Table 1:
Selected studies for epidemiology, evaluation, and management of rheumatologic irAEs
| Author, year (citation) | Study population | N | Results | Comments |
|---|---|---|---|---|
| Inflammatory arthritis | ||||
| Braaten et al. 2020 | ICI-induced IA with at least one follow-up after ICI cessation | 60 | Risk factors for persistent IA after ICI cessation: longer duration ICI, combo ICI therapy. Persistent IA may associate with better tumor response. Patients treated with DMARDs/biologic no worse tumor prognosis. MTX, LEF, SSA, HCQ, TNF-I. | Biased toward patients surviving long enough to have follow up after ICI cessation and for patients engaged in rheumatology care (likely more severe IA). |
| Kim et al. 2017. | ICI-induced IA treated with tocilizuma. | 3 | All patients with symptomatic improvement of IA. One had durable anti-tumor response while on tocilizumab for 18 months. | All 3 patients had melanoma. Difficult to make conclusions with N=3 regarding any effect on tumor response. |
| Subedi et al. 2020. | ICI-treated patients referred for rheumatology consult for IA | 8 | Tenosynovitis, synovitis of wrists and hands most common, also saw bone marrow edema and erosions in 3 patients | Retrospective review- MRI may identify those with high risk IA, larger prospective study needed. |
| Roberts et al. 2019. | Patients with ICI-induced IA treated with HCQ first-line | 11 | Only one patient needed methotrexate, none required biologics. Five patients received corticosteroids for IA or other irAEs in addition. Seven patients had resolution of joint pain. | Small N, but HCQ safe and effective in this population. Deserves additional study given favorable safety profile of HCQ. |
| Buder-Bakhaya et al. 2018. | Patients treated with pembrolizumab or nivolumab (+/− ipilimumab) for metastatic cutaneous malignancy | 26 (arthralgia) | Arthralgia common- 13%. Arthritis in 5–7.6%, depending on whether you count activated OA as inflammatory arthritis. 40% with arthritis needed corticosteroids and 20% other immunosuppression. | Arthralgia can be managed with NSAIDs while those with objective evidence of inflammatory arthritis more often needed corticosteroids. Raises ?: how to classify those with known OA and synovitis on imaging in the setting of ICI. |
| Cappelli et al 2018 | Patients with ICI-induced IA treated with anti-PD-1/PD-L1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy | 30 | Combo therapy: more likely to present with knee arthritis, to have higher CRP, to have other irAEs. TNF-I and methotrexate treated patients with prior tumor response had no tumor progression. | Since earlier in time (less recognition of IA as irAE) and all patients referred to rheum, likely represents more severe IA (80% needed corticosteroids). Follow up time only up to 16 months for evaluating tumor response. |
| Inflammatory arthritis and PMR (same paper) | ||||
| Ghosh et al. 2020 | Patients with IA or PMR due to ICI therapy | 294 (IA) 78 (PMR) |
Median time to onset of arthritis 4 months. Polyarthritis most common joint involvement pattern. Less than 10% positive for RF or anti-CCP. 45% needed additional immunomodulatory therapy beyond steroids. | Systematic literature review of observational studies including case reports. Incomplete data for arthritis joint patterns, serologies, arthritis outcomes based on what was included in the primary studies. Most recent SLR focusing on arthritis. |
| Belkhir et al. 2017 | Patients with seropositive (RF or anti-CCP) IA or PMR after ICI therapy | 4 (PMR) 6 (RA) |
In patients with RA, 5/6 needed steroids, 3 needed DMARD. PMR steroid dosing: prednisone 20–60 mg daily. | Small case series. Seropositive patients are the minority in ICI-induced IA. 2/3 patients with pre-ICI serum already had anti-CCP. |
| PMR | ||||
| Calabrese et al. 2019 | Patients with PMR due to ICI therapy | 20 (case series) 29 (systematic review) |
Case series and SLR. 94% received glucocorticoids (prednisone 7.5 to 60 mg daily). In case series, 30% of patients had normal inflammatory markers. | Attempted to evaluate for EULAR/ACR classification criteria but incomplete data for many cases in SLR. Whether traditional classification criteria should be used for ICI-induced disease is a question. |
| Van der Geest et. Al 2020 | Patients with PMR due to ICI therapy | 6 | Imaging study, 6 with US and 5 with PET. Uptake on PET in shoulders, hip joints, greater trochanters, sternoclavicular joints, interspinous bursae. | Small N, but useful concept given many oncology patients regularly have PET scans for tumor evaluation. |
| Myositis | ||||
| Touat et al. 2018 | Patients with metastatic cancer and myositis due to ICIs | 10 | Heterogeneity in muscle involvement: proximal pattern most common but some with ocular/bulbar/neck primarily. Corticosteroids from 1 mg/kg to 1000 mg IV methylpred used for treatment; 3 needed IVIG or PLEX. | Small number of patients but many have EMG, muscle biopsy data which is useful in describing ICI-induced myositis. |
| Matas-Garcia et al. 2020 | Patients receiving ICI with biopsy-proven inflammatory myopathy | 9 | Some muscle necrosis in all 9, perimysial/perivascular inflammatory infiltrate >> endomysial inflammatory infiltrate. Prednisone 0.5 mg/kg- 2000 mg IV per day, with 5 needing IVIG. | Small N, but helpful data on biopsy characteristics, treatments and outcomes in biopsy-proven myositis. |
| More than one irAE (epidemiology, cancer outcomes) | ||||
| Richter et al. 2019 | Retrospective single center study of ICI treated patients | 43 with rheum irAE | 2% ICI-treated patients developed IA. 71% of those with rheum irAE needed immunosuppression. Only 12% required ICI discontinuation. 2 patients died of myositis. | Likely underestimates prevalence of rheum irAE, particularly mild. IA most common rheumatic irAE. |
| Allenbach et al. 2020 | Rheumatic irAE reported to WHO pharmacovigilance database | 465 (myositis) 606 (IA) 76 (PMR) |
Fatality rate for myositis 24%. Arthritis, myositis more common in those treated with ICI combination therapy. | WHO database requires active reporting, so likely biased toward more severe events. No laboratory or imaging data to confirm diagnoses available. |
| Kostine et al. 2018 | Patients who received ICIs at a single center | N= 524 9 (IA) 11 (PMR) |
19 patients required glucocorticoids, two required methotrexate. Patients with rheum irAEs higher tumor response than those without. |
Only those referred to rheumatology were diagnosed with rheum irAE likely biasing to more severe disease. Collected from 2015–2017 when less awareness of rheum irAEs. |
| Angelopoulou et al. 2020. | Literature review of MSK irAEs | 209 (IA) 51 (myositis) 44 (PMR) |
Prevalence rate of MSK irAEs of 6% in prospective studies. 70% of patients needed corticosteroids and 18% treated with DMARDs. | Question about search technique given fewer cases found than prior SLRs. |
Anti-CCP: anti-cycliic citrullinated peptide antibodies. DMARD: disease modifying anti-rheumatic drug. ICI: immune checkpoint inhibitor. IA: inflammatory arthritis. irAE: immune related adverse event. MSK: musculoskeletal. OA: osteoarthritis. PMR: polymyalgia rheumatica. RA: rheumatoid arthritis. RF: rheumatoid factor. SLR: systematic literature review. MTX: methotrexate. LEF: leflunoide. SSA: sulfasalazine. HCQ: hydroxychloroquine. TNF-I: tumor necrosis factor alpha inhibitors.