Table 1.

Overarching principles and points to consider for the diagnosis and management of rheumatic irAEs

		LoE	GoR	LoA (0–10) mean (SD)
Overarching principles
A.	Rheumatic and musculoskeletal immune-related adverse events can occur as manifestations in cancer patients receiving immunotherapy with checkpoint inhibitors.	n.a.	n.a.	9.6 (0.7)
B.	Management of rheumatic and musculoskeletal immune-related adverse events should be based on a shared decision-making process between patients, oncologists and rheumatologists.	n.a.	n.a.	9.5 (1.1)
C.	Rheumatologists should engage with oncologists to contribute to the inter-disciplinary care of patients presenting with musculoskeletal signs and symptoms.	n.a.	n.a.	9.1 (1.2)
D.	The role of rheumatologists is to assist oncologists in differential diagnosis and to relieve rheumatic and musculoskeletal symptoms to an acceptable level enabling patients to maintain effective cancer immunotherapy.	n.a.	n.a.	9.5 (0.9)
Points to consider
1.	Rheumatologists 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.	4	C	9.5 (1.2)
2.	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.	5	D	9.4 (1.3)
3.	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.	4	C	9.5 (0.9)
4.	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 systemic 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.	4	C	9.4 (1)
5.	csDMARD should be considered in patients with insufficient response to acceptable dose of glucocorticoids or requiring glucocorticoid-sparing.	4	C	9 (1.2)
6.	For patients experiencing severe immune-related rheumatic and systemic 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.	4	C	8.8 (1.2)
7.	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.	5	D	9.4 (1)
8.	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.	4	C	8.9 (1.2)
9.	A pre-existing autoimmune rheumatic and/or systemic disease should not preclude the use of cancer immunotherapy. Baseline immunosuppressive regimen should be kept at the lowest dose possible (for glucocorticoids, below 10 mg 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.	4	C	9 (1.3)
10.	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 rheumatological assessment should be performed.	5	D	9 (1.3)

GoR: A: based on consistent level 1 studies; B: based on consistent level 2 or 3 studies or extrapolations from level 1 studies; C: based on level 4 studies or extrapolations from level 2 or 3 studies; D: based on level 5 studies or on troublingly inconsistent or inconclusive studies of any level.

LoE: 1a: systematic review of RCTs; 1b: individual RCT; 2a: systematic review of cohort studies; 2b: individual cohort study (including low-quality RCT); 3a: systematic review of case–control studies; 3b: individual case–control study; 4: case-series (and poor quality cohort and case–control studies); 5: expert opinion without explicit critical appraisal, or based on physiology, bench research or ‘first principles’.

bDMARD, biological disease-modifying antirheumatic drug; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DMARD, disease-modifying antirheumatic drug; GoR, grade of recommendation; IL-6, interleukin 6; irAEs, immune-related adverse events; IVIg, intravenous immunoglobulin; LoA, level of agreement; LoE, level of evidence; RCT, randomised clinical trial; RMD, rheumatic and musculoskeletal disease; TNF, tumour necrosis factor.