The initiative primarily set out to guide clinicians mainly rheumatologists but also in some countries internists and immunologists who have to play a pivotal role in developing with the oncologists a patientcentred approach to improve the diagnosis and the management of rheumatic immunerelat ID: 934511
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Slide1
EULAR recommendations for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.
Slide2The initiative primarily set out to guide clinicians, mainly
rheumatologists, but also in some countries internists and immunologists, who have to play a pivotal role in developing with the oncologists a patient-centred approach to improve the diagnosis and the management of rheumatic immune-related adverse events (irAEs).The accompanying commentary may also serve as a framework for future longitudinal cohorts and/or clinical studies.
Target population/question
2
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Slide3Methods: According to the EULAR Standardized Operating Procedures*
Methods/methodological approach
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* van der Heijde
et al
Ann Rheum Dis 2016,75:3-15
Consensual approach
Systematic literature research
Consensual approach
FINAL
Recommendations
Slide4Rheumatic and musculoskeletal immune-related adverse events can occur as manifestations in cancer patients receiving immunotherapy (LoE na; LoA 9.6).
Management of rheumatic and musculoskeletal immune-related adverse events should be based on a shared decision-making process between patients, oncologists and rheumatologists (LoE na; LoA 9.5).
Rheumatologists should engage with oncologists to contribute to the inter-disciplinary care of patients presenting with musculoskeletal signs and symptoms (LoE na; LoA 9.1).The role of rheumatologists is to assist oncologists in establishing the diagnosis and to relieve rheumatic and musculoskeletal symptoms to an acceptable level enabling patients to maintain effective cancer immunotherapy (LoE na; LoA 9.5).
Overarching
principles
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Slide5Rheumatologists should be aware of the wide spectrum of clinical presentations of rheumatic and/or systemic immune-related adverse events that often do not fulfil traditional classification criteria of RMDs.
Polymyalgia rheumatica (PMR)-like syndromes and inflammatory arthritis syndromes are two of the major clinical presentations encountered, but a variety of other rheumatic syndromes have been described.Among systemic manifestations, sicca syndrome, sarcoid-like reactions, systemic sclerosis, lupus and all vessel-sized vasculitis have been reported.
Autoantibodies are often absent.May be associated with other organ specific irAEs.LoE 4; LoA 9.5%
Recommendation 1
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Slide6Oncologists should be encouraged to consult rheumatologists promptly for assessment when rheumatic musculoskeletal and systemic signs or symptoms are suspected due to immunotherapy, and rheumatologists should provide facilitated access for such patients.
A prompt rheumatological evaluation should support rapid shared treatment decision to relieve patient symptoms, maintain a good quality of life and allow pursuing an effective cancer immunotherapy. The task force decided not to use the CTCAE grading system to prioritise referral but instead to recommend prompt assessment, ideally before starting glucocorticoids.
LoE 5; LoA 9.4%Recommendation 2
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Slide7Metastases, paraneoplastic syndromes and unrelated rheumatic diseases should be considered as a potential differential diagnosis of rheumatic immune-related events. The comprehensive assessment should be focused on documenting evidence of target organ inflammation, and based on history, clinical features, laboratory tests, imaging and/or biopsy.
.Hypertrophic osteoarthropathy and dermatomyositis as examples of the two more common syndromes encountered. The term “unrelated rheumatic diseases” covers manifestations for which the causal link with cancer immunotherapy is not obvious, such as shoulder tendinitis, lateral epicondylitis, non-inflammatory back pain or complex regional pain syndrome.
Rheumatologist has to document evidence of any organ inflammation according to the symptoms presented (muscle, fascia, vessels, heart, lung, skin, endocrine glands, salivary glands, etc.).
LoE 4; LoA 9.5%Recommendation 3
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Slide8In case of inefficacy of symptomatic treatment and depending on the disease severity, local and/or systemic glucocorticoids should be considered for immune-related rheumatic and connective tissue disease-like symptoms. Dose regimen and route of administration should be decided according to the clinical entity and activity. When improvement is achieved, systemic glucocorticoids should be tapered to the lowest effective dose to control the symptoms.
Intra-articular glucocorticoids should be considered in the context of mono- or oligoarthritis, combined with an analysis of the synovial fluid. Systemic glucocorticoids have been used with a median initial dosage of 20mg/day in arthritis, 60mg/day for vasculitis.
The objective of reaching a dose less than or equal to 10mg/day of equivalent prednisone within weeks or as soon as improvement is achieved was recommended as an acceptable target dose.LoE 4; LoA 9.4%
Recommendation 4
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Slide9csDMARD should be considered in patients with insufficient response to acceptable dose of glucocorticoids or requiring glucocorticoid-sparing.
So far, no specific csDMARD has proven superiority. Methotrexate was the most frequently drug prescribed, followed by hydroxychloroquine then sulfasalazine, either as monotherapy or in combination.Higher proportion of hypersensitivity reactions were reported with sulfasalazine. Few patients with scleroderma-like syndromes received mycophenolate mofetil.
LoE 4; LoA 9%
Recommendation 5 16.12.19
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Slide10For patients experiencing severe immune-related rheumatic and connective tissue disease-like immune-related adverse events or with insufficient response to csDMARD, bDMARD may be considered, with TNF or IL-6 inhibitors being the preferred options for inflammatory arthritis.
Preclinical data supports the use of TNF inhibitors, since they only had a minor influence on T cell activation and the killing ability of tumour-infiltrating lymphocytes. A synergistic effect of TNF inhibitors with checkpoint inhibitors has been demonstrated in mouse models and a phase Ib clinical trial in ongoing in melanoma patients.
Anti-tumour responses were not adversely affected in patients treated with TNF inhibitors (i.e. for severe colitis or arthritis).Some other patients with checkpoint inhibitors-induced severe inflammatory arthritis were treated with tocilizumab.
Due to limited data and concerns about IL-17 inhibition on checkpoint inhibitors efficacy, IL-17 blockade was not recommended.LoE 4; LoA 8.8%
Recommendation 6
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Slide11The decision to hold or to continue the cancer immunotherapy should be based on the severity of rheumatic immune-related adverse events, the extent of required immunosuppressive regimen, the tumour response and its duration, as well as the future oncology treatment plan, in a shared decision with the patient.
Currently, decisions regarding checkpoint inhibitors and immunosuppressive regimens vary from institution to institution according to local practice, with no randomised trials to provide evidence in choosing between holding cancer immunotherapy and/or introducing an immunosuppressive regimen. Some studies reported ongoing clinical benefit in patients who discontinue their cancer immunotherapy for immune-related adverse events.
LoE 5; LoA 9.4%
Recommendation 7 16.12.19
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Slide12Myositis may be a severe condition. Immunotherapy withdrawal needs to be discussed. In the presence of life-threatening manifestations (bulbar symptoms (dysphagia, dysarthria, dysphonia), dyspnoea and myocarditis), high dose of glucocorticoids, IVIg and/or plasma exchange should be considered; immunotherapy withdrawal is always necessary.
Occurs very early after checkpoint inhibitors initiation, often within the first month of treatment.Proximal weakness and myalgia are the major symptoms, which can mimic a PMR-like condition, and increased
creatinin kinase is seen in the majority of patients.Cardiac evaluation (troponin and electrocardiography) must be systematic for any patient with myositis or suspected myositis, since it is frequently associated with myocarditis.
Associated myasthenia gravis encountered in 15% of patients with myositis.Glucorticoids dosage is usually 1-2mg/kg/day +/- intravenous pulses of methylprednisoloneIn refractory situations, abatacept or another T-cell directed therapy may be consider as rescue therapy, after plasma exchanges and IVIg.
LoE 4; LoA 8.9%
Recommendation 8
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Slide13A pre-existing autoimmune rheumatic or connective tissue disease should not preclude the use of cancer immunotherapy. Baseline immunosuppressive regimen should be kept at the lowest dose possible (for glucocorticoids, below 10mg prednisone per day if possible). However, many patients may have a flare of the underlying condition and/or immune-related adverse events, requiring the use of glucocorticoids and/or DMARDs.
A flare of the pre-existing inflammatory or autoimmune disease was observed in half of RA, PsA and myositis patients, 64% of PMR patients, 31% of SA and SLE patients, 43% of Sjögren’s patients, 25% of systemic sclerosis patients and 20% of sarcoidosis patients, but less than 10% had to stop the cancer immunotherapy.
Most flares and irAEs were managed with glucocorticoids, with the need of csDMARDs in some patients. So far, no preventive treatment is needed. Recent preclinical and clinical data highlighted the deleterious impact of baseline glucocorticoids on checkpoint inhibitors efficacy, when used at a dosage of greater than 10mg/day.
Prophylactic TNF inhibition and a possible synergistic effect of TNF inhibitors and checkpoint inhibitors are currently evaluated.LoE 4; LoA 9%
Recommendation 9
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Slide14Before initiation of cancer immunotherapy, there is no indication to test every patient for the presence of autoantibodies. In the case of unexplained rheumatic, musculoskeletal or systemic symptoms, a complete rheumatologic assessment should be performed.
Since autoantibodies are not found in the majority of patients experiencing checkpoint inhibitors-induced rheumatic and connective-tissue like disease, there is no indication to test every patient at baseline.The detection of autoantibodies in an asymptomatic patient would not preclude the start of cancer immunotherapy.
There is one particular situation of thymoma patients who should be tested for anti–acetylcholine receptor (AChR) and anti-striated muscle antibodies before starting checkpoint inhibitors, to identify a high risk of myositis.LoE 5; LoA 9%
Recommendation 10
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Slide15Summary Table Oxford Level of Evidence
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Recommendation
Level of Evidence
1
4
2
5
3
4
4
4
5
4
6
4
7
5
8
4
9
4
10
5
Slide16Rheumatologists should be aware of the wide spectrum of clinical presentations of rheumatic and/or systemic immune-related adverse events that often do not fulfil traditional classification criteria of RMDs.
Oncologists should be encouraged to consult rheumatologists promptly for assessment when rheumatic musculoskeletal and systemic signs or symptoms are suspected due to immunotherapy, and rheumatologists should provide facilitated access for such patients.
Metastases, paraneoplastic syndromes and unrelated rheumatic diseases should be considered as a potential differential diagnosis of rheumatic immune-related events. The comprehensive assessment should be focused on documenting evidence of target organ inflammation, and based on history, clinical features, laboratory tests, imaging and/or biopsy.
In case of inefficacy of symptomatic treatment and depending on the disease severity, local and/or systemic glucocorticoids should be considered for immune-related rheumatic and connective tissue disease-like symptoms. Dose regimen and route of administration should be decided according to the clinical entity and activity. When improvement is achieved, systemic glucocorticoids should be tapered to the lowest effective dose to control the symptoms.
csDMARD should be considered in patients with insufficient response to acceptable dose of glucocorticoids or requiring glucocorticoid-sparing.
Summary of Recommendations in bullet point format
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Slide17For patients experiencing severe immune-related rheumatic and connective tissue disease-like immune-related adverse events or with insufficient response to csDMARD, bDMARD may be considered, with TNF or IL-6 inhibitors being the preferred options for inflammatory arthritis.
The decision to hold or to continue the cancer immunotherapy should be based on the severity of rheumatic immune-related adverse events, the extent of required immunosuppressive regimen, the tumour response and its duration, as well as the future oncology treatment plan, in a shared decision with the patient.
Myositis may be a severe condition. Immunotherapy withdrawal needs to be discussed. In the presence of life-threatening manifestations (bulbar symptoms (dysphagia, dysarthria, dysphonia), dyspnoea and myocarditis), high dose of glucocorticoids, IVIg and/or plasma exchange should be considered; immunotherapy withdrawal is always necessary.
A pre-existing autoimmune rheumatic or connective tissue disease should not preclude the use of cancer immunotherapy. Baseline immunosuppressive regimen should be kept at the lowest dose possible (for glucocorticoids, below 10mg prednisone per day if possible). However, many patients may have a flare of the underlying condition and/or immune-related adverse events, requiring the use of glucocorticoids and/or DMARDs.
Before initiation of cancer immunotherapy, there is no indication to test every patient for the presence of autoantibodies. In the case of unexplained rheumatic, musculoskeletal or systemic symptoms, a complete rheumatologic assessment should be performed.
Summary of Recommendations in bullet point format
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Slide18Summary of Recommendations in lay format
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Read the full lay summary (add hyperlink if provided)
1 star (*) means it is a weak recommendation with limited scientific evidence; 2 stars (**) means it is a weak recommendation with some scientific evidence; 3 stars (***) means it is a strong recommendation with quite a lot of scientific evidence; 4 stars (****) means it is a strong recommendation supported with a lot of scientific evidence.
Recommendations with just 1 or 2 stars are based mainly on expert opinion and not backed up by appropriate clinical studies, but may be as important as those with 3 and 4 stars.
Recommendation
*
Rheumatologists should be aware of the wide variety of possible rheumatic and/or systemic immune-related adverse events
*
Oncologists should consult rheumatologists quickly
when there is
evidence of
rheumatic symptoms being
caused by
immunotherapy
*
Clinical evidence, laboratory tests, imaging and biopsies should be collected to search for inflammation and exclude differential diagnoses
*
If other treatment does not work, steroids
can
be considered for symptoms
that look like
immune-related rheumatic or connective tissue diseases
*
csDMARD should be considered in patients with insufficient response to acceptable dose of glucocorticoids or requiring glucocorticoid-sparing
Slide19Summary of Recommendations in lay format
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Read the full lay summary (add hyperlink if provided)
1 star (*) means it is a weak recommendation with limited scientific evidence; 2 stars (**) means it is a weak recommendation with some scientific evidence; 3 stars (***) means it is a strong recommendation with quite a lot of scientific evidence; 4 stars (****) means it is a strong recommendation supported with a lot of scientific evidence.
Recommendations with just 1 or 2 stars are based mainly on expert opinion and not backed up by appropriate clinical studies, but may be as important as those with 3 and 4 stars.
Recommendation
*
bDMARDs
can be considered for
p
eople with
severe rheumatic and connective tissue disease-like immune-related adverse events or those with insufficient response to
csDMARDs
*
The decision to hold or to continue cancer immunotherapy should be made with
the patient, and
based on the severity of rheumatic adverse events, the tumour response and duration, and the treatment
plan
*
Myositis may be a severe condition,
and stopping i
mmunotherapy needs to be discussed. If there are life-threatening symptoms,
other treatment
options can be used instead
*
Cancer immunotherapy can be used in people who have an autoimmune
rheumatic or connective tissue disease,
while keeping their immunosuppressive treatment
at the lowest dose possible
*
Before starting
cancer immunotherapy, people
are not tested
for autoantibodies, but these should be checked
if there are
rheumatic, musculoskeletal or systemic symptoms
*
Slide20Convenors: Xavier Mariette and Thierry Schaeverbeke
Methodologist: Axel FinckhFellow: Marie KostineMembers of the Task Force: C.O. Bingham 3rd, K. Visser, J. Leipe, H. Schulze-Koops, E. Choy, K. Benesova, T.R. Radstake, A.P. Cope, O. Lambotte, J.E. Gottenberg, Y. Allenbach, M. Visser, C. Rusthoven, L. Thomasen, S. Jamal, A. Marabelle, J. Larkin, J.B.A.G. Haanen, L.H. Calabrese We thank the librarian Catherine Weill (Bibliothèque Interuniversitaire de Santé, Paris, France) for her contribution to the systematic literature search.
Finally, the Task Force gratefully thanks EULAR for financial and logistic support.
Acknowledgements
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