Table 5.

Management of Musculoskeletal irAEs in Patients Treated With ICPis

5.0 Musculoskeletal Toxicities
5.1 Inflammatory arthritis
Definition: A disorder characterized by inflammation of the joints
Clinical symptoms: Joint pain accompanied by joint swelling; inflammatory symptoms, such as stiffness after inactivity or in the morning, lasting > 30 minutes to 1 hour; improvement of symptoms with NSAIDs orcorticosteroids but notwith opioids orother pain medications may also be suggestive of inflammator/ arthritis.
Diagnostic work-up
G1
Complete rheumatologic history and examination of all peripheral joints for tenderness, swelling, and range of motion; examination of the spine   Consider plain x-ray/imaging to exclude metastases and evaluate joint damage (erosions), if appropriate   Consider autoimmune blood panel including ANA, RF, and anti-CCP, and anti-inflammatory markers (ESR and CRP) if symptoms persist; if symptoms are suggestive of reactive arthritis or affect the spine, consider HLA B27 testing
G2
Complete history and examination as above; laboratory tests as above   Consider US ± MRI of affected joints if clinically indicated (eg, persistent arthritis unresponsive to treatment, suspicion for differential diagnoses such as metastatic lesions or septic arthritis)   Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms of arthralgia persist > 4 weeks
G3–4
As for G2   Seek rheumatologist advice and review
Monitoring: Patients with inflammatory arthritis should be monitored with serial rheumatologic examinations, including inflammatory markers, every 4–6 weeks after treatment is instituted.
Grading	Management
All grades	Clinicians should follow reports of new joint pain to determine whether inflammatory arthritis is present; question whether symptom new since receiving ICPi
G1: Mild pain with inflammation, erythema, or joint swelling	Continue ICPi  Initiate analgesia with acetaminophen and/or NSAIDs
G2: Moderate pain associated with signs of inflammation, erythema, or joint swelling, limiting instrumental ADL	Hold ICPi and resume upon symptom control and on prednisone ≤ 10 mg/d  Escalate analgesia and consider higher doses of NSAIDS as needed  If inadequately controlled, initiate prednisone or prednisolone 10–20 mg/d or equivalent for 4–6 weeks  If improvement, slow taper according to response during the next 4–6 weeks; if no improvement after initial 4–6 weeks, treat as G3  If unable to lower corticosteroid dose to < 10 mg/d after 3 months, consider DMARD  Consider intra-articular corticosteroid injections for large joints Referral to rheumatology
G3–4: Severe pain associated with signs of inflammation, erythema, or joint swelling; irreversible joint damage; disabling; limiting self-care ADL	Hold ICPi temporarily and may resume in consultation with rheumatology, if recover to G1 or less  Initiate oral prednisone 0.5–1 mg/kg  If failure of improvement after 4 weeks or worsening in meantime, consider synthetic or biologic DMARD  Synthetic: methotrexate, leflunomide  Biologic: consider anticytokine therapy such as TNF-α or IL-6 receptor inhibitors. (Note: As caution, IL-6 inhibition can cause intestinal perforation; while this is extremely rare, it should not be used in patients with colitis.)  Test for viral hepatitis B, C, and latent/active TB test prior to DMARD treatment  Referral to rheumatology.
Additional considerations  Early recognition is critical to avoid erosive joint damage.  Corticosteroids can be used as partof initial therapy in inflammatory arthritis, butdue to likely prolonged treatment requirements, physicians should considerstarting corticosteroid-sparing agents earlier than one would with other irAEs  Oligoarthritis can be treated early on with intra-articular corticosteroids; consider early referral.  Consider PCP prophylaxis for patients treated with high dose of corticosteroids for > 12 weeks, as per local guidelines.
5.2 Myositis
Definition: A disorder characterized by muscle inflammation with weakness and elevated muscle enzymes (CK). Muscle pain can be present in severe cases. Can be life threatening if respiratory muscles or myocardium are involved
Diagnostic work-up  Complete rheumatologic and neurologic history regarding differential diagnosis; rheumatologic and neurologic examination, including muscle strength; and examination of the skin for findings suggestive ofdermatomyositis. Muscle weakness is more typical of myositis than pain. Consider preexisting conditions that can cause similar symptoms.  Blood testing to evaluate muscle inflammation  CK, transaminases (AST, ALT), LDH, and aldolase can also be elevated  Troponin to evaluate myocardial involvement and other cardiac testing, such as echocardiogram, as needed  Inflammatory markers (ESR and CRP)  Consider EMG, imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain and overlap with neurologic syndromes, such as myasthenia gravis, is suspected  Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as myasthenia gravis  Monitoring: CK, ESR, CRP
G1: Complete examination and laboratory work-up as above
G2: Complete history and examination as above; autoimmune myositis blood panel; EMG, MRI of affected joints  Early referral to a rheumatologist or neurologist
G3–4: As for G2  Urgent referral to a rheumatologist or neurologist
Grading	Management
G1: Mild weakness with or without pain	Continue ICPi  If CK is elevated and patient has muscle weakness, may offer oral corticosteroids, and treat as G2  Offeranalgesia with acetaminophen or NSAIDs ifthereare no contraindications
G2: Moderate weakness with or without pain, limiting age-appropriate instrumental ADL	Hold ICPi temporarilyand may resume upon symptom control, if CKis normal and prednisone dose < 10 mg; if worsens, treat as per G3  NSAIDs as needed  Referral to rheumatologist or neurologist  If CK is elevated three times or more), initiate prednisone or equivalent at 0.5–1 mg/kg  May require permanent discontinuation of ICPi in most patients with G2 symptoms and objective findings (elevated enzymes, abnormal EMG, abnormal muscle MRI or biopsy)
G3–4: Severe weakness with or without pain, limiting self-care ADL	Hold ICPi until G1 or less while off immune suppression and permanently discontinue if any evidence of myocardial involvement  Consider hospitalization for severe weakness  Referral to rheumatologist or neurologist  Initiate prednisone 1 mg/kg or equivalent. Consider 1–2 mg/kg of methylprednisolone IV or higher-dose bolus if severe compromise (weakness severely limiting mobility, cardiac, respiratory, dysphagia)  Consider plasmapheresis  Consider IVIG therapy  Consider other immunosuppressant therapy, such as methotrexate, azathioprine, or mycophenolate mofetil, if symptoms and CK levels do not improve or worsen after 4–6 weeks; rituximab is used in primary myositis but caution is advised given its long biologic duration
Additional considerations: Caution is advised with rechallenging
5.3 Polymyalgia-like syndrome
Definition: Characterized by marked pain and stiffness in proximal upper and/or lower extremities and no signs of true muscle inflammation such as CK elevation or EMG findings of myositis. No true muscle weakness, difficulty in active motion related to pain
Diagnostic work-up
G1
Complete rheumatologic history regarding differential diagnosis and examination of all joints and skin  Check for symptoms of temporal arteritis, such as headache or visual disturbances; refer to ophthalmologist if present, and consider temporal artery biopsy  ANA, RF, anti-CCP  CK to evaluate differential diagnosis of myositis  Inflammatory markers (ESR, CRP)  Monitoring: ESR, CRP
G2: Complete history and examination as above; autoimmune tests as required for differential diagnosis; early referral to a rheumatologist
G3–4: As for G2; see rheumatologist advice and review
Grading	Management
G1: Mild stiffness and pain	Continue ICPi  Initiate analgesia with acetaminophen and/or NSAIDs if there are no contraindications
G2: Moderate stiffness and pain, limiting age-appropriate instrumental ADL	Consider holding ICPi and resuming upon symptom control, prednisolone < 10 mg; if worsens, treat as per G3  Initiate prednisone 20 mg/d or equivalent; if symptoms improve, start to taper dose after 3–4 weeks  If no improvementor need for higherdosages after4weeks, escalate to G3 Consider referral to rheumatology
G3–4: Severe stiffness and pain, limiting self-care ADL	Hold ICPi and may resume, in consultation with rheumatology, if recover to G1 or less; however, note that cases of toxicity returning upon rechallenge have been reported.  Referral to rheumatology  Should initiate prednisone 20 mg/d or equivalent. If no improvement or need for higher dosages for prolonged time, may offer a corticosteroid-sparing agent such as methotrexate or IL-6 inhibition with tocilizumab (Note: As caution, IL-6 inhibition can cause intestinal perforation; while this is extremely rare, it should not be used in patients with colitis or GI metastases). Consider admission for pain control
All recommendations are expert consensus based, with benefits outweighing harms, and strength of recommendations are moderate.

Abbreviations: ADL, activities of daily living; ANA, antinuclear antibodies; CCP, citrullinated protein antibody; CK, creatine kinase; CRP, C-reactive protein; DMARD, disease-modifying antirheumatic drug; EMG, electromyography; ESR, erythrocyte sedimentation rate; ICPi, immune checkpoint inhibitor; IL, interleukin; irAE, immune-related adverseevent; IV, intravenous; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; PCP, Pneumocystis pneumonia; RF, rheumatoid factor; TNF, tumor necrosis factor.