Introduction

Treatment guidelines for immune-related inflammatory arthritis (irAE-IA) in patients with cancer receiving immune checkpoint inhibitors (ICIs) are vague with respect to the use of specific agents. Patients are usually referred to rheumatologists for treatment. We conducted a survey of expert rheumatologists to determine current practices. We also assessed experts’ views on the potential deleterious effects of various agents on tumor progression.

Methods

We conducted a survey of international experts in the treatment of irAE-IA, identified as members of collaborative scientific workgroups in this area. Experts were presented with a case of a patient with moderate irAE-IA and were asked about their preferred management including glucocorticoids, timing and initial choice of disease-modifying antirheumatic drugs (DMARDs), and perception of the deleterious effects of different agents on tumor progression.

Results

We approached 25 experts, of whom 19 (76%) responded. Most experts (63%) agreed on 20 mg or less of prednisone as initial dose. Experts selected methotrexate (41%) or tumor necrosis factor inhibitor (TNFi) (23%) as the initial DMARD if there was no improvement with corticosteroids; most experts (42%) would initiate DMARDs after 4 weeks. For patients whose initial DMARD therapy failed, the second choice was either a tumor necrosis factor inhibitor (TNFi) (38%) or interleukin-6 receptor antagonist (IL6ri) (33%). Experts were most concerned about the potential deleterious effects on tumor progression of abatacept and prednisone at doses of 20 mg or higher.

Conclusion

There was substantial heterogeneity in the initial management of irAE-IA. Further understanding of the pathophysiology of this immunotoxicity can assist in the classification of different presentations, selection of relevant outcomes, and planning of clinical trials to establish optimal therapeutic efficacy while minimizing potential deleterious effects of treatment on immune tumor responses.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, with marked effects on tumor responses for various malignancies. Despite their efficacy, ICI therapy can result in unrestrained immune activation, leading to inflammatory and immune-related adverse events (irAEs), which can occur in various organs and systems, and can lead to significant morbidity.[1] The widespread use of ICIs for the treatment of various cancers has resulted in a marked increase in the incidence of irAEs, including immune-related inflammatory arthritis (irAE-IA).[2–5] The prevalence of irAE-IA ranges from 1–7% after initiation of ICI therapy, with the highest risk occurring after treatment combination of ICIs (anti–PD-1 and anti-CTLA-4 monoclonal antibodies).[5,6] The clinical characteristics of patients with irAE-IA are variable, but most patients are predominantly male, seronegative, and have polyarticular involvement.[5,7] Furthermore, there is evidence that patients with irAE-IA who had a prolonged course of ICIs may develop chronic inflammatory arthritis despite ICI cessation.[8,9] Therefore, it is important to develop strategies for earlier diagnosis and treatment of this disease.

In response to the increasing incidence of irAEs, there have been efforts by different organizations, including the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), and the Society for Immunotherapy of Cancer (SITC) to develop guidelines for the management of irAEs.[10–12] However, owing to the lack of comparative studies into the treatment of irAE-IA, the recommendations for management include broad ranges of doses of corticosteroids and treatment duration along with different recommendations for disease-modifying antirheumatic drugs (DMARDs), including traditional and biologic agents (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, tumor necrosis factor inhibitor [TNFi], or interleukin-6 receptor antagonist [IL6ri]), drugs commonly used in the treatment of rheumatoid arthritis.[10] The European Alliance of Associations for Rheumatology has also published guidance on the diagnosis and management of irAEs.[13] Guidelines recommend prompt referral to rheumatology for management.

Given that irAEs are treated primarily with immunosuppressant drugs, there is concern that some of these agents may affect the efficacy of ICIs and have deleterious effects on tumor progression.[14–17] We recently conducted a review examining the impact of different drugs on tumor progression in patients with cancer who were receiving ICIs, and found conflicting results.[14] As there continues to be a paucity of evidence on the optimal use of therapies for the management of irAE-IA, and most patients are referred to rheumatologists for treatment, we conducted a case-based survey of rheumatologists, experts in the management of irAE-IA, to ascertain preferred practice patterns and views on the potential deleterious effects of various agents on tumor progression.

This study was approved by the Institutional Review Board of the University of Texas MD Anderson Cancer Center. As the study was considered low risk, only a statement of consent, which was provided by completing the survey, was required.

Selection of Participants

We administered a survey to international experts in the management of irAE-IA who are members of the Outcome Measures in Rheumatology (OMERACT) working group of irAEs and/or the Rheumatology Adverse Events Due to Immunotherapy Observational Study (RADIOS). The RADIOS is a newly formed consortium of several academic institutions in the United States, interested in collecting prospective data of patients with cancer who develop irAEs. Experts were invited to participate if they 1) were rheumatologists with current clinical practice including patients with irAE-IA, 2) had at least one publication on irAE-IA, and 3) were members of either of the aforementioned groups (OMERACT or RADIOS).

The survey was sent confidentially, and results were made available in an aggregated form. Participants were informed that results were anonymous. The surveys were administered in 2022, with up to three reminders for completion.

Survey

Experts were queried on their current country of practice, years in practice, average number of patients with rheumatic irAEs seen per year, and whether they were affiliated with a university or academic institution. The case presented in the survey was: “A 60-year-old patient with recent onset immune-related adverse event seronegative polyarthritis, clinical disease activity index (CDAI) of 22, categorized as Grade III as per the Common Terminology Criteria for Adverse events.” The CDAI is a commonly used measure to evaluate disease activity in inflammatory autoimmune arthritis such as rheumatoid arthritis.[18] There were six open-ended questions pertaining to the management of irAE-IA, including initial therapeutic agent of choice and alternative agents in case of initial treatment failure. Secondly, participants were asked to rate multiple drugs used to treat irAE-IA with respect to potential deleterious effects on tumor progression on a 5-point Likert scale from “No concern at all” to “Very concerned.” Drugs included abatacept, azathioprine, hydroxychloroquine, leflunomide, methotrexate, mycophenolate mofetil, TNFi, prednisone, and sulfasalazine. The survey is provided as a supplementary appendix (available online).

Analysis

Statistical analysis was descriptive, primarily reporting frequencies and percentages. Data management and analyses were performed with SPSS software (IBM SPSS Statistics for Windows, version 27.0 [released 2020]; IBM Corp, Armonk, NY).

Participants

The characteristics of experts queried is shown in Table 1. We approached 25 experts, of whom 19 (76%) responded. There were 11 experts from the United States, 5 from Europe, two from Canada, and one from Australia. The median number of years in practice was 10. About half of the experts (n = 10, 54%) had been in clinical practice for more than 10 years. Most experts (n = 12, 63%) managed more than 30 patients with rheumatic irAEs yearly. All participants were affiliated with an academic institution.

Table 1

Characteristics of respondents (N = 19)

Characteristics of respondents (N = 19)
Characteristics of respondents (N = 19)

Initial Management of Immune-Related Inflammatory Arthritis (irAE-IA)

Figure 1a shows the responses to the question: “What dose of daily prednisone would you start the patient on?” The initial prednisone dose varied from 10 to 60 mg with 63% of respondents choosing 20 mg or less. Most participants (n = 18, 95%) stated that oral would be the preferred initial route except for one participant who selected either oral or intravenous as their choice.

Figure 1

Expert recommendations on the prednisone dose for immune-related inflammatory arthritis.

Figure 1

Expert recommendations on the prednisone dose for immune-related inflammatory arthritis.

Close modal

Initial Disease-Modifying Antirheumatic Drugs (DMARD)

The next three questions pertained to the initial administration of DMARDs. The first question was: “What is the highest dose of daily prednisone you would use before adding a DMARD?” The answers ranged from 10 to 60 mg of prednisone with similar distributions (Fig. 1b). Most experts selected 20 mg (n = 7, 37%).

The second question asked about how long one would wait for improvement prior to starting a DMARD. The duration varied from 2 to 12 weeks (with two experts having missing data). One expert chose 2 weeks (5%), five chose 3 weeks (26%), eight chose 4 weeks (42%), two chose 6 weeks (11%), and one chose 12 weeks (5%).

The third question asked what the preferred choice of DMARD would be if a patient’s response was not appropriate (Fig. 2a). There was a variety of different agents and some experts had selected multiple agents. Most respondents chose methotrexate as a potential first-line treatment (n = 9, 41%). The second agent chosen as a first-line treatment was TNFi (n = 5, 23%). Two experts chose “biologic therapy”; however, they did not specify what type.

Figure 2

Expert recommendations on use of disease-modifying antirheumatic drugs and steroid-sparing agents after steroid failure in immune-related inflammatory arthritis.

Figure 2

Expert recommendations on use of disease-modifying antirheumatic drugs and steroid-sparing agents after steroid failure in immune-related inflammatory arthritis.

Close modal

Second Choice of DMARD Therapy

The subsequent two questions pertained to the initiation of a second choice of DMARD therapy if the first failed. The first question asked how long experts would wait prior to changing treatment if there was no response with the first-line DMARD. The answers ranged from 4 to 12 weeks. One expert stated 4 weeks (5%), five chose 6 weeks (26%), six chose 8 weeks (32%), one chose 10 weeks (5%), and six chose 12 weeks (32%).

The second question asked: “What would be your next treatment of choice?” Most experts chose either TNFi (n = 9, 38%) or IL6ri (n = 8, 33%) (Fig. 2b). Any biologic agent, leflunomide, methotrexate, and hydroxychloroquine were also selected.

Concerns About Potential Deleterious Effects of Drugs on Tumor Progression

Experts were queried about the concern of deleterious effects of different therapeutic agents on tumor progression in patients with irAEs. Answers were given in the form of a 5-point Likert scale from “Not concerned at all” to “Very concerned.” The results are shown in Table 2. For most to least concerning, medians (in parenthesis) were as follows: abatacept (5); prednisone 20 mg or higher (4); mycophenolate mofetil (3); prednisone less than 20 mg, methotrexate (MTX), leflunomide, azathioprine, rituximab, TNFi, and IL6ri (2); and hydroxychloroquine and sulfasalazine (1).

Table 2

Concerns about deleterious effects of different agents on tumor progression (N = 19 survey respondents)

Concerns about deleterious effects of different agents on tumor progression (N = 19 survey respondents)
Concerns about deleterious effects of different agents on tumor progression (N = 19 survey respondents)

To our knowledge, this is the first study to query expert opinion on the management of irAE-IA. Our results show substantial variations in the preferences of treatments for the management of irAE-IA among international experts. Furthermore, there was also variation in the preferences of treatment for irAE-IA versus published guidelines. In a prior study, we also found variations in the diagnosis and management of other irAEs among international experts, with respect to ICI-induced hepatitis, nephrotoxicity, or myositis, with and without accompanying myocarditis.[19]

The first component of our questionnaire assessed the preferred dose and route of glucocorticoids for the management of IRAE-IA. Our case presentation included a patient with IRAE-IA with moderate disease activity. The ASCO guidelines recommend that patients be started on 10 to 20 mg of prednisone or prednisone equivalent daily (and do not specify route of administration).[10] Our survey showed that although experts would start prednisone at this range, over a third would initiate treatment at a higher dose of 30 to 60 mg daily. Our case scenario presented a patient with a high disease activity score (CDAI = 22). Yet, guidelines only base their recommendations on the Common Terminology Criteria for Adverse Events CTCAE, which do not provide the granularity used by rheumatologists for decisions about therapy in inflammatory arthritis such as rheumatoid arthritis, where treatments are often recommended on the basis of quantitative evaluation of inflammatory disease activity. There was minimal heterogeneity in the chosen route of administration for glucocorticoids as oral was selected by all except one participant who selected oral or IV administration.

The second component of the survey was to assess when experts believed a glucocorticoid-sparing agent should be started in patients with irAE-IA. The first question queried at what dose of daily prednisone practitioners should consider starting a new agent. The answers varied widely from 10 to 60 mg (Fig. 1b) with 20 mg being the most common answer (37%). Although glucocorticoids are commonly used as first-line treatment for irAE-IA owing to their rapid onset and efficacy, there is concern that they may decrease overall survival, even at doses of 10 mg or lower.[20–22] There is a known positive correlation between irAEs and immunotherapy efficacy, and steroids may slightly reduce this benefit. In addition to their toxicities, up to 20% of irAEs fail to respond to steroids. These concerns may explain why some experts chose to initiate alternative therapies at doses of prednisone as low as 10 mg (n = 10, 21%). We also assessed how long experts would wait prior to starting therapy with DMARDs or corticosteroid-sparing agents. The ASCO guidelines recommend 6 to 8 weeks if there is no improvement with Grade 2 irAE-IA, or after 2 weeks if there is no improvement in Grade 3-4 irAE-IA. A wide variation in responses was observed with answers ranging from 4 to 12 weeks prior to initiating DMARDs or other corticosteroid-sparing agents. ASCO also recommends an increase in corticosteroid dose at 4 weeks as opposed to initiation of DMARD; however, owing to the potential toxicity of corticosteroids many rheumatologists may prefer to initiate DMARD early on, as this is the preferred therapeutic management for patients with rheumatoid arthritis for whom treatment with prednisone 10 mg daily is not recommended. Experts were queried on the initial drug of choice for corticosteroid-sparing therapy in nonresponders. Most experts chose methotrexate (41%), followed by TNFi (23%). Guidelines do not specify which agent is preferred. Also, there have been no comparative trials to evaluate the efficacy and safety of these agents to treat irAE-IA, as most data are from observational studies and case series.[3–5,17,23] This likely explains the heterogeneity among first-line treatments in patients with irAE-IA. A recent study of 147 patients with irAE-IA showed that the time to arthritis improvement was faster with TNFi or IL6ri than with methotrexate, but that the time to cancer progression, as measured by hazard ratios (HRs), was significantly shorter for TNFi than for MTX (HR, 3.27; 95% CI, 1.21–8.84), with borderline results for IL6ri (HR, 2.37; 95% CI, 0.94–5.98).[17]

We assessed when experts would consider a second DMARD after failure of the first one. There are currently no guidelines for sequential DMARD therapy for irAE-IA. Time ranged from 4 to 12 weeks. Some of this heterogeneity may be attributed to providers’ first choice. For example, it may take 6 weeks to titrate methotrexate up to an effective dose, which would not be deemed a “failure” at that time, versus a biologic agent that can have a more rapid onset of action. The second choice of therapeutic agent was another biologic (most often TNFi or IL6ri).

We also assessed how concerned experts were with respect to the potential deleterious effects of different therapeutic agents on tumor progression. The most concerning agents were abatacept, janus kinase inhibitors (JAKi), and a continued prednisone dose of 20 mg or higher daily. Abatacept is a CTLA4 agonist, in contrast with ipilimumab, which is a CTLA4 antagonist, and it has broad immunosuppressant effects. There are concerns that abatacept could inhibit the antitumor effects of these agents. Furthermore, some observational studies have shown an increased risk of malignancy in patients with rheumatoid arthritis treated with abatacept.[16,24] There is also concern that higher doses of glucocorticoids may decrease the response of tumor efficacy. Our recently published review summarized the literature on the reported association of corticosteroids with tumor progression in patients receiving ICIs.[14] There is a paucity of knowledge on how these drugs may affect tumor progression, as studies are sometimes contradictory, but there are some signals indicating worse cancer outcomes in patients who receive corticosteroids than for those who do not. Experts were not as concerned about TNFi and IL6Ri, with a median of 2 in the Likert scale. Current data are insufficient to determine whether TNFi or IL6Ri affect tumor progression in patients with ICIs; however, early data suggest that there are no deleterious effects of these agents on tumor progression, with some publications even proposing that they may have clinical benefits for cancer outcomes.[25-27] Nevertheless, the only study examining these agents in irAE-IA, mentioned above, showed worse survival with these therapies. However, the study was small and could not account for relevant confounding factors related to the indications for treatment, which could have impacted survival.[17]

Our survey has limitations. We had a small sample size, primarily because at this time we wanted to query the views of expert rheumatologists in this field, which is still a small community. We did not survey expert oncologists who may feel comfortable treating patients with irAE-IA despite guidance from professional societies to refer patients to rheumatology. Although we included an international panel of experts, most are from the United States and there was no representation from Asia, Africa, or South America. Again, most of the experts at this time, on the basis of our criteria, are from either North America or Europe. Finally, some of the differences observed may be due to different healthcare systems. For instance, in some countries it may be difficult to prescribe biologic agents without a prior therapeutic trial of methotrexate or other conventional DMARD.

In summary, this survey shows that there are substantial variations among experts in therapeutic practice patterns for the treatment of irAE-IA in patients with cancer receiving ICIs. Our findings highlight the need to conduct prospective controlled studies and comparative trials to determine the best treatment options for patients with irAE-IA that maximize efficacy without impairing antitumor immune effects.

The authors are grateful to the other experts who participated in the survey: Anne Bass (Hospital for Special Surgery, New York, NY), Karolina Benesova (University of Heidelberg, Germany), Cassandra Calabrese (Cleveland Clinic, Cleveland, OH), Laura Cappelli (Johns Hopkins University, Baltimore, MD), Carmela K. Chan (Hospital for Special Surgery, New York, NY), Ernest Choy (Cardiff University, UK), Nilasha Ghosh (Hospital for Special Surgery, New York, NY), Marie Hudson (McGill University, Montreal, QB, Canada), Jamal Shahin (University of British Columbia, Vancouver, BC, Canada), Tamiko Katsumoto (Stanford University, Palo Alto, CA), Sang T. Kim (University of Texas MD Anderson Cancer Center, Houston, TX), Marie Kostine (Centre Hospitalier Universitaire de Bordeaux, France), Conny van der Laken (Amsterdam Rheumatology and Immunology Center, Vrije Universiteit, Amsterdam, The Netherlands), David Liew (Austin Health, Melbourne, Australia), Pankti Reid (University of Chicago, Chicago, IL), Hendrik Schulze-Koops (Ludwig-Maximilians-University of Munich, Germany), and Jeffrey Sparks (Brigham and Women’s Hospital, Boston, MA).

1.
Postow
MA,
Sidlow
R,
Hellmann
MD.
Immune-related adverse events associated with immune checkpoint blockade
.
New Engl J Med
.
2018
;
378
:
158
168
.
2.
Jamal
S,
Hudson
M,
Fifi-Mah
A,
Ye
C.
Immune-related adverse events associated with cancer immunotherapy: a review for the practicing rheumatologist
.
J Rheumatol
.
2020
;
47
:
166
175
.
3.
Pundole
X,
Abdel-Wahab
N,
Suarez-Almazor
ME.
Arthritis risk with immune checkpoint inhibitor therapy for cancer
.
Curr Opin Rheumatol
.
2019
;
31
:
293
299
.
4.
Cappelli
LC,
Gutierrez
AK,
Baer
AN,
et al
Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab
.
Ann Rheum Dis
.
2017
;
76
:
43
50
.
5.
Leipe
J,
Christ
LA,
Arnoldi
AP,
et al
Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy
.
RMD Open
.
2018
;
4
:
e000714
.
6.
Arnaud-Coffin
P,
Maillet
D,
Gan
HK,
et al
A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors
.
Int J Cancer
.
2019
;
145
:
639
648
.
7.
Ghosh
N,
Tiongson
MD,
Stewart
C,
et al
Checkpoint inhibitor-associated arthritis: a systematic review of case reports and case series
.
J Clin Rheumatol
.
2021
;
27
:
e317
e322
.
8.
Braaten
TJ,
Brahmer
JR,
Forde
PM,
et al
Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation
.
Ann Rheum Dis
.
2020
;
79
:
332
338
.
9.
Chan
KK,
Tirpack
A,
Vitone
G,
et al
Higher checkpoint inhibitor arthritis disease activity may be associated with cancer progression: results from an observational registry
.
ACR Open Rheumatol
.
2020
;
2
:
595
604
.
10.
Schneider
BJ,
Naidoo
J,
Santomasso
BD,
et al
Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update
.
J Clin Oncol
.
2021
;
39
:
4073
4126
.
11.
Haanen
J,
Carbonnel
F,
Robert
C,
et al
Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
.
Ann Oncol
.
2017
;
28
:
iv119
iv142
.
12.
Brahmer
JR,
Abu-Sbeih
H,
Ascierto
PA,
et al
Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events
.
J Immunother Cancer
.
2021
;
9
:
e002435
.
13.
Kostine
M,
Finckh
A,
Bingham
CO,
et al
EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors
.
Ann Rheum Dis
.
2021
;
80
:
36
48
.
14.
Bruera
S,
Suarez-Almazor
ME.
The effects of glucocorticoids and immunosuppressants on cancer outcomes in checkpoint inhibitor therapy
.
Front Oncol
.
2022
;
12
:
928390
.
15.
Maslov
DV,
Tawagi
K,
Kc
M,
et al
Timing of steroid initiation and response rates to immune checkpoint inhibitors in metastatic cancer
.
J Immunother Cancer
.
2021
;
9
:
e002261
.
16.
Wadström
H,
Frisell
T,
Askling
J.
Malignant neoplasms in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors, tocilizumab, abatacept, or rituximab in clinical practice: a nationwide cohort study from Sweden
.
JAMA Intern Med
.
2017
;
177
:
1605
1612
.
17.
Bass
AR,
Abdel-Wahab
N,
Reid
PD,
et al
Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis
.
Ann Rheum Dis
.
2023
;
82
:
920
926
.
18.
Quality measurement. American College of Rheumatology
. Accessed Dec 5, 2024. rheumatology.org/quality-measurement
19.
Riveiro-Barciela
M,
Soler
MJ,
Barreira-Diaz
A,
et al
Expert clinical management of severe immune-related adverse events: results from a multicenter survey on hot topics for management
.
J Clin Med
.
2022
;
11
:
5977
.
20.
Arbour
KC,
Mezquita
L,
Long
N,
et al
Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer
.
J Clin Oncol
.
2018
;
36
:
2872
2878
.
21.
Bruyère
CL,
Souquet
PJ,
Dalle
S,
et al
Investigating the impact of immune-related adverse events, glucocorticoid use and immunotherapy interruption on long-term survival outcomes
.
Cancers (Basel)
.
2021
;
13
:
2365
.
22.
De Giglio
A,
Mezquita
L,
Auclin
E,
et al
Impact of intercurrent introduction of steroids on clinical outcomes in advanced non-small-cell lung cancer (NSCLC) patients under immune-checkpoint inhibitors (ICI)
.
Cancers (Basel)
.
2020
;
12
:
2827
.
23.
Kim
ST,
Tayar
J,
Trinh
VA,
et al
Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series
.
Ann Rheum Dis
.
2017
;
76
:
2061
2064
.
24.
de Germay
S,
Bagheri
H,
Despas
F,
et al
Abatacept in rheumatoid arthritis and the risk of cancer: a world observational post-marketing study
.
Rheumatology
.
2019
;
59
:
2360
2367
.
25.
Perez-Ruiz
E,
Minute
L,
Otano
I,
et al
Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy
.
Nature
.
2019
;
569
:
428
432
.
26.
Lesage
C,
Longvert
C,
Prey
S,
et al
Incidence and clinical impact of anti-TNFα treatment of severe immune checkpoint inhibitor-induced colitis in advanced melanoma: The Mecolit Survey
.
J Immunother
.
2019
;
42
:
175
179
.
27.
Dimitriou
F,
Hogan
S,
Menzies
AM,
et al
Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy
.
Eur J Cancer
.
2021
;
157
:
214
224
.

Author notes

Source of Support: This research was funded by ISCIIII-FEDER and ISCIII-RETICS REDinREN (grant numbers PI17/00257, PI21/01292, RD16/0009/0030, and RICORS RD21/0005/0016) and Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR). The study was also supported in part by the University of Texas MD Anderson’s Cancer Center Support Grant from the National Cancer Institute (NCI P30 CA016672).

Competing Interests

Conflict of Interest: The authors disclosed the following support unrelated to this work. Dr. Riveiro-Barciela: consultant fees from participation on advisory boards for GSK and grants from Gilead; Dr. Meara: speaker fees and participation in advisory boards for Abbvie, Amgen, Aurinia, GSK, Sanofi; Dr. Suarez-Almazor: consultant fees from Syneos Health. Dr. Bruera has no conflicts of interset.

This work is published under a CC-BY-NC-ND 4.0 International License.

Supplementary data