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Immunotherapy can cause joint pain and swelling, stiffness in the shoulders and hips, a dry mouth and eyes, or, rarely, muscle inflammation. Mild cases are treated with painkillers or anti-inflammatories; others need steroids and a rheumatologist, and immunotherapy often continues. Muscle weakness, trouble swallowing or breathlessness is urgent, because muscle inflammation can affect the heart.
Inflammatory arthritis affects 1 to 7% of trial participants; polymyalgia-like syndromes, sicca syndrome, vasculitis and myositis are less common (SITC 2021). Myositis (about 1% on PD-(L)1 inhibitors) is the dangerous one: it overlaps with myocarditis and myasthenia gravis and can involve the breathing muscles.
SITC 2021: refer grade 2 or persistent events to a rheumatologist; for arthritis, ESR, CRP, rheumatoid factor, anti-CCP, ANA, a joint count and imaging; prednisone 10 to 20 mg/day for grade 2 and 40 to 60 mg/day for grade 3 or more (LE: 1); TNF inhibitors, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine or IL-6 receptor inhibitors when steroids fail or long-term treatment is needed (LE: 1). Myositis: grade 3 holds the checkpoint inhibitor and starts prednisone 1 mg/kg, with any myocardial involvement meaning permanent discontinuation.
EULAR 2021, the rheumatologists' statement, differs in emphasis: NSAIDs or analgesics first for mild to moderate symptoms; glucocorticoids only when these fail, tapered to the lowest effective dose; no methylprednisolone pulses or high-dose oral steroids outside life-threatening disease and myositis, because of concern for the anti-tumour response; a conventional DMARD when more than 10 mg/day prednisone is needed; TNF or IL-6 inhibitors preferred for refractory arthritis; holding immunotherapy as a shared decision; and withdrawal always for life-threatening myositis.
Why: New pain in someone with advanced cancer may be the cancer itself, not the immunotherapy.
“Metastases, paraneoplastic syndromes and unrelated rheumatic diseases should be considered as a potential differential diagnosis of rheumatic immune-related events.”
European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 · LoE 4; LoA 9.5
Why: These tests and scans confirm inflammation and help choose treatment.
“Initial diagnostic evaluation for patients with possible inflammatory arthritis should include ESR, CRP, rheumatoid factor, anti-CCP and ANA, and joint count and radiological investigation of the affected joint(s) where appropriate (with X-ray, MRI, or ultrasound) in consultation with a rheumatologist.”
Why: A rheumatologist can choose treatments that control symptoms while keeping immunotherapy going.
“Patients with grade ≥2 (or persistent) rheumatological irAEs such as inflammatory arthritis, PMR/GCA, vasculitis, myositis, or sicca syndrome should be referred to a rheumatologist for choice and interpretation of diagnostic testing as well as management recommendations.”
Why: Many mild cases settle without steroids.
“In the absence of contraindications, symptomatic treatment including non-steroidal anti-inflammatory drugs and/or analgesics should be the initial treatment for mild-to-moderate rheumatic manifestations.”
European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021
Why: Steroids calm joint inflammation; the dose rises with severity.
“Corticosteroid dosing for inflammatory arthritis and PMR may start at 10–20 mg/day of prednisone equivalents for grade 2 symptoms. For grade ≥3 symptoms, higher dosages of 40–60 mg/day of prednisone equivalents may be required”
Why: Long or high steroid doses carry their own harms and may blunt the immunotherapy.
“When improvement is achieved, systemic glucocorticoids should be tapered to the lowest effective dose to control the symptoms”
European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 · LoE 4; LoA 9.4
Why: These drugs let the steroid dose come down.
“csDMARD should be considered in patients with insufficient response to acceptable dose of glucocorticoids or requiring glucocorticoid-sparing”
European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 · LoE 4; LoA 9
Why: These have been used in refractory immune-related arthritis without clear harm to the cancer response.
“For patients experiencing severe 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”
European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 · LoE 4; LoA 8.8
Why: Most arthritis can be treated while immunotherapy carries on; the choice depends on the person's cancer and goals.
“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”
European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 · LoE 5; LoA 9.4
Why: Muscle inflammation often comes with myocarditis or myasthenia, which can be fatal.
“For patients with grade 3 myositis, ICIs should be held until myositis is grade ≤1 while off immune suppression and permanently discontinued if there is any evidence of myocardial involvement. Prednisone should be initiated at 1 mg/kg or equivalent.”
Why: Severe myositis can stop the breathing and swallowing muscles working.
“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”
European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 · LoE 4; LoA 8.9
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
SITC 2021 and EULAR 2021 agree on early rheumatology referral, excluding cancer and other causes, steroid-sparing drugs when steroids fail, and full-strength treatment with withdrawal of immunotherapy for life-threatening myositis. They differ on how hard to treat arthritis with steroids. SITC allows 40 to 60 mg/day prednisone for grade 3 or more (LE: 1, with the grade resting on evidence from rheumatic disease outside immunotherapy). EULAR starts with NSAIDs or analgesics, did not recommend methylprednisolone pulses or high-dose oral steroids outside life-threatening disease and myositis because of concern for the anti-tumour response, and adds a conventional DMARD once more than 10 mg/day prednisone is needed. EULAR is the specialist rheumatology statement and the more recent of the two on this question; both rest on case series and expert opinion, with no randomised trials.
SITC, Journal for ImmunoTherapy of Cancer 2021 · European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021
Where it differs: NSAIDs or analgesics first; intra-articular steroid for one or a few joints; systemic steroids only when these fail, tapered within weeks; no pulses or high-dose oral steroids outside life-threatening complications and myositis; conventional DMARD above 10 mg/day prednisone.
Evidence: LoE 4 to 5; task force level of agreement 8.8 to 9.5 out of 10.
European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021
Where it differs: Prednisone 10 to 20 mg/day for grade 2 and 40 to 60 mg/day for grade 3 or more, with sicca syndrome of grade 2 or more treated with 20 to 40 mg/day tapered over 4 to 6 weeks.
Evidence: LE: 1 for both dosing recommendations.
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Prednisone 10 to 20 mg/day for grade 2 and 40 to 60 mg/day for grade 3 or more arthritis or polymyalgia | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| TNF inhibitors, methotrexate, leflunomide, hydroxychloroquine, sulfasalazine or IL-6 receptor inhibitors for refractory or long-term arthritis | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Grade 2 or more sicca syndrome: prednisone 20 to 40 mg/day tapered over 4 to 6 weeks “Patients with grade ≥2 sicca syndrome may be treated with 20–40 mg/day of prednisone equivalents, subsequently tapered over 4–6 weeks” | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| No methylprednisolone pulses or high-dose oral steroids outside life-threatening complications and myositis “Because of concerns of glucocorticoids on antitumour responses, the task force did not recommend using methylprednisolone pulses or high-dose oral glucocorticoids in the absence of life-threatening complications and myositis, even in severe presentations, and favoured the concept of glucocorticoid sparing where rheumatologists have extensive experience with alternative options.” | task force text (not a numbered point) | European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 |
| Pre-existing autoimmune rheumatic disease does not preclude immunotherapy; keep baseline prednisone below 10 mg/day if possible “A pre-existing autoimmune rheumatic and/or systemic disease should not preclude the use of cancer immunotherapy.” | LoE 4; LoA 9 | European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 |
| No routine autoantibody testing before immunotherapy “Before initiation of cancer immunotherapy, there is no indication to test every patient for the presence of autoantibodies.” | LoE 5; LoA 9 | European Alliance of Associations for Rheumatology (EULAR), Annals of the Rheumatic Diseases 2021 |
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