoriatic arthritis with inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs), according to a study published in 

The prevalence of axial disease in patients with psoriatic arthritis ranges from 5% to 70%, and patients under-report axial symptoms due to the prominence of peripheral pain. Secukinumab, a human interleukin-17A antagonist, is approved for use in patients with psoriatic arthritis, but optimal use recommendations for axial psoriatic arthritis remain challenging, as do the definition criteria for the condition. Moreover, the targeted assessment of secukinumab on axial disease in psoriatic arthritis has never been investigated in a randomized-controlled trial.

In this phase 3b randomized-controlled trial, dubbed MAXIMISE, Xenofon Baraliakos, MD, of Ruhr-University Bochum in Germany, and colleagues evaluated the efficacy and safety of secukinumab 300 mg and 150 mg in managing axial disease in psoriatic arthritis. A total of 498 patients (≥18 years, Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] score ≥4, spinal pain score ≥40 by Visual Analogue Score [VAS]) with an inadequate response to NSAIDs.

Of the patients, 167 were randomly assigned to secukinumab 300 mg, 165 to secukinumab 150 mg, and 166 to placebo. A total of 425 patients completed the trial through to week 52.

The primary and key secondary endpoints were met. Improvement in ASAS20 (Assessment of SpondyloArthritis international Society) was seen in 63% of participants assigned to secukinumab 300 mg and 66% of those assigned to secukinumab 150 mg, versus 31% of the placebo group. The odds ratio (95% confidence interval) for reaching ASAS20 response comparing secukinumab 300 mg and 150 mg versus placebo was 3.8 (2.4 and 6.1) and 4.4 (2.7 and 7.0; 

<0.0001). Similar patterns were seen with ASAS40.

“In addition, MRI assessments demonstrated that secukinumab 300 mg and 150 mg significantly improved Berlin MRI scores versus placebo, providing objective evidence of reduced inflammation in both the spine and the SIJ for patients treated with secukinumab,” determined investigators.

Clinical improvements were sustained through week 52 with secukinumab, while patients on placebo who switched to secukinumab at week 12 improved considerably. The types and incidence of adverse events with secukinumab were similar to placebo at week 12.

Investigators concluded, “the results will help inform treatment decision-making and deepen the clinical understanding of axial psoriatic arthritis, one of the disease manifestations lacking universally acceptable definition criteria.”

Baraliakos X, Gossec L, Pournara E, et al. Secukinumab in patients with psoriatic arthritis and axial manifestations: results from the double-blind, randomised, phase 3 MAXIMISE trial [published online ahead of print, 2020 Dec 17]. 

. 2020;annrheumdis-2020-218808. doi:10.1136/annrheumdis-2020-218808

Improvement in ASAS20 (Assessment of SpondyloArthritis international Society) was seen in 63% of participants assigned to secukinumab 300 mg and 66% of those assigned to secukinumab 150 mg, versus 31% of the placebo group. 

Secukinumab Improves Axial Disease in Psoriatic Arthritis

Patients with rheumatic and musculoskeletal diseases are more likely to suffer severe outcomes associated with coronavirus disease 2019 (COVID-19), however, the incidence of such complications has decreased as the pandemic has progressed, according to a recent comparative cohort study published in 

Investigators sought to determine whether the rates of hospitalization, intensive care unit (ICU) admission, mechanical ventilation, acute kidney injury, renal replacement therapy, and death in patients with rheumatic and musculoskeletal disease and COVID-19 changed from the first 90 days of the pandemic (beginning January 2020) compared with the second 90 days (beginning April 2020). The team relied on data from TriNetX, a multicenter electronic health record, to gather information on individuals diagnosed with COVID-19 and their associated outcomes, and then performed a subgroup analysis for patients with rheumatic and musculoskeletal diseases specifically.

Investigators assessed outcomes within 30 days of a COVID-19 diagnosis and used an exposure score method to match 1:1 for demographics, previous hospitalizations, and laboratory results. The research team also took into account improvements in testing, supportive care, and treatment methods between the first 90 days of the pandemic and the second.

Rheumatic and musculoskeletal diseases examined included “

, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, Sjögren's syndrome, other systemic connective tissue diseases, systemic vasculitis (including antineutrophil cytoplasmic antibody-associated vasculitis, Behçet's disease, polyarteritis nodosa, and giant cell arteritis), polymyalgia rheumatica, and gout.”

A total of 8540 patients with rheumatic and musculoskeletal diseases who had been diagnosed with COVID-19 were included in the study—2811 in the early cohort and 5729 in the subsequent cohort. Hospitalization risk was lower in the later cohort (32.4% vs 45.4%). Further, intensive care unit admission (7.9% vs 14.3%), mechanical ventilation (3.6% vs 9.1%), acute kidney injury (13.8% vs 20.7%), renal replacement therapy (.06% vs 1.2%), and death (4.5% vs 9.3%) were lower in the later cohort versus the earlier one. For those hospitalized, the combined risk of intensive care unit admission, mechanical ventilation, and death were also lower in the later cohort (30.7% vs 41.3%).

For those hospitalized, the mean ages were 65 years in the first cohort and 64 years in the second. The exposure score matched cohorts “were similar in terms of demographics, comorbidities, rheumatic and musculoskeletal disease diagnoses, creatinine, BMI, glucocorticoid use, oral disease-modifying anti-rheumatic drug (DMARD) use, and previous hospitalizations.”

Although the risk of severe outcomes among patients with rheumatic and musculoskeletal diseases and COVID-19 decreased over time, use of some therapeutics increased. Among patients in the exposure score matched hospitalized subgroup, 27 patients (2.5%) in the early cohort received remdesivir compared with 120 patients (11%) in the late cohort. Dexamethasone use was similarly up, with 80 patients (7.3%) receiving it in the early cohort compared with 270 patients (24.8%) in the late one.

Use of therapies such as tocilizumab and hydroxychloroquine, however, decreased in this patient population as the pandemic progressed. Forty-two patients (3.9%) and 473 patients (43.4%) received tocilizumab and hydroxychloroquine, respectively, in the early cohort compared with 32 patients (2.9%) and 112 patients (10.3%) in the late cohort.

Limitations, including misclassification, secular trends in ICD-10 documentation, patients who received subsequent care outside of the network, and availability of and access to COVID-19 tests, were accounted for throughout the study. Investigators do not believe that these limitations would be enough to skew the data between cohorts as their findings were consistent across all end points in their primary analysis. Additionally, changes in standards for hospitalization and mechanical ventilation procedures are not enough to negate the improvement in mortality rate between the 2 groups.

“In this large, population-based cohort study in the USA, we found improved outcomes for patients with rheumatic and musculoskeletal diseases after COVID-19 diagnosis in more recent months of the pandemic compared with earlier months, including lower risks of death, respiratory failure, and renal failure,” investigators concluded. “This finding is probably multifactorial, due to increased testing capacity allowing for detection of milder cases, improved supportive care, and improved treatments.”

The risks of severe complications for patients with rheumatic and musculoskeletal diseases have seemingly lowered as the pandemic continues to spread across the country. However, those with rheumatic and other autoimmune conditions remain at a higher risk when compared with the rest of the population. Findings suggested that “the risk of death remains substantial, with 5-6% of patients dying within 30 days of diagnosis of COVID-19.” Investigators continue to push for improvements in prevention and treatment in order to protect those with compromised immune systems.

Jorge A, D'Silva KM, Cohen A, et al. Temporal trends in severe COVID-19 outcomes in patients with rheumatic disease: a cohort study [published online ahead of print, 2020 Dec 24]. 

. 2020;10.1016/S2665-9913(20)30422-7. doi:10.1016/S2665-9913(20)30422-7

Investigators found "improved outcomes for patients with rheumatic and musculoskeletal diseases after COVID-19 diagnosis in more recent months of the pandemic compared with earlier months, including lower risks of death, respiratory failure, and renal failure."

Improved COVID-19 Outcomes for Patients With Rheumatic Diseases

Continuing bisphosphonates for an additional five years after an initial five years of treatment does not reduce the risk of hip fracture, however continuing it for two more years may provide some benefits, suggests a study published on JAMA Network Open

Bisphosphonate drugs are the first-line therapy for osteoporosis and there is strong evidence to support their use for three to five years

. They are then usually discontinued because the benefits of continuing therapy are uncertain.

To examine whether there are any benefits from continuing therapy beyond this point, researchers conducted a retrospective study using data from electronic health records of Kaiser Permanente members in Northern and Southern California. They included data on 29,685 female patients who initiated oral bisphosphonate therapy with alendronate, risedronate, or ibandronate between January 1, 1997 and September 30, 2009 and had received treatment for at least five years. At this point patients either discontinued therapy or continued it for an additional two or five years, and all were monitored for hip fracture for five years. A six-month grace period was allowed for discontinuation of therapy.

Dr Joan Lo, MD, a research scientist with the Kaiser Permanente Northern California Division of Research, said: “We found that hip fracture risk in women did not differ if women stopped bisphosphonate use after five years or stayed on the medication for 10 years. Whether there is a benefit to staying on the drug for seven years needs to be further studied in randomized trials.”

A total of 507 hip fractures were recorded during the five years of follow up. Analysis of the data revealed that compared with discontinuing bisphosphonates, there were no differences in the cumulative incidence of hip fracture if women remained on therapy for two or five additional years (five-year risk difference [RD], −2.2 per 1000 individuals; 95% CI, −20.3 to 15.9, and 5-year RD, 3.8 per 1000 individuals; 95% CI, −7.4 to 15.0 respectively).

While five-year differences in hip fracture risk were not significantly different between continuation for five additional years compared with continuation for only two additional years (five-year RD, 6.0 per 1000 individuals; 95%CI, −9.9 to 22.0), results for interim hip fracture risk suggested that there may be a small potential benefit from continuing for an additional two years. Interim hip fracture risk appeared lower if women discontinued after two additional years (three-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 and four-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3) but only when the six-month grace period was used to define discontinuation as this allowed the inclusion of a greater number of women.

Dr Lo emphasized that the study only looked at hip fracture and did not focus on patients with specific rheumatologic disorders who may be at higher risk for fracture. “The optimal duration of osteoporosis treatment remains unclear. Many experts recommend an assessment after five years of treatment, with discontinuation of therapy for those with a lower fracture risk,” she explains. “Future clinical trials should examine whether there is a benefit of two additional years of treatment after the first five years (ie, seven years total) and the optimal treatment interval for higher risk populations also needs to be studied.”

All women included in the study were at least 60% adherent to bisphosphate treatment in each of the five years after treatment initiation, according to dispensing data. Women were excluded from the study if they had previously received intravenous bisphosphonate or etidronate, or taken denosumab, teriparatide, raloxifene, or oestrogen in the past two years prior to the index date. They were also excluded if they had advanced or end-stage kidney disease (a metabolic bone condition), secondary or metastatic cancer, or multiple myeloma.

1. Izano MA, Lo JC, Adams AL, et al. Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women. 

. 2020;3(12):e2025190. Published 2020 Dec 1. doi:10.1001/jamanetworkopen.2020.25190

2. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's Guide to Prevention and Treatment of Osteoporosis [published correction appears in Osteoporos Int. 2015 Jul;26(7):2045-7]. 

. 2014;25(10):2359-2381. doi:10.1007/s00198-014-2794-2

Bisphosphonates Show No Significant Benefit for Hip Fracture Risk after Five Years

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A range of biologic therapies are available as options for treating patients with rheumatoid arthritis who do not respond to first-line conventional DMARDs, but which to choose and why? Test your knowledge of biologics with this quiz.