| 5.1. Inflammatory arthritis |
Work-up and evaluation: - G1:
- Complete rheumatologic history and examination of all peripheral joints for tenderness, swelling, and range of motion. Examination of the spine.
- Consider plain radiograph or imaging to exclude metastases and evaluate joint damage (erosions) if appropriate.
- Consider autoimmune blood panel including ANA, RF, anti-CCP, and inflammatorymarkers (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 ultrasound ± MRI imaging of affected joints if clinically indicated (eg, persistent arthritis unresponsive to treatment, and suspicion for differential diagnoses such as metastatic lesions or septic arthritis). Consider arthrocentesis if septic arthritis or crystal-induced arthritis is suspected.
- Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms persist >4 weeks.
- G3-4:
- As for grade 2.
- Seek rheumatologist advice and review.
- Test for viral hepatitis B, C, and latent or active TB test before DMARD treatment. Repeated screening labs annually in patients who require biologic treatment for >1 year until treatment is completed.
Monitoring: - Patients with IA should be monitored with serial rheumatologic examinations, including inflammatory markers, every 4 to 6 weeks after treatment is instituted.
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| Grading | Management |
| All grades. | - Clinicians should follow reports of new joint pain to determine if IA is present. Question whether symptoms new since receiving ICPi.
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| G1: Mild pain with inflammation, erythema, or joint swelling. | - Continue ICPi.
- Initiate analgesia with acetaminophen and/or NSAIDs.
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| G2: Moderate pain associated with signs of inflammation, erythema, or joint swelling; limiting instrumental ADL. | - Consider holding ICPi.
- Escalate analgesia and consider higher doses of NSAIDS as needed.
- If inadequately controlled, initiate prednisone 10 to 20 mg/day or equivalent.
- If improvement, slow taper according to response during the next 4 to 6 weeks. If no improvement after initial 4 weeks treat as G3.
- If unable to lower corticosteroid dose to below 10 mg/day after 6 to 8 weeks, consider DMARD.
- Consider intra-articular steroid injections for large joints.
- Referral to rheumatology.
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| G3-4: Severe pain associated with signs of inflammation, erythema, or joint swelling; irreversible joint damage; disabling; and limiting self-care ADL. | - Hold ICPi temporarily and may resume in consultation with rheumatology, if recover to ≤G1.
- Initiate oral prednisone 0.5 to 1 mg/kg/day.
- If failure of improvement after 2 weeks or worsening in meantime, consider synthetic or biologic DMARD.
- Synthetic: methotrexate, leflunomide, hydroxychloroquine, and sulfasalazine alone or in combination.
- Biologic: Consider anticytokine therapy such as TNF-alpha or IL-6 antagonists. NOTE: As a caution, IL6 inhibition can cause intestinal perforation. Although this is extremely rare, it should not be used in patients with concomitant immune-related colitis.
- Referral to rheumatology.
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Additional considerations: - Early recognition is critical to avoid erosive joint damage.
- Corticosteroids can be used as part of initial therapy in IA, but because of likely prolonged treatment requirements, physicians should consider starting steroid-sparing agents earlier than one would with other irAEs.
- Oligoarthritis can be treated early on with intra-articular steroids, consider early referral.
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| 5.2. Myositis |
Work-up and evaluation: - Complete rheumatologic and neurologic history regarding differential diagnosis and rheumatologic and neurologic examination including muscle strength, and examination of the skin for findings suggestive of dermatomyositis. Muscle weakness is more typical of myositis than pain. Consider pre-existing conditions that can cause similar symptoms.
- Blood testing to evaluate muscle inflammation, CK, and aldolase. Transaminases (AST and ALT) and LDH can also be elevated.
- Troponin to evaluate myocardial involvement. Other cardiac testing such as ECG and echocardiogram or cardiac MRI.
- Autoantibody testing to evaluate possible concomitant myasthenia gravis (anti-AChR and antistriational antibodies).
- 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 (eg, anti-TIF1-gamma, anti-NXP2, and other myositis autoantibodies as indicated), especially if patient had muscle-related manifestations before receiving ICPi.
- Urinalysis for rhabdomyolysis.
Monitoring: - CK, ESR, CRP, and aldolase if CK has not been elevated:
- G1: Complete examination and laboratory work-up as above.
- G2: Complete history and examination as above; autoimmune myositis blood panel; EMG, MRI imaging of affected joints. Early referral to a rheumatologist or neurologist.
- G3-4: As for grade 2. Urgent referral to a rheumatologist or neurologist.
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| Grading | Management of myositis alone¶ |
| G1: Mild weakness with or without pain. | - Continue ICPi.
- If CK and/or aldolase are elevated and patient has muscle weakness may offer oral corticosteroids, starting prednisone at 0.5 mg/kg/day. Offer analgesia with acetaminophen or NSAIDs for myalgia if there are no contraindications.
- Consider holding statins.
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| G2: Moderate weakness with or without pain limiting age-appropriate instrumental ADL. | - Hold ICPi temporarily and may resume upon symptom control, if CK is normal and prednisone dose <10 mg/day; if worsens, treat as per G3.
- NSAIDs as needed.
- Referral to rheumatologist or neurologist.
- If CK is elevated (times 3 ULN or more), initiate prednisone or equivalent at 0.5 to 1 mg/kg/day.
- May require permanent discontinuation of ICPi in cases with G2 symptoms if patient had other objective findings of severe muscle involvement such as very elevated enzymes, or extensive involvement as determined by EMG, MRI or histology. ICPi should not be restarted until CK is normal and clinical manifestations of myositis are resolved.
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| G3-4: Severe weakness with or without pain; limiting self-care ADL. | - Hold ICPi.
- Consider hospitalization for patients with severe weakness severely limiting mobility, respiratory, dysphagia, or rhabdomyolysis.
- Urgent referral to rheumatologist and/or neurologist.
- Initiate prednisone 1 mg/kg/day or equivalent.
- For patients with severe compromise, administer methylprednisolone bolus dose of ≥1 to 2 mg/kg IV.
- Consider plasmapheresis in patients with acute or severe disease as guided by rheumatology or neurology.
- Consider IVIG therapy, noting onset of action is slower. NOTE: Plasmapheresis immediately after IVIG will remove immunoglobulin.
- Consider other immunosuppressant therapy including biologics (eg, rituximab), TNF-alpha, or IL-6 antagonists if symptoms worsen or if no improvement after 2 weeks. Other synthetic immunosuppressants such as methotrexate, azathioprine, or mycophenolate mofetil could be considered for maintenance,Δ or if symptoms and CK levels do not resolve entirely after 4 weeks. Rituximab is used in primary myositis.
- Consider permanent discontinuation of ICPi.
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Additional considerations: - Caution is advised with rechallenging.
- With elevated transaminases, consider differential with immune-mediated hepatitis.
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| 5.3. Polymyalgia-like syndrome |
Work-up and evaluation: - G1: Complete rheumatologic history regarding differential diagnosis and examination of all joints and skin. Rarely patients may also develop concomitant GCA. Check for symptoms of temporal arteritis, such as headache, visual disturbances, or jaw claudication. Urgent referral to ophthalmologist if present and consider temporal artery biopsy as permanent visual loss can occur within days of symptom onset.
- ANA, RF, and anti-CCP.
- CK to evaluate differential diagnosis of myositis.
- Inflammatory markers (ESR and CRP).
- Monitoring: ESR and CRP.
- ≥G2: Complete history and examination as above; autoimmune tests as required for differential diagnosis.
- Early referral to a rheumatologist.
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| Grading | Management |
| G1: Mild stiffness and pain. | - Continue ICPi.
- Initiate analgesia with acetaminophen and/or NSAIDs if there are no contraindications.
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| G2: Moderate stiffness and pain; limiting age-appropriate instrumental ADL. | - Consider holding ICPi and resuming upon symptom control, prednisone <10 mg; if worsens, treat as per G3.
- Initiate prednisone 20 mg/day or equivalent. If symptoms improve, start to taper dose after 3 to 4 weeks.
- If no improvement or need for higher dosages after 4 weeks, escalate to G3.
- Consider referral to rheumatology.
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| G3-4: Severe stiffness and pain; limiting self-care ADL. | - Hold ICPi and may resume, in consultation with rheumatology, if recover to ≤G2. However, note that cases of toxicity returning upon rechallenge have been reported.
- Referral to rheumatology.
- Should initiate prednisone 40 mg/day or equivalent. If no improvement or need for higher dosages for prolonged time, may offer a steroid sparing agent such as synthetic drugs (eg, methotrexate) or biologic agents (eg, IL-6 antagonists). NOTE: As caution, IL-6 inhibition can cause intestinal perforation. Although this is extremely rare, it should not be used in patients with immune-related colitis.
- Consider admission of patients with severe symptoms.
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Additional considerations: - IL-6 antagonists may be the preferred steroid-sparing agents for management of polymyalgia-like syndrome as they are already approved for use in patients with GCA.
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