Rheumatic and musculoskeletal irAEs occur in 10% of patients with cancer receiving ICI therapy.

Arthralgia and myalgia are the most frequent IR-rheumaticmanifestations (incidence rates: 1%-43% and 2%-20%,respectively). Since they can also occur secondary to paraneoplastic manifestations or other cancer therapy, it is challenging to define whether symptoms are IR or if they relate to other irAEs, such as endocrine irAEs. Myalgia secondary to myositis should be ruled out. After evaluationand exclusion of differential diagnoses, symptomatic treatment [analgesics  nonsteroidal anti-inflammatory drugs(NSAIDs)] should be initiated.

Arthritis isdefined as joint stiffness and swelling and can present asmono-, oligo- or polyarthritis with frequent tenosynovitis.

Initial evaluation should include joint count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP),antinuclear antibodies (ANAs), analysis of synovial fluid whenever possible, X-rays and ultrasound (US) of affectedjoints.

NSAIDs should be considered in patients with mild forms of arthritis and intra-articular CS should be used in cases of mono- or oligoarthritis. Most patients, however, will require systemic CSs, which should be initiated at a moderate dose of 10-20 mg prednisone. Some patients will require long-term, low- to moderate-dose CS to enable ICI treatment continuation.

Early referral to a rheumatologist should be considered (grade 2 symptoms) before startingCSs, in cases of insufficient response to acceptable doses ofCS and in cases requiring CS-sparing regimens. In these patients, csDMARDs should be considered such as methotrexate, hydroxychloroquine or sulfasalazine. For severe inflammatory arthritis or insufficient response to acsDMARD, IL-6R inhibitors (preferred) or TNF-a inhibitorsmay be considered.

ICI treatment continuation should be evaluated on an individual basis.

PMR presents as an acute, predominantly bilateral shoulder and/or hip pain with morning stiffness and possible swelling of the hands and knees.

Diagnostic evaluation should include ESR, CRP (which may be normal), RF, anti-CCP, creatine kinase (CK) level (to rule out myositis owing to a similar clinical presentation), X-rays and US of affected joints. Giant cell arteritis should be ruled out.

Management of IRPMR is based on prednisone 10-20 mg/day for grade >2 symptoms, progressively tapered when improvement is achieved. For CS-dependent or -refractory cases, referral to a rheumatologist is recommended and methotrexate or IL-6R inhibitors should be considered, holding ICI treatment in cases of grade >3 symptoms should be considered.

IR-sicca syndrome includes mostly dry mouth and, less frequently, dry eyes and arthralgia; neurological manifestations are rare. Importantly, dry mouth may be related to the use of other drugs (i.e. morphine), RT orinfection (candidiasis).

Patients with suspected IR-sicca syndrome should be tested for ANAs, anti-Sjögren-syndrome-related antigen A autoantibodies, anti-Sjögren syndrome type B antigen, RF and C3 and C4 complement; ideally, a minor salivary gland biopsy should be carried out.

Symptomatic treatment, pilocarpine and hydroxychloroquine may be considered for any grade of IR-sicca syndrome. Systemic CSs are advocated only for extraglandular manifestations or grade 3 symptoms.

Withdrawal of ICI should be discussed in cases of grade 3symptoms.

Myositis is a rare (1%) but potentially life-threatening irAE. For cases of IR-myositis, the median exposure to ICI therapy is 4 weeks. Clinical presentation includes myalgia with axial, limb-girdle, bulbar and oculomotor weakness.

IR-myositis can be a fatal complication of ICIs due to both the involvement of bulbar muscle and secondary myocardial inflammation.Over 80% of patientswith IR-myositis experience a favourable clinical outcomewithin several months after ICI discontinuation and immunomodulatory treatment.

Diagnostic evaluation should include myositis-associated autoantibodies, MRI and electromyogram (EMG) biopsy. Fasciitis is frequently reported on MRI.

For grade 2 symptoms, CSs represent the first therapeutic choice and should be initiated at 0.5-1 mg/kg/day prednisone. In the presence of bulbar symptoms (dysphagia, dysarthria, dysphonia), dyspnoea and/or myocarditis, high-dose CS (pulses then 1-2 mg/kg) and additional treatment options such as IVIG and/or plasma exchange or selective separation may be necessary(40% of patients).

In patients with moderate symptoms(grade 2), improvement is often noted within days after ICI discontinuation.

In refractory cases, IL-6R inhibitors may be considered,as well as TNF-a inhibitors if there is associated fasciitis. ICI treatment withdrawal is necessary for grade >1 symptoms.

Purple: general categories or stratification; turquoise: combination of treatments or other systemic treatments; white: other aspects of management.Ab, antibody; AChR, acetylcholine receptor; ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibody; ANCA, anti-neutrophil cytoplasmicantibody; AST, aspartate aminotransferase; CCP, cyclic citrullinated peptide; CK, creatine kinase; CRP, C-reactive protein; CS, corticosteroid; CT, computed tomography;EMG, electromyogram; ESR, erythrocyte sedimentation rate; HLA, human leukocyte; ICI, immune checkpoint inhibitor; IL-6R, interleukin 6 receptor; IR, immune-related;i.v., intravenous; IVIG, intravenous immune globulin; LDH, lactate dehydrogenase; MG, myasthenia gravis; MMF, mycophenolate mofetil; MRI, magnetic resonanceimaging; NSAID, nonsteroidal anti-inflammatory drug; PET, positron emission tomography; PMR, polymyalgia rheumatica; RF, rheumatoid factor; RS3PE, remittingseronegative symmetrical synovitis with pitting oedema; TNF, tumour necrosis factor; US, ultrasound.aFor myositis, search for life-threatening manifestations (bulbar symptoms, dyspnoea, myocarditis)d and carry out complete diagnostic work-up: CK, AST, ALT, LDH,ferritin, troponin I or T,e myositis-associated Abs, paraneoplastic Abs, MRI, EMG  biopsy on an individual basis, anti-AChR Abs if myasthenia gravis. Rule out dermatomyositis if skin involvement.bInflammatory arthritis (either mono-, oligo- or polyarthritis, psoriatic arthritis, RS3PE syndrome) and polymyalgia rheumatica-like syndrome are the two major clinicalpresentations encountered.cIncreased CK level reported in most patients with myositis while usually within the normal range in patients presenting with myalgia.dIn case of associated MG or myocarditis, refer to specific section. eHigh-sensitivity troponin T is expressed by skeletal muscle, including regenerating skeletal muscle tissue, whereas high-sensitivity troponin I is specific to themyocardium. In case of myositis, troponin T could be increased without myocardium involvement.

• Early referral to a rheumatologist should be considered(grade 2 symptoms) before starting CSs, in cases of insufficient response to acceptable doses of CSs and incases requiring CS-sparing regimens [V, B].
• Initial evaluation of possible IR-inflammatory arthritis orIR-PMR should include joint count, analysis of synovial fluid whenever possible, ESR, CRP, RF, CCP, ANAs (for inflammatory arthritis), X-rays and US of affected joints [IV, A].
• CK level must be assessed in patients experiencing myalgia or PMR to rule out myositis. If elevated,myositis-associated autoantibodies, MRI and EMG biopsy should be considered
• Following a definitive diagnosis, symptomatic treatment(analgesics +/- NSAIDs) should be initiated for arthralgia and myalgia [IV, B].
• In patients with mild forms of arthritis or with mono- oroligoarthritis, NSAIDs and/or intra-articular CSs should be considered [IV, B].
• Prednisone 10-20 mg/day should be initiated ingrade 2 IR-inflammatory arthritis and IR-PMR, and then progressively tapered following improvement. A higher dosage (0.5 mg/kg) may be considered if no improvement, as well as csDMARDs (methotrexate, hydroxychloroquine or sulfasalazine) or bDMARDs [antiIL-6R (preferred), TNF-a inhibitor] for severe or persistent symptoms. ICI treatment continuation should be evaluated on an individual basis [IV, A].
• Prednisone 0.5-1 mg/kg should be initiated in grade 2IR-myositis. In the presence of life-threatening manifestations, high-dose CSs, IVIG and/or plasma exchange/selective separation should be considered; ICI withdrawal is always necessary [IV, A]
• Symptomatic treatment, pilocarpine and hydroxychloroquine may be considered for any grade of IR-sicca syndrome, after testing for specific autoantibodies and, if possible, minor salivary gland biopsy. Systemic CSs are advocated only in cases of extra-glandular manifestations or grade 3 symptoms [IV, B].