According to a new study conducted by researchers at Hospital for Special Surgery (HSS) in New York City and presented at the ACR annual meeting, there has been a significant increase in anti-IL17 and anti-phosphodiesterase-4 (anti-PDE4) medications being used as initial treatment for PsA since 2018, which may reflect their inclusion as potential initial therapy in the ACR/NPF guidelines, as well as the importance placed by patients on medication side effects.

“Regarding patient medication preferences, we found patients highly value preservation of their joint and function as well as safety,” said lead study author Monica Schwartzman, MD, MS, a rheumatologist at HSS. “We can use these findings to help us tailor our therapy to achieve the best outcomes for our patients.”

PsA is a very heterogenous disease with five distinct patterns of arthritis, which can make it challenging to treat. The disease is associated with a myriad of extra articular manifestations, including skin psoriasis, uveitis, and enthesitis, as well as comorbidities such as metabolic syndrome and depression.

The investigators sent surveys to patients in the HSS PsA registry. Preferences were ranked on a five-point Likert scale ranging from “not at all important” to “extremely important.” The median age of the 137 respondents was 60 years, and the median duration of PsA skin symptoms, joint symptoms, and PsA diagnosis by a physician was 19, 12, and 8 years respectively.

The survey solicited information regarding phenotypic features and characteristics of the respondent’s PsA, demographics, initial and current therapy, and medication preferences. Preference domains included medication efficacy for skin and joint disease, time to onset of efficacy, mode and frequency of administration, cost and insurance coverage, need for laboratory monitoring, side-effect profile, ability to affect function, and advice from physicians, peers, or commercial entities.

The researchers found that 62% of patients were first treated with non-steroidal anti-inflammatory drugs (NSAIDs). The most common initial immunomodulatory medications were anti-tumor necrosis factor (TNF)-α (35%), followed by methotrexate (19%), anti-PDE4 (12.4%), other conventional synthetic disease modifying anti-rheumatic medications (csDMARDs) (11.7%), anti-IL17 (5.1%), and anti-IL23 (2.9%). At survey administration, the most common immunomodulatory therapies were anti-TNF-α (30%), followed by anti-IL17 (20.4%), methotrexate (10.2%), anti-PDE4 (8.8%), other csDMARDs (8.0%), Janus kinase inhibitors (2.2%), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA 4) (1.5%), while 28% of patients were not on any immunomodulatory therapy. Following the publication of the 2018 ACR/NPF updated guidelines for PsA, a significantly higher percentage of patients’ first medications was an anti-IL17 compared to 2018 or earlier (30% vs 3.5% P<0.001). This pattern was also seen with anti-PDE4 medications (40% vs 11.5% P<0.012).

Medication preferences most respondents ranked as “extremely important” were prevention of joint damage (80%), ability to perform daily activities (71%), prevention of pain (70%), rheumatologist recommendation (63%), and medication side effects (62%).

“At HSS, more patients with PsA are being started on an anti-TNF before methotrexate. This likely reflects the fact that many of these patients have axial disease that methotrexate cannot treat effectively,” said Lisa A. Mandl, MD, MPH, a rheumatologist at HSS and a study coauthor. “Patients with PsA, who are often younger, are telling us they want to be treated with medication which will keep them mobile and active. It is important to take into consideration when making therapeutic decisions that alleviating pain is not the only concern. Medications like NSAIDs, which may be effective for pain relief, are not aligned with patient’s long-term goals, as they are not an effective disease-modifying agent.”

Dr. Schwartzman said the 2018 guidelines on PsA from the ACR/NPF support a wider range of medications as initial therapy. “Over the last decade or so, our treatment armamentarium has expanded in an incredible way for this disease, and it includes medications with novel mechanisms of action.” She added the increasing use of newer agents with novel mechanisms of action may “indicate a therapeutic need unfulfilled by traditional medications.”

The researchers say more research is needed on the 28% of patients who were not receiving any immunomodulatory therapy. Left untreated, PsA can lead to functional impairment, poor quality of life, and significant morbidity and mortality.

Findings identified long-haul COVID was particularly high for smokers, patients with comorbidities such as asthma or lung disease, cancer, chronic kidney disease, diabetes, congestive heart failure or myocardial infarction, and those taking corticosteroids.

“Knowing the impact of this problem is critical,” said Medha Barbhaiya, MD, MPH, a rheumatologist at HSS who led the study. “For rheumatology patients, long-haul COVID may be particularly challenging as these patients already have significant chronic health issues and warrants further investigation.”

Dr. Barbhaiya and her colleagues presented their study, “Risk Factors for ‘Long Haul’ COVID-19 in Rheumatology Outpatients in New York City,” at the American College of Rheumatology (ACR) annual meeting.

For the study, Dr. Barbhaiya’s group emailed surveys to 7,505 men and women aged 18 years and older who had been treated at HSS for rheumatologic complaints between 2018 and 2020. Participants were asked if they had received a positive test for COVID-19 or if they had been told by a healthcare provider that they had contracted the infection.

The researchers defined long-haul COVID-19 infections as those with symptoms lasting one month or longer, whereas limited-duration cases were considered those with symptoms lasting less than one month.

Among the 2,572 individuals who completed the survey, nearly 56% of patients who reported having contracted COVID-19 said their symptoms lasted at least one month. Only two patients in the study had a previous diagnosis of fibromyalgia — a condition marked by fatigue, muscle aches and other symptoms that have been associated with long-haul COVID — suggesting that overlap between the two disorders is minimal.

“Our findings do not suggest that symptoms of fibromyalgia are being misinterpreted as long haul COVID in patients with rheumatic diseases, which is something that has been raised as a possibility,” said Lisa A. Mandl, MD, MPH, a rheumatologist at HSS and senior author of the new study.

HSS researchers plan to use the data as part of a longitudinal analysis of rheumatology patients with long-haul COVID to determine if the lingering symptoms of the infection interfere with their rheumatologic conditions. Ongoing surveillance of these patients will provide important insight on the long-term impact of COVID-19 in patients with rheumatic disease.

“The results may provide some reassurance to physicians who are taking care of women with rheumatic diseases who become pregnant or who are contemplating pregnancy during the pandemic, because there does not seem to be an increased risk of COVID-19, but the findings need to be interpreted with caution given that in other national datasets including the Centers for Disease Control and Prevention data, pregnant patients who get COVID-19 have been shown to have potentially more severe outcomes,” said lead study author Medha Barbhaiya, MD, MPH, rheumatologist at HSS and assistant professor of medicine and healthcare policy & research, Weill Cornell Medicine.

For their study, Dr. Barbhaiya and her colleagues emailed an online COVID-19 survey to 26,045 patients in the Division of Rheumatology at HSS. 7,094 responded with 1,547 in the targeted population of women age 18 to 50. 4% reported pregnancy.

The prevalence of self-reported COVID-19 was similar in pregnant and non-pregnant women (8% vs. 9% respectively; P=0.76). Among women with COVID-19, pregnant women had a shorter duration of symptoms (P<0.01) and were more likely to experience loss of smell or taste (P=0.02) than non-pregnant women. A systemic rheumatic disease was present in approximately three-fourths of women, with no differences when stratified by pregnancy or COVID-19 status. While 67% of pregnant women reported changes to prenatal care during the pandemic, 23% of postpartum women stated the pandemic affected delivery.

“These findings are novel and should be investigated in other cohorts. Future studies will hopefully assess the long-term outcomes of rheumatology patients and their offspring who were exposed to COVID-19 during pregnancy, which our cross-sectional study could not address,” said Dr. Barbhaiya.

“Why pregnant patients are more likely to present with these symptoms warrants further study. This unique finding may help us better understand the immunology of both conditions,” said senior study author Lisa A. Mandl, MD, MPH, rheumatologist at HSS and assistant professor of medicine and healthcare policy & research, Weill Cornell Medicine. “These data also suggest that testing for COVID-19 in otherwise well pregnant women who lose their sense of taste or smell may help in the timely identification of COVID-19 in these vulnerable patients.”

HSS is the world’s largest academic medical center specialized in musculoskeletal health, spanning orthopedics, rheumatology and related disciplines. The HSS Research Institute maintains 20 laboratories dedicated to solving debilitating orthopedic and rheumatic conditions such as arthritis, bone and soft tissue injuries, autoimmune diseases, and musculoskeletal pain and deformities. There, more than 300 dedicated personnel focus on tissue repair, improving surgical outcomes, autoimmunity and inflammation, genomics, new treatments, and precision medicine.

“HSS has a long history of contributing to the collective base of clinical and basic science knowledge and finding healthcare solutions for complex conditions,” said Louis A. Shapiro, President and CEO, HSS. “We’re proud that through the joint efforts of our institution and philanthropic support, we will have the ability to make a strong impact on this growing and vital area of research.”

“As experts in inflammatory disorders and in the development of interventions for overactive immune responses, the clinicians and researchers at HSS are well-positioned to investigate many of the adverse effects of COVID-19,” says Lionel B. Ivashkiv, MD, Chief Scientific Officer at the HSS Research Institute. “This includes studying the causes of these adverse effects as well as how to prevent and treat them.”What follows are descriptions of the first group of funded projects in basic/translational research:

Activation of pDCs by SARS-CoV-2 and Its Impact on Macrophage Response

Principal Investigator: Franck Barrat, PhD

Co-Investigator: Marie-Dominique Ah Kioon, PhD

This project will study cell types that are responsible for cytokine storm syndrome — the hyperactive immune response seen in people with COVID-19 — by looking at how certain immune cells are activated by SARS-CoV-2. Research in mice infected with SARS-CoV, a coronavirus similar to the one that causes COVID-19, has suggested that plasmacytoid dendritic cell precursors (pDCs) are key to the immune response to infection. These pDCs activate macrophages, which in turn secrete cytokines. In the SARS-CoV research, depletion of pDCs appeared to protect the mice from lethal lung injury. Using blood samples from donors, the investigators will study the pathway by which pDCs activate macrophages and look at ways to therapeutically block that process.

Inhibiting RNA Polymerase II Transcription Complexes in Macrophages to Target COVID-19–Associated Cytokine Storm

Principal Investigator: Inez Rogatsky, PhD

Co-Investigators: Steven Josefowicz, PhD, and Robert P. Fisher, MD, PhD

This pilot project will dissect the role of macrophages in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS), the main driver of COVID-19-associated mortality. We will test small-molecule inhibitors of RNA Polymerase II (Pol II) transcription complexes for their ability to modulate type I interferon and inflammatory pathways in monocytes/macrophages. This research will be done using cultured macrophages as well as donor blood and blood from COVID-19 patients.

Mechanisms of Cytokine Storm in Patients with COVID-19

Principal Investigator: Mary K. Crow, MD

Co-Investigators: Mikhail Olferiev, MD, and Lionel B. Ivashkiv, MD

The objectives of this study are to describe the process of the cytokine storm in people with COVID-19 and to identify biologic predictors of a favorable outcome in patients with severe cases of the disease. The project aims to characterize immune cell populations seen in COVID-19 patients who experience cytokine storm and compare them to those patients who do not, to compare the immune response before and after patients are given the anti-inflammatory drug anakinra, and to identify measures that suggest patients are more likely to decline and eventually require mechanical ventilation. The research will employ blood samples from HSS patients who are being treated for COVID-19 at New York–Presbyterian Hospital and who meet certain other qualifications.

What follows are descriptions of the first group of funded projects in the areas of clinical and health outcomes research:

Response to and Recovery from TKA in Patients with Antibodies to SARS-CoV-2

Principal Investigator: Miguel Otero, PhD

Co-Investigators: Meghan Kirksey, MD, PhD, and Peter K. Sculco, MD

It is unknown if people who have been exposed to COVID-19 may be at higher risk of experiencing an abnormal immune response following surgery, resulting in poor outcomes. This study will evaluate the response to and recovery from total knee arthroplasty (TKA) in people who have antibodies to COVID-19 — a marker of exposure. This study will include both patients who have COVID-19 antibodies and those who don’t, to act as controls. Patients will be followed for six weeks after surgery and evaluated for the presence of certain immune markers in the blood, as well as symptoms of inflammation including pain and stiffness in the joint.

SARS-CoV-2 Exposure and the Role of Vitamin D Among Hospital Employees

Principal Investigator: Emily M. Stein, MD, MS

Co-Investigators: Theresa T. Lu, MD, PhD; Andy O. Miller, MD; Jeri Nieves, PhD; and Alana Serota, MD

It is unknown if people with vitamin D deficiency may be more likely to become infected with COVID-19. This study will investigate vitamin D status and associated immune markers as risk factors for COVID-19 infection in a cohort of healthcare workers. Healthcare workers are at higher risk of contracting COVID-19 than the general population, making them a good group to study. Vitamin D is critical for immune function and is known to be protective against respiratory-tract infection and tuberculosis. This prospective, observational study will follow healthcare workers at HSS and at other healthcare facilities for one year, to determine whether levels of vitamin D and certain immune cells in the blood make someone more susceptible to COVID-19 infection.

Association of Immunomodulatory Medication Use and Social Determinants of Health with COVID-19 Infection in Systemic Rheumatic Disease Patients in New York City

Principal Investigator: Medha Barbhaiya, MD, MPH

Co-Investigators from HSS: Lisa Mandl, MD, MPH; Catherine MacLean, MD, PhD; Vinicius Antao, MD, PhD; Jane Salmon, MD; and Mayu Sasaki, MPH

Other Co-Investigators: Candace Feldman, MD, MPH (of Brigham and Women’s Hospital); Debra D’Angelo, MS (of Weill Cornell Medicine)

Using data from the INSIGHT Clinical Research Network, a central repository containing longitudinal electronic health data for residents of New York City, investigators will assemble a cohort of patients being treated with immunomodulatory medications for rheumatic disease. This patient population will then be used to study the effect of these medications on COVID-19 incidence and outcomes. Retrospective data will be used to evaluate the incidence and severity of COVID-19 in these patients. Patients will also be studied prospectively to determine whether there’s a relationship between COVID-19 infection and future rheumatic disease as well as to study connections between infection and future psycho-social issues.

Assessment of Surgical Outcomes in the COVID-19 Pandemic Era

Principal Investigator: Andy O. Miller, MD

Co-Investigators: Scott A. Rodeo, MD, and Mark Fontana, PhD

Investigators will implement a patient registry to evaluate how COVID-19 affects outcomes and complication rates after orthopedic surgery. This registry, along with COVID-19 screening procedures, will provide the tools to address specific research questions. Among these questions are determining the incidence of current and prior infection among the HSS surgical population, the clinical features associated with current and prior infections in this patient population, and whether COVID-19 status affects short-term complication rates.

What follows is a description of an integrated multidisciplinary study being undertaken jointly by the Adult Reconstruction and Joint Replacement (ARJR) Perioperative Research Group, Anesthesiology and Rheumatology:

Prediction and Prevention of Postoperative Blood Clots in COVID-19 Patients

Principal Investigators: Friedrich Boettner, MD; Kethy M. Jules-Elysee, MD; Lisa A. Mandl, MD, MPH

Co-Investigators: ARJR surgeons: Alejandro Gonzalez Della Valle, MD; Jason Blevins, MD; David J. Mayman, MD; Peter K. Sculco, MD; Geoffrey H. Westrich, MD and Thomas P. Sculco, MD

Medicine/Rheumatology: Medha Barbhaiya, MD, MPH; Doruk Erkan, MD, MPH; Deanna Jannat-Khah, DrPH

Pathology: Thomas W. Bauer, MD, PhD

Anesthesiology: Stavros G. Memtsoudis, MD, PhD, MBA; Alexandra Sideris, PhD

ARJR: Amethia Joseph, MHA; Ethan Krell, MS

Weill Cornell Medicine: Raymond David Pastore, MD

Recent literature suggests that one of the major complications seen in people with COVID-19 is thrombosis (the formation of blood clots) due to endothelial dysfunction, persistent inflammation and potentially antiphospholipid antibodies. As elective surgeries resume, those with prior exposure to SARS-CoV-2 will inevitably present for treatment, and some may have perioperative management considerations related to their risk of deep-vein thrombosis. This project will use, a noninvasive device that can determine clotting risks, to investigate whether people who have had COVID-19 have a more dysfunctional endothelium preoperatively and at 24 hours after surgery. The investigators will measure antiphospholipid antibodies and inflammatory markers, and evaluate the prevalence of asymptomatic post-operative deep-vein thrombosis in people who undergo TKR and have SARS-CoV-2 antibodies.

COVID-19 Translational Research Core at HSS

Principal Investigator: Theresa Lu, MD, PhD

Co-Investigators: Jessica Andrés-Bergós, PhD; Miguel Otero, PhD and Emily M. Stein, MD, MS

The COVID-19 Translational Research Core (TRC) was designed to fill critical gaps in the resources needed to promote the broad range of COVID-19–related clinical and translational research at HSS. The TRC will provide consultation on the design and implementation of COVID-19 research in the areas of orthopedics, rheumatology and metabolic bone disease; support for a COVID-19 biobank; and technical expertise and facilities required for clinical and translational researchers working on COVID-19–related projects. The TRC staff will help to acquire, house, and track biospecimens from investigator-initiated COVID-19–related research studies.