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Global Rheumatology Research: Frontiers, Challenges, and Opportunities

Joshua b. bilsborrow.

1 Section of Rheumatology, Allergy & Immunology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States

2 Veterans Affairs Connecticut Healthcare System, West Haven VA Medical Center, West Haven, Connecticut, United States

DR. Ingris Peláez-Ballestas

3 Rheumatology Department, Hospital General de México “Dr. Eduardo Liceaga,” Mexico City, Mexico

Bernardo Pons-Estel

4 Centro Regional de Enfermedades Autoinmunes y Reumáticas (GO-CREAR), Rosario, Santa Fe, Argentina

Christiaan Scott

5 Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, Western Cape, South Africa

PROF. Xinping Tian

6 Department of Rheumatology, Peking Union Medical College Hospital, Beijing, China

DR. Graciela S. Alarcon

7 Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States and School of Medicine, Universidad Peruana Cayetano Heredia, Lima, Perú.

DR. Richard Bucala

Dr. laura b. lewandowski.

8 National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, United States

DR. Evelyn Hsieh

Introduction.

Rheumatologic and musculoskeletal diseases (RMDs) are important causes of morbidity and mortality worldwide. ( 1 ) The World Health Organization (WHO) considers musculoskeletal conditions to be the leading cause of disability worldwide, and the greatest independent contributors to chronic pain. ( 2 ) Population-based surveys from low- and middle-income countries (LMICs) have demonstrated similar rates of RMDs compared with high-income countries. ( 3 ) However, rheumatology remains underdeveloped in many low resource settings with regards to health care access, clinical practice, education, training, and research. ( 4 )

A review of the adult and pediatric rheumatology literature published between May 2019 and May 2020 and indexed in PubMed and Web of Science Core Collection * demonstrated that the only LMICs represented among the top twenty publishing nations were Brazil and India. The overwhelming majority of authors were from high-income countries ( Figure 1A ). This discrepancy highlights the substantial knowledge gap that exists regarding the global burden of RMDs, and the need to expand research capacity in LMICs to better understand how differing geographies, ethnic and genetic backgrounds, environmental variations, endemic infections, and health system disparities influence the epidemiology and outcomes of RMDs around the world.

The scope and vicious cycle of the global rheumatology research gap. Panel A. Map demonstrating the top 20 countries represented by authors of publications in adult and pediatric rheumatology from May 2019 to May 2020. Panel B. Without a rheumatology-trained workforce, a vicious cycle develops leading to decreased access to care, and decreased research regarding the mechanisms, epidemiology, treatments, and outcomes of rheumatic and musculoskeletal diseases. These factors contribute to missed diagnoses, under-treatment of rheumatic diseases, and poor outcomes. Under-reporting of rheumatic diseases drives under-recognition and under-funding at the national and institutional levels for rheumatology care, research, education, and health policy and funding. The human figures represent the number of patients with rheumatic disease; black indicates patients diagnosed and grey patients those missed or under-diagnosed. With each vicious cycle, more patients are missed, and the problem is compounded.

A Call to Action

We convened an innovative session at the 2019 American College of Rheumatology (ACR) Annual Meeting titled, Frontiers and Opportunities in Global Rheumatology Research, which brought researchers together from different parts of the globe to address the critical need to improve rheumatology research capacity and training opportunities. This session – co-sponsored by the ACR Committee on Research, the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIAMS), and the Fogarty International Center (FIC) – explored the unique challenges and rewards of building global collaborative platforms and discussed opportunities for research training and funding. The session opened with remarks from NIAMS and FIC leadership, followed by presentations from researchers representing three different geographic regions who have developed ongoing and successful international collaborations. Approximately 100 participants attended the session, including healthcare providers, research scientists, trainees, and administrators representing the Americas, Africa, Europe, Asia, and Oceania.

The presentations provided an informed and thoughtful starting point for the subsequent open forum discussion, which encouraged viewpoints and perspectives from the audience members coming from around the world. During this open forum, audience members asked questions and shared their own experiences in global rheumatology research. Two scribes recorded the themes. Attendees also completed a brief survey to evaluate the session and to share additional perspectives.

Several key themes emerged from the session and should be prioritized for further exploration by all stakeholders working to advance global rheumatology research platforms, including investigators (mentors and trainees), institutions, policy makers, and funders.

Research Funding.

Funding for research can be a significant obstacle for academic rheumatologists, especially at the early career stage. Funding is even more challenging for rheumatologists pursuing global health research careers. Whereas certain fields ( e.g. , infectious diseases and oncology) have a comparatively robust landscape of global funding mechanisms, many RMD funding agencies restrict their awards to domestic investigators and institutions, or stipulate that funds must be spent in the ‘home country,’ which limits the possibilities for international work.

In the U.S., the NIH has historically been an important resource for global health research funding. NIH funding agencies have increased their global research support by 140% between 2011 and 2018. ( 5 ) During their opening remarks, the NIAMS and FIC leadership encouraged researchers to consider developing proposals for global projects with translatable applications to the health and welfare of U.S. patients. Similarly, government funding agencies from other countries face obligations within their programs and initiatives to balance global priorities with advancing the health and welfare of their domestic populations.

Other potential sponsors include non-governmental organizations and private pharmaceutical enterprises. The Rheumatology Research Foundation (RRF), Wellcome Trust, and International League of Associations for Rheumatology (ILAR) were highlighted as just some of the funders who have supported international collaborations to further rheumatology research and education. Moving forward, diversification and growth of potential funding sources for global RMD research is imperative.

Finally, it was acknowledged that non-communicable disease (NCD)-specific funding agencies may have an interest in expanding globally but may hesitate due to lack of familiarity with the research landscape in LMICs, and limited experience working with foreign institutions from an administration and regulatory standpoint. One approach to bridge these gaps is to partner with existing global health programs. For example, the FIC Global Health Program for Fellows and Scholars provides 12-month, mentored, hands-on global health research experiences to trainees from the U.S. and LMICs through an extensive network of well-established LMIC sites. ( 6 ) While initially focused heavily on communicable diseases, over the years the program’s portfolio has expanded to include a broad spectrum of NCD-related topics. This expansion was made possible through co-sponsorship by institutes and centers with expertise in NCDs, including the National Heart Lung Blood Institute (NHLBI), the National Cancer Institute (NCI), and more recently, NIAMS.

Mentorship and Research Training Opportunities.

Early career investigators also face significant challenges in finding mentorship in the field of global rheumatology. Many LMICs have a limited number of rheumatology providers (or none), and those individuals may not have sufficient time beyond clinical care to engage in research, much less provide mentorship and training. ( 7 ) In many cases, those individuals may not have received formal research training due to the paucity of local opportunities. Their institutions also may not incentivize research or may lack the collaborative networks with universities or public health departments needed to make research practical. This vicious cycle severely jeopardizes the pipeline for future rheumatology researchers in regions where data on RMDs are most lacking ( Figure 1B ). Early-career investigators may encounter difficulties identifying global rheumatology mentors within their institutions. As such, individuals who are interested in global rheumatology research may need to consider mentorship relationships with established international collaborators in other specialties. Fortunately, there are growing networks of international rheumatologists and musculoskeletal disease experts such as the Global Alliance for Musculoskeletal Health (GAMH) ( https://gmusc.com ) and the COVID-19 Global Rheumatology Alliance (GRA) ( https://rheum-covid.org ) to which new investigators can reach out.

Infrastructure.

In many LMICs, health care budgets can be extremely limited, and NCDs have not historically been prioritized. As such, the capacity to build and maintain infrastructure for basic rheumatology care is often lacking. ( 8 ) The scarcity of rheumatology-related resources and infrastructure creates pragmatic barriers to research. Rheumatologic diseases are complex, and many diagnoses require access to laboratory and imaging studies for confirmation. Clinical, translational, and basic science research have a range of physical infrastructure and technical capacity needs including: consistent and accurate medical record keeping systems; clinical or laboratory research space, equipment, and technology; ability to collect, store, and analyze biological specimens; animal laboratory facilities; trained and dedicated institutional review boards; research staff with technical support skills; and investigators trained in research methods, statistics, and manuscript and grant writing. A lack of research infrastructure may be compounded by language barriers and lower institutional incentives to publish. ( 9 ) While acknowledging the dedication and resourcefulness of teams that have successfully overcome these challenges to generate high-quality research platforms in low-resource settings, during the open forum discussion, participants simultaneously voiced the very tangible ways in which limitations in one or more of these areas can significantly challenge feasibility, efficiency, and scalability of research efforts and infrastructure.

Creating sustainable platforms for rheumatology research requires longitudinal vision, commitment, interdisciplinary partnerships, and flexibility. For example, in many LMICs, the comparatively sophisticated infrastructure for HIV care and research—built through more than 20 years of investment by the global community—is increasingly being leveraged to develop NCD models of care and research, and could be applied to rheumatology as well. ( 10 ) Given the key role of musculoskeletal health as a driver of many NCD outcomes, partnering directly with other major NCD fields ( e.g. , cardiology, oncology, pulmonology, or endocrinology) may be a viable strategy. ( 11 ) Additionally, while investment in rheumatology within an individual country may be modest, regional partnerships that address mutual priorities may offer accessible and synergistic opportunities for research infrastructure development. ( 12 ) Finally, in order to address wide internal disparities ( e.g. , urban vs rural) of clinical and research infrastructure, some countries have leveraged the expertise of major academic centers to create national training programs. ( 13 )

Health Policy and Advocacy.

There is a critical role for using scientific evidence as a tool to guide advocacy and policy change. The absence of systematically collected epidemiologic data on local burden of RMDs leads to under-quantification and under-recognition of these conditions and makes it impossible to measure their impact on important downstream outcomes, such as costs to the health system and individuals, disability, unemployment, and mortality. Without these data, patients, families, providers, and advocates have limited grounds upon which to appeal to national policymakers and international agencies for increased investment in RMD infrastructure and workforce development. Furthermore, if RMDs are not studied in diverse geographic settings and populations, the full spectrum of phenotypes cannot be defined, nor the environmental, genetic, and socio-cultural factors that influence presentation and disease progression. The relationships between components of this vicious cycle are illustrated in Figure 1B .

Finally, it is of paramount importance that RMDs are actively integrated into broader global discourse related to NCDs, aging, health systems, and health policy. ( 14 ) For example, the WHO Model List of Essential Medicines comprises 460 medicines considered to be the most efficacious, safe, and cost–effective that meet minimum needs for a basic health-care system to address priority conditions, and serves as the guide for national formularies in over 150 countries. The 2019 update included, for the first time, a biologic DMARD (adalimumab and its biosimilars) in addition to the conventional synthetic DMARDS previously listed. The Pediatric Task Force for Musculoskeletal Health has similarly advocated for changes to address gaps in the pediatric rheumatic diseases section of this list ( 15 ).

Conclusions and Future Directions

The future of global rheumatology research is bright, but there remains much collaborative work to be done, with partners and stakeholders across all regions, to further develop and expand this nascent field. The global rheumatology community is poised to increase its research efforts and to collaborate on innovative topics previously unexplored. However, in order for this to be possible, key barriers such as the paucity of funding and mentorship, limited research infrastructure in LMICs, and health policies that do not prioritize rheumatology will first need to be addressed.

Acknowledgements

We would like to all of those from the global rheumatology community who participated in the 2019 Annual Meeting session, Frontiers and Opportunities in Global Rheumatology Research , and shared their thoughtful perspectives and experiences. Special appreciation to the American College of Rheumatology (ACR), the U.S. National Institutes of Health (NIH) National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIAMS), and the Fogarty International Center for co-sponsoring this session. We would like to thank Ngozi Afulezi for her support in organizing the session and Dr. Kathleen Vazzana for her contribution to recording the session. We would like to thank Brigit Sullivan, MLS for the literature search, Ya-Ling Lu, MLS for the country annotation of publications, and Alicia Livinski, MLS for critical reading of this manuscript. Dr. Lewandowski is supported by the NIAMS Intramural Research Program (IRP). Dr. Hsieh is supported by the NIH/Fogarty International Center K01TW009995, and the Rheumatology Research Foundation K Supplement Award.

Conflicts of Interests:

The authors declare no conflicts of interest.

* The literature search was conducted using the PubMed (U.S. National Library of Medicine) and Web of Science Core Collection (Clarivate Analytics) databases by a medical librarian in April 2020. The search was limited by publication date from May 2019 through May 2020. For the adult rheumatology search, the search terms were connected with the OR Boolean operator and were: rheumatoid arthritis, psoriatic arthritis, spondyloarthropathy, SLE, scleroderma, systemic sclerosis, vasculitis, dermatomyositis, polymyositis, osteoarthritis, gout, and osteoporosis. For the pediatric rheumatology search, the search terms were connected with the OR Boolean operator and were: juvenile idiopathic arthritis, SLE, periodic fever syndromes, chronic multifocal osteomyelitis, rheumatic fever, juvenile dermatomyositis, and pain syndrome. The articles were categorized by the affiliation of all authors on each retrieved article from the literature searches. A country was assigned to each article based on the author affiliation. If an article had authors from multiple countries, each country was assigned to the article ( e.g. , if a paper had authors from both the United States and France, the article would be assigned to both countries).

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Article Contents

Choosing a supervisor, choosing a student, supervision—getting going, supervision—following it through, conclusions.

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How to supervise a thesis—best practice

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D. A. Isenberg, M. Salmon, on behalf of the Research Training Committee of the British Society for Rheumatology, How to supervise a thesis—best practice, Rheumatology , Volume 39, Issue 5, May 2000, Pages 560–562, https://doi.org/10.1093/rheumatology/39.5.560

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Many rheumatologists during the course of their training will undertake a period of clinical or basic research, on average from 2 to 4 yr, which will result in the publication of one or more papers and the submission of a thesis. The committee has expressed its views about the pros and cons of undertaking an MD or a PhD (or even an MSc) elsewhere [ 1 ]. Although there has been a tradition that the MD is an unsupervised degree, in our view this practice should be strongly discouraged. Whichever of these degrees is eventually submitted, the student requires supervision. Supervision should be a symbiotic relationship; it is certainly not a trivial one and much time and thought needs to be given to the task.

The traditional practice of limited or no supervision for clinical research fellows is not satisfactory, because no one can do research instinctively. The scientific method and process of research as initiated by Galileo and formalized by Bradley some 300 yr ago has a complex methodology and approach that requires training. Indeed, Bradley trained assistants in the traditional apprenticeship model that is still appropriate for students today. We do not expect people to work out for themselves how to practice medicine, or mend cars; it is rather unreasonable to assume that people can do science in this way. The inevitable consequences of a large number of clinical fellows beavering away in an unsupervised fashion are wasted time and money. And worse! Work undertaken in this way will inevitably be poorly designed, controlled, executed and unpublishable (or would be better unpublished). For the individual concerned, pressures and disappointments arise when it becomes obvious that his or her efforts to further their careers are going to be thwarted by inadequate data.

Unfortunately, too many of today's supervisors grew up in this environment, and consequently many have little idea of what is required to do good science themselves. Some take the view that if they had to suffer like this and make their own way, why should the present generation be spoon‐fed? Perhaps the best reason, from a purely selfish point of view, is that the supervisor's reputation is invested in this work, just as much as the student's.

We propose a list of important issues that must be addressed if a student is to undertake research. These principles apply equally to laboratory‐ and non‐laboratory‐based research.

The bare essentials of doing research are:

(1) Being able to access and read the literature effectively, in a focused and directed manner. It is important that the student should be able to identify the key questions addressed by a publication, identify the strategy used to address them and determine whether it was appropriate, and verify whether the results presented justify the conclusions. The ability to learn suitable techniques from the literature should be developed later.

(2) The student must construct an overall world‐view of the subject.

(3) A clear focus and understanding of the specific questions to be addressed is vital. Unless the student ‘owns’ the questions themselves the resulting work is unlikely to address them very effectively. This means that the student must understand precisely why the questions are being asked, their broader implications and why particular approaches are being used.

(a) The process of study design. Is the experiment chosen the best way to address the question? Is it flawed? Is it valid? Where and what are the potential sources of error?

(b) If undertaking clinical research, who is being studied and why. Is it ethical? Consider issues of study population, disease classification, activity and damage.

(c) How the appropriate controls will be identified and performed.

(d) How clear and precise record keeping will be undertaken.

(e) How the data will be analysed and interpreted.

(5) Research ethics and the responsibilities of a scientist to both the scientific community and the general population.

The supervisor and student have a joint responsibility to ensure that the student learns these essentials.

The apprenticeship model for research supervision has stood the test of time when used properly. Good supervision is more likely to be rewarded by an enthusiastic and productive student who frequently becomes a valuable long‐term collaborator. Student and supervisor are in many ways tied together for the rest of their careers. Failure can often come back to haunt both parties.

Some students may have a great yearning to study a given topic, which is clearly best undertaken at a particular centre. However, most rheumatologists in training end up undertaking MD or PhD research, more as a result of serendipity, i.e. being in a particular place at a given time. This is not necessarily the best method to go about choosing how to spend three years of your life! Any potential student coming into contact with a potential supervisor, would do well to ask him/her some particular questions about the proposed research and their potential role in it, e.g. what is it about; is it relevant to rheumatology; will there be sufficient support to facilitate the work; is there a clear and testable hypothesis; does the question posed in the hypothesis seem worth asking; is the question clear and well defined; is it interesting? A logical extension of these questions is whether the potential supervisor has an overall strategy for his/her research group which is logical, clear and internally consistent. It is axiomatic in research that the quality of the answers obtained relates directly to the quality of the questions asked.

The student would be well advised to assess the potential supervisor's track record. The Internet greatly facilitates enquiries about the publication record (and not just how many articles have been published but in which journals). General enquiries should ascertain whether the potential supervisor has a good reputation for providing responsible ‘care and attention’ to previous students. It may be a good idea to talk to one or two. A good supervisor should be well versed in the local university guidelines for supervision and with the rules for completion and submission of theses. It is also essential that MD and PhD studies are adequately funded at the outset before the studentship gets under way. Although local sources may be available for many potential rheumatology researchers, obtaining funds will often mean writing applications to major funding bodies such as the Arthritis Research Campaign and/or the Wellcome Trust.

From the potential student's point of view, especially students seeking to undertake more laboratory‐based research when they may well not have undertaken such research for a number of years, it is important to establish the conditions in which the potential supervisor's laboratory operates. Are there people around to help answer the simple practical questions if the supervisor him/herself no longer does bench work or is not available? Are other adjunctive sources of help, e.g. a statistician, readily available? Likewise, once results have been obtained is specialist expertise available to help analyse them.

It can be flattering to have potential students knocking on your door and asking to come and work for you. However, once a particular topic has been agreed as a potential focus for a thesis, the supervisor is probably well advised to ask the student to write an essay based on the current literature about the problem to be addressed. The quality of the product and insight into the problems ahead should be assessed before entering into a ‘solemn and binding’ commitment to take on the student.

A good supervisor will always emphasize the importance of reading voraciously to his/her student. The thing which, rightly, most annoys an MD or PhD examiner is the inability of a candidate to be able to understand his/her experiments in context. Background reading is essential, whatever your project and as much as possible should be undertaken before the student's research starts. From day one the student must keep a full record of their experiments which is available for the supervisor to review. Obviously the degree of supervision will depend on the MD/PhD student's prior knowledge and expertise. With some students, especially in the early days, the supervisor may need to spend several hours per week providing detailed and critical guidance as necessary.

The perfectly planned and executed 3‐yr series of experiments without an identifiable hitch, is a pipe dream. Indeed on occasion a side experiment provides a far more interesting answer and/or series of other experiments than the original plan. In this case, as in others, chance favours the prepared mind—but you do of course have to have the chance! However, any decision to change radically the course of an MD/PhD programme requires careful consideration by both the supervisor and the student.

Those undertaking clinical research must pay special attention to ethical issues—getting ethical committee approval for research which involves patients in any way is not a formality.

Whatever type of research a student might be doing, it is important to encourage him/her to make the best possible use of information sources, e.g. the library, the Internet, the relevant local seminars. Do not hesitate to consult statisticians early, acquire computer skills if you do not have them, and do not underestimate writing up time (see later).

Clinicians undertaking laboratory research invariably come from an environment in which work is orientated around the fulfilment of well‐defined tasks. One of the main difficulties of entering a laboratory is that the whole ethos of work is different. Whole weeks may pass without successfully completing any task. Although it is always possible to learn from failure, sometimes the lessons can be learned too late to be useful. Days are often unstructured, until one learns to organize one's own laboratory time.

Regular consultation between supervisor and student is essential. The precise frequency must vary according to the way things are going, the availability of the supervisor (he/she is encouraged to be liberal with their time) and the extent to which the student is able to ‘self start’ his/her own experiments. In any event we recommend that a supervisor should meet the student on a formal basis at least once a week, making themselves available as and when required on other occasions. However, the student should be aware that their supervisor has many other calls on his/her time and make their demands reasonable!

In an increasing number of universities the system of ‘one student–one supervisor’ is being replaced by a supervisory committee. This comprises a ‘day‐to‐day’ supervisor who can advise/direct on immediate issues/problems, a second supervisor who can help advise on the direction the research is taking and finally an external advisor. This is usually someone from outside the student's own department who can be called upon to arbitrate or be impartial if the student has complaints about the supervisor or vice versa. This system really seems to work. The onus is on the student to arrange the meetings specified in a log book (usually 1 week, 6 weeks, 3 months, 6 months, 1 yr, 18 months, 2 yr, 30 months).

Many universities now insist on registering students initially for an MPhil or equivalent and only changing this to a PhD after the production and assessment of a 1‐yr transfer report. This process keeps both the student and the supervisor on their toes.

Once the data have begun to ‘flow’, the student should be encouraged to communicate it. The local academic meeting is a good starting place, but regional, national and international meetings should then be considered. Even more important is getting your work published in decent journals. A thesis based on three or four peer‐reviewed manuscripts is much more likely to ‘sail through unscathed’. However, the student must be made aware early on of how long it takes to write up. Probably 6–9 months before the end of the project is due the supervisor and student should review the strategy for those experiments to be completed and those to be considered optional extras. These concerns about timing apply in particular to students planning an immediate return to full‐time clinical duties. It is extremely hard to write up a thesis if you have a busy clinical job.

Doing research is not easy. Most students go through a bad patch (often at 3–6 months into their research time) and need support and encouragement to persist and succeed. Good supervision cannot, unfortunately, be taken for granted and not every student can be a research natural. In Tables 1 and 2 we highlight some key issues for both student and supervisor which should help to eliminate the more obvious pitfalls.

Suggested check list for a potential supervisor

Suggested check list for a potential student

Correspondence to: D. A. Isenberg.

Gordon C, Salmon M. Postgraduate degrees for rheumatology trainees: an options appraisal of MD, PhD and MSc degrees. Rheumatology 1999 ; 38 : 1290 –3.

Recommended reading

Delamont S, Atkinson P, Odette P. Supervising the PhD—A guide to success. Milton Keynes: Open University Press, 1997.

Phillips EM, Pugh DS. How to get a PhD. Milton Keynes: Open University Press, 1994.

Holtom D, Fisher E. Enjoy writing your science thesis or dissertation! London: Imperial College Press, 1999.

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PEDIATRIC RHEUMATOLOGY

Multisystem inflammatory syndrome in children incidence and severity (March 2024)

Although multisystem inflammatory syndrome in children (MIS-C) is increasingly rare as the overall COVID-19 burden declines, it continues to be associated with substantial morbidity. In 2023, 117 patients with MIS-C were reported to the Centers for Disease Control and Prevention, resulting in an estimated incidence of 0.11 cases per million person-months [ 7 ]. Of these patients, 50 percent required care in an intensive care unit, 34 percent experienced shock, and 27 percent experienced cardiac dysfunction; mortality was 2.6 percent (3 patients). More than 80 percent of patients were SARS-CoV2 vaccine eligible but had not been vaccinated; among 20 patients who had been vaccinated, 60 percent likely had waning immunity at the time of diagnosis. This study suggests that MIS-C severity remains high, but that SARS-CoV2 vaccination may provide some degree of protection. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis", section on 'Epidemiology' .)

RHEUMATOID ARTHRITIS

Reduction of immunosuppression in patients with rheumatoid arthritis (April 2024)

Whether patients with stable rheumatoid arthritis (RA) can be tapered off conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) is unclear. In a randomized trial exploring this question in 160 patients with RA in remission for at least one year on a stable csDMARD regimen, patients assigned to continue full-dose csDMARD therapy were most likely to remain in remission at three years (80 percent) [ 8 ]. Those assigned to half-dose therapy or discontinuation (after half-dose therapy for one year) had lower rates of ongoing remission (57 and 38 percent, respectively). While this study highlights a high risk of relapse among patients with RA following a reduction in immunosuppression, it also demonstrates that some patients do not require full-dose therapy to remain in remission. Additional studies are required to identify which patients with RA are most likely to tolerate reduction or discontinuation of csDMARD therapy. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Adequate treatment response' .)

Extra-articular rheumatoid arthritis and mortality (March 2024)

Rheumatoid arthritis (RA) is a systemic inflammatory disease that can have extra-articular manifestations, which may be severe (eg, rheumatoid vasculitis) or nonsevere (eg, rheumatoid nodules). In a study that examined outcomes of 296 patients diagnosed with RA from 1985 to 1999 and 611 patients diagnosed from 2000 to 2014, extra-articular manifestations were associated with an increased risk of mortality among all patients (hazard ratio 3.0 for severe and 1.8 for nonsevere manifestations) [ 9 ]. However, the 10-year cumulative incidence of extra-articular RA declined between the two cohorts (45 versus 32 percent). Despite the declining incidence of extra-articular RA, the presence of any extra-articular features continues to be associated with a poor prognosis. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Risk factors for premature mortality' .)

Plain radiographs in the initial evaluation of rheumatoid arthritis (March 2024)

Patients suspected of having rheumatoid arthritis (RA) are routinely evaluated with plain radiographs of the hands and feet. However, whether this is an effective strategy has not been well established. In a study of 724 patients suspected of having RA, erosions were found in only 32 patients (4.4 percent), and radiographs led to a change in disease classification for only 2 patients (0.3 percent) [ 10 ]. Patients who lacked RA-associated autoantibodies and/or acute phase reactant elevation were less likely to demonstrate RA-associated erosions. Although the yield for these outcomes was low, plain radiographs may be useful for establishing alternate diagnoses that can mimic RA (eg, pseudogout) and can identify other findings associated with RA that guide management (eg, periarticular osteopenia). (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Radiologic studies' .)

Abatacept for the prevention of rheumatoid arthritis (February 2024)

There is interest in whether biologic agents can be used to prevent the development of rheumatoid arthritis (RA) in high-risk patients. In a recent trial, 213 patients at risk of developing RA based on inflammatory joint pain and the presence of RA-associated autoantibodies were randomly assigned to 12 months of abatacept (a T cell costimulation modulator) or placebo and followed for an additional 12 months [ 11 ]. The proportion of patients who remained arthritis-free was higher in the abatacept group at 12 months (93 versus 69 percent) and 24 months (70 versus 59 percent); improvements in pain, function, and quality of life at 12 months were not sustained at 24 months. This study provides evidence that pharmacotherapy can delay the onset of RA in select populations, but prevention may require ongoing therapy. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Clinical trials examining preventive therapies' .)

Triglycerides and cardiovascular risk in rheumatoid arthritis (January 2024)

Triglycerides may be particularly important to the pathogenesis of cardiovascular disease among patients with rheumatoid arthritis (RA). In a nationwide, population-based cohort study of >15,000 statin-naïve patients with RA in Korea, the risk of major adverse cardiovascular events was higher among patients with the highest baseline triglyceride levels (≥149 mg/dL) compared with those with the lowest triglyceride levels (≤72 mg/dL; adjusted hazard ratio 1.7) [ 12 ]. The same relationship was not seen with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or total cholesterol. This study implies that careful management of triglycerides may be particularly important to prevent cardiac events among patients with RA. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Risk factors specific to rheumatoid arthritis' .)

SCLERODERMA AND OTHER SYSTEMIC RHEUMATIC DISEASES

Phosphodiesterase type 5 inhibition for Raynaud phenomenon (January 2024)

Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil and tadalafil are widely used to treat digital ischemia from Raynaud phenomenon. In an updated meta-analysis of nine randomized trials comprising 411 patients with Raynaud phenomenon (most of whom had scleroderma), treatment with PDE5 inhibition resulted in three fewer attacks weekly and a reduction in the average duration of the attacks by five minutes [ 13 ]. However, PDE5 inhibition led to minimal to no reduction in the pain associated with Raynaud phenomenon. This study implies that while PDE5 inhibition has a modest impact on the duration and frequency of Raynaud attacks, it might not be adequate to address all symptoms experienced by patients with severe disease. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Phosphodiesterase type 5 inhibitor' .)

SPONDYLOARTHRITIS AND PSORIATIC ARTHRITIS

Tumor necrosis factor inhibitors for females with psoriatic arthritis (March 2024)

Tumor necrosis factor (TNF) inhibitors are commonly used as first-line therapy for the treatment of psoriatic arthritis (PsA). In a multicenter observational study of nearly 7700 patients with PsA who received initial treatment with a TNF inhibitor, females were less likely than males to have achieved low disease activity at 6 months (64 versus 78 percent) [ 14 ]. Females were also less likely to remain on a TNF inhibitor (50 versus 64 percent at 24 months). These data imply that TNF inhibitors may be less effective for females than males with PsA, and females should be followed closely after treatment initiation. (See "Treatment of peripheral psoriatic arthritis", section on 'Reasons for failure' .)

Diagnosis of axial spondyloarthritis using nonsteroidal anti-inflammatory agents (March 2024)

There is a long-standing belief that a dramatic response to nonsteroidal anti-inflammatory agents (NSAIDs) differentiates axial spondyloarthritis (axSpA) from other causes of lower back pain. However, in a recent prospective study of 68 consecutive patients with axSpA and 165 patients with chronic back pain from other causes who were treated with NSAIDs for four weeks, patients with axSpA were only modestly more likely to report at least 50 percent improvement in back pain (23 versus 16 percent), and the difference was not statistically significant [ 15 ]. Although this result casts some doubt on the diagnostic utility of an NSAID trial, the study was small and nonrandomized, and it does not exclude the possibility that some NSAIDs may be better than others at distinguishing axSpA from other diagnoses. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'History' .)

SYSTEMIC LUPUS ERYTHEMATOSUS AND SJÖGREN'S DISEASE

Adverse effects of low-dose glucocorticoids in patients with systemic lupus erythematosus (April 2024)

Glucocorticoids (GCs) are frequently required for disease control in patients with systemic lupus erythematosus (SLE) but can cause multiple adverse effects; whether low doses of GCs offer a more acceptable balance of risks and benefits is uncertain. In a national cohort study in Sweden that followed over 5300 adults with SLE for up to 15 years, compared with patients not taking oral GCs, those taking GCs had higher rates of multiple adverse outcomes, including overall mortality, various bacterial and viral infections, gastroduodenal ulcers, hypertension, osteoporosis, osteonecrosis, and cataracts [ 16 ]. Patients taking low-dose GCs (<5 mg/day) had relatively lower risks for adverse effects compared with those taking higher doses, but still had higher risks compared with patients who were not taking GCs. These results underscore the importance of using the lowest GC dose possible to control SLE activity and monitoring for adverse effects, even in patients taking low doses. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Prognosis' .)

Histopathologic characteristics of Sjögren's disease (April 2024)

A diagnosis of Sjögren's disease (SjD) is typically established by identifying lymphocytic periductal infiltrates (ie, a "focus") in a salivary gland biopsy. In a study including 103 patients with suspected SjD, labial gland biopsies were examined for histopathologic features associated with this diagnosis [ 17 ]. The presence of at least one focus per 4 mm 2 salivary tissue (ie, a focus score ≥1) had the highest sensitivity for a diagnosis of primary SjD (82 percent). However, other histopathologic features (ie, germinal centers, lymphoepithelial lesions, plasma cell shift) were more specific for this diagnosis. This study implies that examining salivary gland biopsies for features other than the focus score may help confirm a diagnosis of SjD. (See "Diagnosis and classification of Sjögren's disease", section on 'Salivary gland biopsy' .)

Telitacicept in patients with Sjögren's disease (March 2024)

Novel therapies are under investigation for Sjögren's disease (SjD). Telitacicept is a fusion protein that combines a recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and the fragment crystallizable (Fc) domain of human immunoglobulin G. In a small randomized trial in 42 patients with primary SjD, telitacicept 160 mg subcutaneously weekly reduced the EULAR Sjögren's syndrome disease activity index (ESSDAI) compared with placebo, attributed to improvements in lymphadenopathy, glandular swelling, arthritis, and skin disease [ 18 ]. Telitacicept has regulatory approval in China and is under review in the United States for other indications; larger studies are needed in patients with SjD. (See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Other agents in clinical trials' .)

CD19 CAR-T cell therapy for systemic autoimmune disease (March 2024)

CD19 chimeric antigen receptor (CAR) T cell therapy, which has been used to treat certain hematologic malignancies, may be a potential pathway to target pathogenic B cells in systemic autoimmune disease. In a recent case series, 15 patients with severe autoimmune disease (systemic lupus erythematosus, systemic sclerosis, or idiopathic inflammatory myositis) received CD19 CAR-T cell therapy; over a median of 15 months, all patients had rapid B-cell depletion and improved disease activity and could stop immunosuppressive therapy [ 19 ]. Important safety events included cytokine release syndrome (11 patients), possible mild immune effector cell-associated neurotoxicity syndrome, and severe pneumonia. These preliminary data suggest that CD19 CAR-T cell therapy may be beneficial for multiple types of systemic autoimmune diseases and warrants further evaluation. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Agents under investigation' .)

Sjögren's disease and head and neck cancers (January 2024)

Patients with Sjögren's disease (SjD) are known to have an increased risk of lymphoproliferative disease, but they may also have a higher risk of head and neck cancers. In a population-based study in Taiwan that included nearly 39,000 patients with SjD and over 150,000 propensity-matched controls, the prevalence of head and neck cancers was higher among patients with SjD (1.8 versus 1.2 percent) [ 20 ]. This was predominantly due to an increased prevalence of oral cavity, oropharynx, nasopharynx, and thyroid cancers. Patients with SjD should be monitored carefully for both lymphoproliferative disease and head and neck cancers. (See "Overview of the management and prognosis of Sjögren's disease", section on 'Prognosis' .)

Tofacitinib in patients with polymyalgia rheumatica (May 2024)

Findings from a small proof-of-concept study suggest that tofacitinib , a Janus tyrosine kinase inhibitor, may be effective for the treatment of polymyalgia rheumatica (PMR). In this study, 67 patients with newly diagnosed PMR were randomly assigned to receive tofacitinib (5 mg twice daily) or prednisone 15 mg daily (followed by a subsequent taper) [ 21 ]. At the end of 12 and 24 weeks, patients had an equivalent response to both therapies, as measured by acute phase reactants (ie, erythrocyte sedimentation rate, C-reactive protein) and the PMR Activity Score (PMR-AS). More data with longer-term follow-up are needed to determine whether tofacitinib is an effective substitute for glucocorticoids for patients with PMR. (See "Treatment of polymyalgia rheumatica", section on 'Limited role for glucocorticoid-sparing therapies' .)

Antithyroid drugs and ANCA-associated vasculitis (May 2024)

Some cases of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) have been linked to the use of antithyroid drugs (ATD), although data are limited. In a recent retrospective study of 45 patients with ATD-induced AAV, nearly half were positive for myeloperoxidase (MPO)-ANCA, and 33 percent were positive for both MPO-ANCA and proteinase 3 (PR3)-ANCA [ 22 ]. Patients were most likely to present with cutaneous manifestations and arthralgias; in 16 percent of cases, discontinuation of the ATD led to resolution of vasculitis, while the remaining patients were treated with an immunosuppressive agent. This study highlights that some patients with ATD-induced AAV may not require immunosuppression, and that ATD-induced AAV should be considered in patients who present with both MPO-ANCA and PR3-ANCA, a combination rarely seen in other forms of AAV. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis' .)

Ultrasound for the diagnosis of giant cell arteritis (April 2024)

Vascular ultrasound is being investigated as a substitute for biopsy for the diagnosis of giant cell arteritis (GCA). In a prospective cohort study including 229 patients with suspected GCA, a prediction model using both a clinical prediction algorithm and a quantitative ultrasound was able to classify 74 percent of patients as having either a low or high probability for GCA [ 23 ]. The prediction model misclassified 2 percent of patients as low probability who eventually were diagnosed as having GCA; an additional 3 percent of patients classified as high probability for GCA were eventually reclassified as having other diagnoses. Although this study suggests that temporal artery biopsy may not be necessary to evaluate all patients with suspected GCA, it was conducted by rheumatologists who were specifically trained to use ultrasound for GCA. Until such expertise is more broadly available, we continue to evaluate patients with suspected GCA with temporal artery biopsies. (See "Diagnosis of giant cell arteritis", section on 'Patients with a positive biopsy or imaging' .)

Tocilizumab and short prednisone tapers for giant cell arteritis (January 2024)

Tocilizumab may allow patients with giant cell arteritis to tolerate very short prednisone tapers. In a recent study, 30 patients with newly diagnosed or relapsing giant cell arteritis were treated with 52 weeks of subcutaneous tocilizumab (162 mg weekly) and an eight-week prednisone taper (starting with 60 mg daily) [ 24 ]. All patients entered remission after four weeks of therapy; 77 percent remained in a glucocorticoid-free remission by one year. Among patients who relapsed, the mean time to relapse was 16 weeks. Although select patients receiving tocilizumab for giant cell arteritis may be appropriate for a very short prednisone taper, larger studies are needed before broad implementation. (See "Treatment of giant cell arteritis", section on 'Unproven or ineffective agents' .)

OTHER RHEUMATOLOGY

Risk of autoimmune inflammatory rheumatic disease following COVID-19 (May 2024)

The risk of developing autoimmune inflammatory rheumatic diseases (AIRDs) following COVID-19 has recently been studied (eg, rheumatoid, psoriatic, and spondyloarthritides and connective tissue disorders) [ 25 ]. A Korean and Japanese cohort analysis of 22 million patients reported an increased risk of AIRDs in patients who had COVID-19 compared with uninfected patients (hazard ratio [HR], 1.25 [Korea], 1.79 [Japan]) and with patients who had influenza (HR, 1.30 [Korea], 1.14 [Japan]). The risk appeared to diminish over time and was likely reduced by vaccination. Clinicians should be aware of the risk of AIRD following COVID-19 and investigate appropriately when suspected. (See "COVID-19: Clinical presentation and diagnosis of adults with persistent symptoms following acute illness ("long COVID")", section on 'Physical symptoms' .)

Genetic risk factors in Lofgren syndrome (May 2024)

There are relatively little long-term follow-up data regarding patients presenting with Lofgren syndrome, which is a form of sarcoidosis characterized by acute arthritis, hilar adenopathy, and erythema nodosum. In a retrospective study of 380 patients diagnosed with Lofgren syndrome, 11 percent of patients experienced disease relapse after a median of 5.5 years [ 26 ]. Patients who were human leukocyte antigen (HLA) DRB1*03 positive were more likely to relapse with Lofgren syndrome than with other manifestations of sarcoidosis. Of the HLA-DRB1*03-negative patients who developed a chronic arthritis, 67 percent were also HLA-DRB1*15 positive. Although these results need to be replicated, HLA genotyping may help identify patients with Lofgren syndrome who are more likely to develop a chronic arthritis and may benefit from long-term follow-up. (See "Sarcoid arthropathy", section on 'Acute arthritis and Lofgren syndrome' .)

Remission maintenance therapy for IgG4-related disease (March 2024)

Whether patients with immunoglobulin G4-related disease (IgG4-RD) should receive remission maintenance therapies is unclear. In an open-label trial of 146 patients with IgG4-RD who were in remission for at least 12 months and were randomly assigned to continue or discontinue immunosuppressive therapies, relapse within 18 months occurred in 52 percent of those assigned to stop all immunosuppression and 12 to 14 percent of those who continued oral immunosuppressive therapies (eg, mycophenolate mofetil, leflunomide ) with or without glucocorticoids [ 27 ]. Unfortunately, the study was not able to identify clinical predictors of benefit from prolonged immunosuppression. However, the study implies that, like other rheumatic diseases, IgG4-RD has a substantial relapse rate, which may be mitigated by maintenance therapies. (See "Treatment and prognosis of IgG4-related disease", section on 'Maintenance therapy' .)

Clinical features of VEXAS syndrome (March 2024)

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a severe, late-adult onset autoinflammatory disease involving the nuclear factor kappa B (NFkB) pathway. The spectrum of clinical manifestations and features of this disease are demonstrated in three recent studies: In a French cohort, patients had an increased risk of serious infections, primarily bacterial and viral but also including invasive fungal and atypical infections despite antimicrobial prophylaxis and may be attributable to intrinsic immunodeficiency in addition to being associated with Janus kinase (JAK) inhibitor therapy [ 28 ]. In an Italian cohort, several patients with myelodysplastic syndrome progressed to acute myeloid leukemia [ 29 ]. In a Spanish cohort, UBA1 mosaicism was detected in both hematopoietic and nonhematopoietic tissues, indicating that the mutational event occurs during early embryonic development, not adulthood as was previously suspected [ 30 ]. The mortality rate was high in all cohorts, ranging from 12 to 40 percent. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome' .)

Revised classification criteria for antiphospholipid antibody syndrome (November 2023)

Antiphospholipid antibody syndrome (APS) presents with a wide array of clinical manifestations that can cause significant morbidity, making it both an important area for research and also challenging to define in studies. The American College of Rheumatology and the European Alliance of Associations for Rheumatology have recently updated the classification criteria for APS to allow more rigorous classification in research; these criteria should not substitute for clinical judgment when diagnosing APS [ 31 ]. The new criteria include a broader range of clinical manifestations (eg, microvascular complications, cardiac valve disease, thrombocytopenia, changes to pregnancy morbidity), risk stratification of macrovascular events, and a more nuanced weighting system for antiphospholipid antibodies (eg, considering immunoglobulin G versus immunoglobulin M isotypes). (See "Diagnosis of antiphospholipid syndrome", section on 'Classification criteria' .)

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Editorial article, editorial: innovation in rheumatic diseases.

• 1 Patient Innovation, Lisbon, Portugal
• 2 Copenhagen Business School, Copenhagen, Denmark
• 3 NOVA School of Business and Economics, Universidade NOVA de Lisboa, Lisbon, Portugal
• 4 CHRC, Comprehensive Health Research Center, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal
• 5 EpiDoC Unit, Chronic Diseases Research Centre, NOVA Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal
• 6 Rheumatology Unit, Hospital Lusiadas, Lisbon, Portugal
• 7 Rheumatology Unit, Hospital CUF Tejo, Lisbon, Portugal
• 8 Rheumatology Unit, Centro Hospitalar Lisboa Central, Lisbon, Portugal

Editorial on the Research Topic Innovation in Rheumatic Diseases

Rheumatic diseases are high prevalence diseases which affect people of all ages. Inflammatory rheumatic conditions warrant for an early diagnosis and an effective treatment so patients can better manage their disease and its effects. On another hand, osteoporosis and osteoarthritis affect elderly population the most; with the increasing number of older people in countries worldwide, it leads to a major impact on patients' well-being and on society's high economic costs due to healthcare and social resources consumption. Thus, innovation has become a hot topic that aims to solve sustainability of healthcare systems and patients' real needs. In that sense, innovation in rheumatic diseases presents a wide broad of topics, namely novel disease management and treatment approaches, new drugs, therapies, and medical devices, as well as additions to fundamental research.

All these challenging issues justify the edition of our Research Topic “Innovation in Rheumatic Diseases” which, as we expect, can bring up some of the breakthroughs and point out good practices to tackle rheumatic health needs. This group of papers has in common the fact that they cover practical approaches focused on innovation in rheumatic disorders, which include disease knowledge, diagnosis, disease management, well-being improvement, and treatment.

This Research Topic gathers 11 papers from different research groups that deal with distinct aspects of innovation in rheumatic diseases—advances in diagnosis, new mechanisms of disease, innovative technologies, artificial intelligence applications and new contributes to health innovation arena. Eight of them are original research, one clinical trial, one review and one brief research report.

On one side, the rheumatology diseases understanding reveal to be a relevant topic for 4 different research groups. Ingegnoli et al. reviewed the connection between autonomic nervous system and rheumatoid arthritis (RA), where the authors explored common cardiac and mental health-related RA comorbidities with potential relationships to systemic and joint inflammation. Chen et al. performed a population-based study to investigate the relation between anti-phospholipid syndrome (APS) and the risk of newly diagnosed systemic lupus erythematosus (SLE), which showed a significant correlation mainly within the 1st years of APS diagnosis, which highlights the need for vigilance of SLE-associated symptoms in patients recently diagnosed APS. Ma et al. successfully established biomarkers and diagnostic patterns for RA early diagnosis, using serum protein profiles analysis by MALDI-TOF-MS combined with magnetic beads, proteomic analysis and biomarkers identification and quantification, involving patients with different disease activity score (in remission, with low disease activity, with moderate disease activity, and with high disease activity). Finally, Gau et al. investigated the impact of anti-neutrophil cytoplasmic antibodies (ANCAs) on clinical manifestation, organ involvement and outcomes in pediatric-onset systemic lupus erythematosus patients; the authors found an indication that patients with ANCAs tend to have hematuria and an absence of typical renal immunofluorescence histology, but no difference in clinical presentations and treatment outcomes, although further studies are needed to verify those findings.

On another hand, rheumatic diseases diagnosis is also a relevant topic. Monti et al. howed that color duplex sonography of temporal arteries and large vessels, combined with a fast-track approach, contributed to a substantial reduction of permanent visual loss in giant cell arteritis, one of the most feared complications, by shortening the time to diagnosis and treatment initiation. In a different approach, Cipolletta et al. presented an automatic deep-learning algorithm for informative ultrasound image analysis for assessing metacarpal head cartilage integrity, which may contribute to the enhancement of ultrasound reliability for this task and support beginner sonographers during ultrasound training in the future.

New treatment approaches for different rheumatologic diseases were also highlighted by different researchers. Li et al. presented a cohort study that suggests that adding Chinese herbal medicines to conventional therapy may reduce subsequent risk of hearing loss in RA patients, although prospective randomized trials are still recommended to further support a causal relationship. In a different work, Wu et al. evaluated the positive efficacy and safety of a Chinese medicine formula combined with methotrexate in active RA patients' treatment, in comparison with the combination of methotrexate and leflunomide. Luo et al. compared the efficacy and safety of glucocorticoids combined with cyclophosphamide or mycophenolate mofetil in immunoglobulin G4-related diseases patients.

Regarding strategies to tackle rheumatic diseases-based needs, Quaresma et al. presented a user-friendly, easy to apply and effective quantitative support tool “OrthoRehab” that can assist physicians/therapists when choosing the most suitable ankle-foot orthosis for each patient with foot dysfunction—one of the most likely consequences of RA. In a different approach comparing to the previous described work, Jacinto et al. showed that patients and their caregivers also present a significant and high-value innovative profile, since these unusual innovators develop novel solutions to solve their own needs whenever the market isn't providing any answer to it.

We believe the papers published in this Research Topic show a comprehensive vision of relevant aspects of innovation in rheumatic diseases and can help to increase knowledge and awareness around these themes. Enjoy the reading!

Author Contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors are grateful for the funding provided by the Fundação para a Ciência e Tecnologia (FCT) through the project PTDC/EGE-OGE/7995/2020 Healthcare Innovation and Entrepreneurship for Impact: Creating a Resilient, Safe, and Crowd-based Innovation System.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Keywords: innovation, rheumatic diseases, lupus, rheumatoid arthritis, diagnosis, treatment

Citation: Jacinto MJ, Oliveira P, Rodrigues AM and Canhão H (2022) Editorial: Innovation in Rheumatic Diseases. Front. Med. 8:801515. doi: 10.3389/fmed.2021.801515

Received: 25 October 2021; Accepted: 01 December 2021; Published: 05 January 2022.

Edited and reviewed by: Savino Sciascia , University of Turin, Italy

Copyright © 2022 Jacinto, Oliveira, Rodrigues and Canhão. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Helena Canhão, helenacanhao@gmail.com

This article is part of the Research Topic

Innovation in Rheumatic Diseases

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Drugs can reduce recurrence after bowel cancer surgery, new thesis suggests

by Claes Björnberg, Umea University

A thesis at Umeå University shows that certain non-steroidal anti-inflammatory drugs, known as NSAIDs, can help patients who have undergone surgery for colorectal cancer. These patients suffer fewer recurrences of cancer and fewer leaks at the surgical site, so-called anastomotic leakage.

The researchers investigated whether NSAIDs, if taken in the first week after surgery for rectal cancer, could reduce the risk of recurrence-free survival. No conclusive effect were seen. This may be because there is no effect, that there were too few patients in the study, that different NSAIDs were used, or that a longer treatment with NSAIDs may be needed to see an effect.

"When we included a larger group of patients in the study, we saw positive effects in those treated with NSAIDs. These patients had a reduced rate of cancer recurrence, especially for left-sided colon cancer, and a reduced rate of anastomotic leakage," says the study's author Oskar Grahn, Department of Diagnostics and Intervention.

Furthermore, the biological processes that can explain why anastomotic leakage negatively affect long-term cancer outcomes were investigated. They discovered that even though patients who suffered anastomotic leakage or intra-abdominal abscess had normal levels of a protein called C-reactive protein (CRP) 41 days after surgery, there were 72 proteins that were upregulated and five that were downregulated still. This suggests that there may still be harmful processes going on in the body, even though one might think that the negative effects already have passed.

Finally, it was studied how common a certain mutation of the gene for the enzyme cyclooxygenase (COX-2) is among patients with colorectal cancer in Sweden. COX-2 is one of the enzymes that NSAIDs inhibit. However, it was not possible to confirm a previous finding showing that this mutation could be linked to an increased risk of anastomotic leakage.

In conclusion, research suggests that NSAIDs may have beneficial effects on cancer recurrence and anastomotic leakage in patients with colorectal cancer , depending on the location of the tumor and the anastomosis. This is especially the case for left-sided colon cancer, as these tumors often overexpress COX-2.

"Further research is needed to confirm these results and to investigate whether a longer treatment with NSAIDs could have an even greater effect," says Oskar Grahn.

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