Regulation of Inflammation in Autoimmune Diseases 2020View this Special Issue
Review Article | Open Access
Yan Xiao, Lin Zeng, Qinglin Shen, Zhiyong Zhou, Zhifang Mao, Qin Wang, Xiquan Zhang, Yingliang Li, Weirong Yao, "Diagnosis and Treatment of Rheumatic Adverse Events Related to Immune Checkpoint Inhibitors", Journal of Immunology Research, vol. 2020, Article ID 2640273, 8 pages, 2020. https://doi.org/10.1155/2020/2640273
Diagnosis and Treatment of Rheumatic Adverse Events Related to Immune Checkpoint Inhibitors
Immune checkpoint inhibitors (ICIs) have completely changed the treatment of cancer, and they also can cause multiple organ immune-related adverse reactions (irAEs). Among them, rheumatic irAE is less common, mainly including inflammatory arthritis, rheumatic myalgia/giant cell arteritis, inflammatory myopathy, and Sjogren’s syndrome. For oncologists, rheumatism is a relatively new field, and early diagnosis and treatment is very important, and we need to work closely with experienced rheumatologists. In this review, we focused on the incidence, clinical characteristics, and treatment strategies of rheumatic irAE.
In recent years, immune checkpoint inhibitors (ICIs) have made significant breakthroughs in cancer treatment. A large number of clinical trials at home and abroad have confirmed that ICIs is a broad-spectrum, long-lasting, safe, and effective antitumor drug . It can inhibit and kill tumor cells by enhancing the antitumor immune function of the body. It has shown a remarkable clinical effect in the treatment of many kinds of malignant tumors. At present, it has been approved by FDA for melanoma, lung cancer, renal cell carcinoma, Hodgkin’s lymphoma, head and neck tumor, and urothelial carcinoma . According to its mechanism of action, ICIs can be divided into three categories: programmed cell death protocol 1 (PD-1), programmed cell death protocol ligand 1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors [3, 4].
ICIs can enhance the antitumor effect of T cells by blocking the negative regulatory signals of T cells and also affect the immune tolerance of human normal tissues, resulting in immune-related adverse events (irAEs) [5, 6]. irAEs are very common in clinic, and they can occur in almost any organ during or after the treatment of ICIs, generally involving the skin, digestive tract, and endocrine system, but rheumatic irAEs seem to be less common [7–9]. In clinical practice, the common terminology criteria adverse events (CTCAE) are usually used to grade irAEs [10, 11] (for details, see Table 1). The severity is divided into G1: mild or asymptomatic; no intervention is needed; G2: moderate, affecting instrumental activities of daily living (ADL), such as shopping; limited intervention is needed; G3: serious, medical events, limiting self-care ADL, requiring hospitalization; G4: life-threatening events, requiring emergency treatment; and G5: deaths related to adverse reactions. Although most of the irAEs are levels 1 to 2, there is still 0.5%-18.0% in more than level 3 of adverse reactions, even life-threatening .
Rheumatic irAEs are different from other organs’ irAEs and traditional autoimmune diseases. Rheumatic irAEs can persist for a long time even after termination of treatment [13, 14]. Rheumatic irAEs have a wide range of manifestations, mainly including inflammatory arthritis (IA), polymyalgia rheumatica (PMR)/giant cell arteritis (GCA), inflammatory myopathy (IM), and Sjogren’s syndrome (SS). These irAEs are mainly described in patients without autoimmune diseases in the past. However, it has also been reported recently that patients with underlying rheumatic diseases have relapsed and developed new irAEs after receiving ICI treatment.
At present, clinicians have a relatively poor understanding of rheumatic irAEs. Although there are few fatal complications, it will significantly affect the functional activities of cancer patients and limit the use of ICIs . Therefore, this review will focus on the pathogenesis, incidence, clinical characteristics, and treatment strategies of rheumatic irAEs.
2. Pathogenesis of Rheumatic irAEs
CTLA-4 and PD-1/PD-L1 are important immunosuppressive molecules in the immune system, which can inhibit the activation of effector T cells and maintain the balance between the activation and inhibition of T cells. CTLA-4 acts on the early stage of T cell activation, while PD-1/PD-L1 inhibits the activated T cells in the effective stage . ICIs can enhance the antitumor activity by blocking CTLA-4 and PD-1/PD-L1 to activate effector T cells, especially CD8+ T cells, and destroying the signal transduction pathway that inhibits tumor immunity . At present, there are few studies on the pathogenesis of irAEs. The possible mechanisms can be summarized as follows: (1) overactivation of effector T cells, (2) reduction of regulatory T cell function, (3) large-scale release of IFN-γ and TNF, (4) toxic effects of macrophages and neutrophils, and (5) antibody produced by B cells. Therefore, further research is needed to explore the potential mechanism of rheumatic irAEs.
3. Incidence of Rheumatic irAEs
The mechanism of action of different types of ICIs is different, which leads to different incidence of irAEs. In general, the incidence of irAEs of CTLA-4 mAb was higher than that of PD-1/PD-L1 mAb . A meta-analysis showed that the prevalence of irAEs with CTLA-4 monoclonal antibody could be as high as 75% , while the prevalence of irAEs with PD-1 and/or PD-L1 monoclonal antibody was about 30% . In addition, CTLA-4 mAb has more serious toxicity than PD-1/PD-L1 mAb. It has been found that 43% of the patients treated with ipilimumab have level 3 or more toxic events, while less than 20% of the patients are treated with PD-1/PD-L1 mAb .
At present, the description of rheumatic irAEs mainly comes from case reports, which is easy to be ignored in clinical practice . So far, the most common symptoms of rheumatic irAEs are arthralgia/arthritis and myalgia/myositis, with the prevalence of 1-43% and 2-20%, respectively . In a phase III clinical trial for melanoma, the incidence of joint pain secondary to ipilimumab was about 5%, the incidence of joint pain secondary to pembrolizumab was 9%-20%, the incidence of joint pain secondary to nivolumab was 5%-16% , and the incidence of joint pain treated by ipilimumab and nivolumab combination was 10.5% . According to reports, the incidence of myositis caused by ICIs is 0.15-1.28%, and the probability of concomitant myocarditis is as high as 32.0% . However, in the relevant literature of ICI clinical trials, few studies describe PMR and GCA, and one retrospective study reported that the incidence of PMR caused by ICI treatment was 0.2-2.0% [26, 27]. A case of giant cell arteritis was reported in a phase I clinical trial of in the treatment of metastatic melanoma. Dry syndrome caused by ICIs has also been reported recently . In the clinical trial of nivolumab in the treatment of metastatic melanoma, 24% of the patients had dry mouth. In the clinical trial of nivolumab in the treatment of renal cancer, 3.0-11.0% of patients also have dry mouth .
In fact, the authenticity of the incidence of rheumatic irAEs is usually limited [13, 14]. On the one hand, the codes of rheumatism/musculoskeletal adverse events used in clinical trials are inconsistent. For example, arthritis can be encoded as joint pain, joint effusion, and musculoskeletal pain. If the AE code is not strictly standardized, the coding of the same symptom may be different. Therefore, the similar encoding can be integrated to better reflect the real incidence rate of rheumatic irAEs. On the other hand, the reason is the classification of CTCAE used in current clinical trials. In many clinical trials, only level 3 adverse events are reported, while rheumatic irAEs are usually mild, so they are easy to be missed. CTCAE classifies many rheumatic adverse events requiring corticosteroid or ICI treatment into level 1 or level 2. The rCTCAE compiled by OMERACT evaluates the applicability of CTCAE used in the field of oncology in the field of rheumatology, reclassifies the coded adverse events, and classifies similar symptoms into higher categories [30, 31]. Therefore, the incidence of rheumatic/musculoskeletal irAEs may be higher if this rCTCAE is used.
4. Clinical Characteristics of Rheumatic irAEs
4.1. Inflammatory Arthritis (IA)
IA is a group of diseases characterized by arthritis . The clinical manifestations of inflammatory arthritis caused by ICIs are various, which can be divided into two categories: one is similar to rheumatoid arthritis (RA), which mainly affects small joints (metacarpophalangeal joint, proximal interphalangeal joint, and the wrist and knee), which is different from the traditional RA. This kind of patients is not common in women. In the early stage of the disease, tendon involvement is more prominent, and rheumatoid factor (RF) and anti-citrulline peptide antibody (ACPA) are usually negative . Another is similar to spinal arthritis (SPA), which is characterized by oligoarthritis, mainly involving in large joints, such as inflammatory back pain, adhesion point inflammation, and phalangitis [14, 31, 33, 34]. A few patients also have reactive arthritis (conjunctivitis with oligoarthritis, asymptomatic urethritis) and psoriatic arthritis [26, 35, 36]. However, HLA-B27 was not positive in these patients .
A number of research results show that the time of joint pain after the application of ICIs is from 2 to 24 months, and the median time of joint pain disappearance is months, but musculoskeletal symptoms may last for more than one year [37–41].
4.2. PMR (Polymyalgia Rheumatica)/GCA (Giant Cell Arteritis)
PMR is an inflammatory disease, mostly in the elderly, which mainly occurs in the age of more than 50 years. Its typical clinical features are persistent pain and morning stiffness in the neck, scapula, and pelvic belt, sometimes with systemic symptoms, such as mild peripheral arthritis and dorsal edema [23, 29, 41–43]. The auxiliary examination showed that the inflammatory index was significantly increased, RF and ACPA were generally negative, and low dose hormone () was effective. The imaging manifestations of bursitis of deltoid muscle and tenosynovitis of the biceps under the shoulder may be the characteristics of RA or PMR [44, 45]. GCA is a kind of vasculitis, which mainly invades the major arteries, such as one or more branches of the carotid artery (especially the temporal artery), accompanied by granuloma formation, which is relatively rare in China . PMR and GCA represent different clinical manifestations in the same disease process. Patients with GCA often have PMR, so the two diseases are often discussed together .
After the use of ICIs, the clinical and imaging manifestations of PMR are almost the same as those of traditional PMR. In most cases, RF and ACPA are negative [23, 39, 47, 48]. It can be seen that there is a significant increase in the inflammatory index, but some studies have found that there is no increase in CRP in this part of patients with typical clinical characteristics of PMR . And some patients did not respond to low-dose prednisone . Only a few patients will cause GCA after using ICIs, mainly manifested as headache, tenderness of temporal artery, intermittent lameness of mandible, and transient diplopia. The pathological biopsy findings are consistent with the traditional GCA . It has been reported that the attack time of PMR/GCA secondary to ICIs is 10 days to 1 year [23, 26, 47].
4.3. Inflammatory Myopathy (IM)
IM is a group of heterogeneous diseases; the main pathological features are inflammatory cell infiltration and myofibrillar necrosis of skeletal muscle . Different types of IM can involve different target organs such as the skin and muscle, so the clinical manifestations are complex. Among them, idiopathic inflammatory myopathies (IIMS), including polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM), have unknown etiology and are related to autoimmunity. The IM caused by ICIs is relatively rare, and its clinical manifestations are consistent with PM. It is often manifested as myalgia, weakness of proximal muscle, ptosis of the upper eyelid, and elevation of muscle enzyme. Compared with IIMS, the symptoms of such patients are usually sudden attack, usually within two months of ICI treatment, and the symptoms generally last for 5 days to 115 weeks [25, 50].
Different from the traditional IM, the classic dermatomyositis rash caused by ICIs is rare in IM patients. The response of intravenous immunoglobulin may be poor. The specific antibody of serum myositis is usually negative, and the axial part or facial muscles may be involved [51–54]. And the frequency of overlap with myocarditis and myasthenia gravis in these patients was higher than that of traditional IM . Therefore, the diagnosis should be differentiated from tumor-related myocarditis and myasthenia gravis. A small number of patients will also have myositis syndrome with fasciitis . Up to now, there is no case of IM caused by ICIs with the unique histological characteristics of inclusion body myositis. Although the overall incidence of myositis is not high, the mortality rate can reach 17.0%, second only to myocarditis . At the same time, the mortality rate of myocarditis or other neuromuscular diseases is higher, which is usually caused by heart failure or respiratory failure [50, 57]. It is worth noting that there may be cases with normal muscle enzymes or muscle involvement, but no myasthenia or myalgia [58–63]. In view of the high mortality rate of myositis, we should pay attention to the dynamic monitoring of muscle enzyme changes in patients with clinical high suspicion of IM and carry out muscle biopsy if necessary.
4.4. Sjogren’s Syndrome (SS)
SS is a chronic inflammatory autoimmune disease involving mainly exocrine glands such as salivary glands and lacrimal glands . The main clinical manifestations are dry mouth, dry eyes, rampant caries, and mumps. The serum autoantibody is anti-SSA or anti-SSB (+), and the dry mouth is responsive to sialidase treatment. Warner  et al. discussed the clinicopathological characteristics of SS related to ICI treatment, evaluated 20 patients with xerostomia, and found that the median interval between ICI treatment and xerostomia attack was 70 days, mainly manifested as more serious xerostomia symptoms at night or after exercise, hoarseness of voice, change of taste, sensitivity to spicy or acid food, and abnormal parotid swelling or tenderness. Only 2 of them were positive for RA and anti-SSA. Labial salivary gland biopsy (LSGB) showed mild to severe sialitis, which was different from traditional SS, with diffuse lymphocytic infiltration and acinar injury. There were T lymphocyte aggregation in 8 patients, mainly CD3+ T cells; PD-1/PD-L1 was positive. In addition, it has been reported that 4 cases of severe salivary hypofunction after treatment with nivolumab, ipilimumab, or combination therapy have been described. Anti-Ro antibody is negative, only 1 case has parotitis, parotid ultrasound shows hypoechoic focus, and anti-LA/SSB antibody indicates positive .
5. Treatment of Rheumatic irAEs
For the whole process management of rheumatic irAEs, the European Society for Medical Oncology (EMSO), the National Comprehensive Cancer Network (NCCN), and the Chinese Society of Clinical Oncology (CSCO) have developed immune-related toxicity management guidelines according to the consensus of experts. These guidelines were issued by consensus of experts from various disciplines, and no prospective test was conducted [65, 66]. Recent studies have shown that patients with rheumatic irAEs have better prognosis in tumor treatment than other irAEs . Therefore, it is very important for oncologists to properly manage these rheumatic irAEs.
5.1. Treatment Strategy of Inflammatory Arthritis
IA is the most common clinical manifestation in rheumatic irAEs. In consideration of this diagnosis, it is necessary to evaluate the joint function and improve the laboratory tests such as ESR/CRP, ANA, RF, and ACPA, and it is feasible to determine the number of joint involvements by joint X-ray, MRI, or musculoskeletal ultrasound. ESMO, NCCN, and CSCO guidelines all provide specific recommendations for the treatment of IA, and the overall treatment principles are basically the same (Table 2). For patients above the G2 level, patients whose symptoms last more than 6 weeks or need more than 20 mg of prednisone per day and cannot decrease to less than 10 mg/D within 4 weeks should be considered to be transferred to rheumatology department .
5.2. Treatment Strategy of RA and GCA
The incidence rate of PMR and GCA is low. For patients with suspected PMR, ESR and CRP are necessary. Ultrasound examination of the shoulder and buttocks is also necessary. If visual symptoms or headache occurs, then temporal artery ultrasound and biopsy are considered. At present, only suggestions for PMR/GCA treatment are put forward in NCCN guidelines. The treatment principle of PMR is shown in Table 3. The difference between the treatment strategy of GCA and PMR lies in stopping immunotherapy immediately after diagnosis, giving 1 mg/kg/D prednisone and decreasing in quantity within 8-12 weeks. If accompanied by visual symptoms, consider steroid pulse therapy (methylprednisolone 500-1000 mg) and consult with the eye. For GCA, the rheumatology department should be consulted even for mild cases to prevent permanent organ damage .
5.3. Treatment Strategy of Myositis or Myalgia
IM is also one of the common clinical manifestations of rheumatic irAEs. Once it occurs, the mortality is high. During the diagnosis, we should perfect the examination of creatine kinase/aldolase, troponin, myositis antibody, muscle MRI, and electromyogram; take muscle biopsy if necessary; and focus on the possibility of myasthenia gravis or myocarditis. The ESMO guidelines do not mention the treatment of ICI-related myositis. See Table 4 for the treatment principles of NCCN and CSCO compass for the disease. The treatment principles of the two are slightly different. For G1 patients, NCCN guidelines consider the need to stop immunotherapy, while CSCO guidelines consider whether to continue to use ICIs through a comprehensive assessment of patients’ muscle strength. In the actual clinical work, for all suspected cases of myositis, myasthenia, and creatine kinase elevation, we should keep a high vigilance and timely refer to the rheumatology department or neurology department to avoid life-threatening situations .
5.4. Treatment Strategy of Sjogren’s Syndrome and Other Connective Tissue Diseases
There are no specific and detailed treatment suggestions for SS and other connective tissue diseases. The treatment of these diseases mainly refers to the treatment principle of traditional rheumatism and adjusts the dosage of glucocorticoid and immune checkpoint inhibitors according to the severity of organ involvement. Most of the patients with SS described in the case reports were treated with systemic glucocorticoids, with an average dose of prednisone of 40 mg/D, and a few patients with severe disease were treated with IVIG and other immunosuppressive therapy [41, 67, 68]. Pilocarpine, as a muscarinic receptor agonist, can also effectively improve the symptoms of xerostomia. Similarly, other connective tissue diseases can be treated with systemic hormone. For example, in one patient with lupus nephritis after treatment with ipilimumab, renal function was significantly improved after treatment with 1 mg/kg prednisone .
With the wide application of ICIs, the emergence of irAEs in clinical work has brought many challenges to oncologists but also opened up new research areas. Among them, rheumatic irAEs are relatively rare, mainly including inflammatory arthritis, rheumatic myalgia/giant cell arteritis, inflammatory myopathy, and Sjogren’s syndrome. These diseases should be distinguished from traditional rheumatic diseases. At present, irAEs are generally classified by CTCAE and managed according to the standard international guidelines. The therapeutic drugs mainly include NSAIDs, glucocorticoids, and DMARDs. For oncologists, rheumatism is a relatively new field, we must improve the understanding of rheumatic irAEs, understand its pathogenesis, clinical characteristics, and treatment methods.
Although the overall incidence of rheumatic irAEs is not high, we still need to be vigilant. Oncologists need to actively cooperate with experienced rheumatologists to improve the diagnosis rate of rheumatic irAEs, timely referral so as not to delay the treatment opportunity, and at the same time, weigh the advantages and disadvantages to decide whether to continue the treatment of ICIs.
Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Yan Xiao, Lin Zeng, and Qinglin Shen contributed equally to this work.
- D. S. Chen and I. Mellman, “Elements of cancer immunity and the cancer-immune set point,” Nature, vol. 541, no. 7637, pp. 321–330, 2017.
- W. Pönisch, R. Alten, and C. Baerwald, “Autoimmune reactions to immune checkpoint inhibitors,” Zeitschrift Für Rheumatologie, vol. 76, Supplement 2, pp. 57–62, 2017.
- A. Hoos, “Development of immuno-oncology drugs -- from CTLA4 to PD1 to the next generations,” Nature Reviews Drug Discovery, vol. 15, no. 4, pp. 235–247, 2016.
- M. A. Postow, M. K. Callahan, and J. D. Wolchok, “Immune checkpoint blockade in cancer therapy,” Journal of Clinical Oncology, vol. 33, no. 17, pp. 1974–1982, 2015.
- M. Z. Afzal, R. Mabaera, and K. Shirai, “Metastatic uveal melanoma showing durable response to anti-CTLA-4 and anti-PD-1 combination therapy after experiencing progression on anti-PD-1 therapy alone,” Journal for Immunotherapy of Cancer, vol. 6, no. 1, p. 13, 2018.
- A. Inno, G. Metro, P. Bironzo et al., “Pathogenesis, clinical manifestations, and management of immune checkpoint inhibitors toxicity,” Tumori Journal, vol. 103, no. 5, pp. 405–421, 2017.
- L. Calabrese and X. Mariette, “The evolving role of the rheumatologist in the management of immune-related adverse events (irAEs) caused by cancer immunotherapy,” Annals of the Rheumatic Diseases, vol. 77, no. 2, pp. 162–164, 2018.
- J. S. Weber, F. S. Hodi, J. D. Wolchok et al., “Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma,” Journal of Clinical Oncology, vol. 35, no. 7, pp. 785–792, 2017.
- V. M. Thomas, P. Bindal, S. A. Alexander, and K. McDonald, “Nivolumab-induced hepatitis: a rare side effect of an immune check point inhibitor,” Journal of Oncology Pharmacy Practice, vol. 26, no. 2, pp. 459–461, 2020.
- A. Trotti, A. D. Colevas, A. Setser, and E. Basch, “Patient-Reported outcomes and the evolution of adverse event reporting in oncology,” Journal of Clinical Oncology, vol. 25, no. 32, pp. 5121–5127, 2007.
- M. W. Schoen, E. Basch, L. L. Hudson et al., “Software for administering the National Cancer Institute’s patient-reported outcomes version of the common terminology criteria for adverse events: usability study,” JMIR Human Factors, vol. 5, no. 3, article e10070, 2018.
- S. Champiat, O. Lambotte, E. Barreau et al., “Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper,” Annals of Oncology, vol. 27, no. 4, pp. 559–574, 2016.
- L. H. Calabrese, C. Calabrese, and L. C. Cappelli, “Rheumatic immune-related adverse events from cancer immunotherapy,” Nature Reviews Rheumatology, vol. 14, no. 10, pp. 569–579, 2018.
- L. C. Cappelli, A. A. Shah, and C. O. Bingham III, “Immune-related adverse effects of cancer immunotherapy— implications for rheumatology,” Rheumatic Diseases Clinical North America, vol. 43, no. 1, pp. 65–78, 2017.
- S. Jamal, M. Hudson, A. Fifi-Mah, and C. Ye, “Immune-related adverse events associated with cancer immunotherapy: a review for the practicing rheumatologist,” The Journal of Rheumatology, vol. 47, no. 2, pp. 166–175, 2020.
- L. Dyck and K. H. G. Mills, “Immune checkpoints and their inhibition in cancer and infectious diseases,” Europe Journal of Immunology, vol. 47, no. 5, pp. 765–779, 2017.
- D. Day and A. R. Hansen, “Immune-related adverse events associated with immune checkpoint inhibitors,” Biodrugs Clinical Immunotherapeutics Biopharmaceuticals & Gene Therapy, vol. 30, no. 6, pp. 571–584, 2016.
- S. Bowyer, P. Prithviraj, P. Lorigan et al., “Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy,” British Journal of Cancer, vol. 114, no. 10, pp. 1084–1089, 2016.
- S. Baxi, A. Yang, R. L. Gennarelli et al., “Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis,” BMJ Clinical Research, vol. 360, no. 14, p. 793, 2018.
- K.-A. Lee, H. R. Kim, and S. Y. Yoon, “Rheumatic complications in cancer patients treated with immune checkpoint inhibitors,” The Korean Journal of Internal Medicine, vol. 34, no. 6, pp. 1197–1209, 2019.
- L. C. Cappelli, A. A. Shah, and C. O. Bingham III, “Cancer immunotherapy-induced rheumatic diseases emerge as new clinical entities,” RMD Open, vol. 2, no. 2, article e000321, 2016.
- L. C. Cappelli, A. K. Gutierrez, C. O. Bingham III, and A. A. Shah, “Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature,” Arthritis Care and Research, vol. 69, no. 11, pp. 1751–1763, 2017.
- R. Belkhir, S. L. Burel, L. Dunogeant et al., “Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment,” Annals of the Rheumatic Diseases, vol. 76, no. 10, pp. 1747–1750, 2017.
- J. Larkin, V. Chiarion-Sileni, R. Gonzalez et al., “Combined nivolumab and ipilimumab or monotherapy in untreated melanoma,” New England Journal Medicine, vol. 373, no. 1, pp. 23–34, 2015.
- A. Moreira, C. Loquai, C. Pföhler et al., “Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors,” Euroupe Journal of Cancer, vol. 106, pp. 12–23, 2019.
- M. Kostine, L. Rouxel, T. Barnetche et al., “Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study,” Annals of the Rheumatic Diseases, vol. 77, no. 3, pp. 393–398, 2018.
- B. Le Burel, S. Champiat, C. Mateus et al., “Prevalence of immune-related systemic adverse events in patients treated with anti-programmed cell death 1/anti-programmed cell death-ligand 1 agents: a single-centre pharmacovigilance database analysis,” Europe Jounal of Cancer, vol. 82, pp. 34–44, 2017.
- V. Capozzi, S. Makhoul, E. Aprea et al., “PTR-MS characterization of VOCs associated with commercial aromatic bakery yeasts of wine and beer origin,” Molecules, vol. 21, no. 4, p. 483, 2016.
- R. J. Motzer, B. I. Rini, D. F. McDermott et al., “Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial,” Journal of Clinical Oncology, vol. 33, no. 13, pp. 1430–1437, 2015.
- T. Woodworth, D. E. Furst, R. Alten et al., “Standardizing assessment and reporting of adverse effects in rheumatology clinical trials II: the rheumatology common toxicity criteria v. 2.0,” Journal of Rheumatology, vol. 34, no. 6, pp. 1401–1414, 2007.
- I. Puzanov, A. Diab, K. Abdallah et al., “Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group,” Journal for Immunotherapy of Cancer, vol. 5, no. 1, p. 95, 2017.
- A. Haikal, E. Borba, T. Khaja, G. Doolittle, and P. Schmidt, “Nivolumab-induced new-onset seronegative rheumatoid arthritis in a patient with advanced metastatic melanoma: a case report and literature review,” Avicenna Journal of Medicine, vol. 8, no. 1, pp. 34–36, 2018, 8.
- M. Tocut, R. Brenner, and G. Zandman-Goddard, “Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors,” Autoimmunity Reviews, vol. 17, no. 6, pp. 610–616, 2018.
- K. Ohnuma, R. Hatano, N. H. Dang, and C. Morimoto, “Rheumatic diseases associated with immune checkpoint inhibitors in cancer immunotherapy,” Modern Rheumatology, vol. 29, no. 5, pp. 721–732, 2018.
- S. Law-Ping-Man, A. Martin, E. Briens, L. Tisseau, and G. Safa, “Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced lung cancer,” Rheumatology, vol. 55, no. 11, pp. 2087–2089, 2016.
- B. Ruiz-Bañobre, E. Pérez-Pampín, J. García-González et al., “Development of psoriatic arthritis during nivolumab therapy for metastatic non-small cell lung cancer, clinical outcome analysis and review of the literature,” Lung Cancer, vol. 108, pp. 217–221, 2017.
- M. H. Smith and A. R. Bass, “Arthritis after cancer immunotherapy: symptom duration and treatment response,” Arthritis Care Research, vol. 71, no. 3, pp. 362–366, 2019.
- M. J. Mooradian, M. Nasrallah, J. F. Gainor et al., “Musculoskeletal rheumatic complications of immune checkpoint inhibitor therapy: a single center experience,” Seminars in Arthritis and Rheumatism, vol. 48, no. 6, pp. 1127–1132, 2019.
- M. Lidar, E. Giat, D. Garelick et al., “Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors,” Autoimmunity Reviews, vol. 17, no. 3, pp. 284–289, 2018.
- L. C. Cappelli, A. K. Gutierrez, A. N. Baer et al., “Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab,” Annals of the Rheumatic Diseases, vol. 76, no. 1, pp. 43–50, 2016.
- C. Calabrese, E. Kirchner, K. Kontzias, V. Velcheti, and L. H. Calabrese, “Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity,” RMD Open, vol. 3, no. 1, article e000412, 2017.
- M. L. Gauci, B. Baroudjian, P. Laly et al., “Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome induced by nivolumab,” Seminars in Arthritis and Rheumatism, vol. 47, no. 2, pp. 281–287, 2017.
- K. Nakamagoe, T. Moriyama, H. Maruyama et al., “Polymyalgia rheumatica in a melanoma patient due to nivolumab treatment,” Journal Cancer Research Clinical Oncology, vol. 143, no. 7, pp. 1357-1358, 2017.
- C. Salvarani, F. Cantini, L. Boiardi, and G. G. Hunder, “Polymyalgia rheumatica and giant-cell arteritis,” The New England Journal of Medicine, vol. 347, no. 4, pp. 261–271, 2002.
- B. Dasgupta, M. A. Cimmino, H. Maradit-Kremers et al., “2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative,” Annals of the Rheumatic Diseases, vol. 71, no. 4, pp. 484–492, 2012.
- M. Gonzalez-Gay, E. Matteson, and S. Castaneda, “Polymyalgia rheumatica,” The Lancet, vol. 390, no. 10103, pp. 1700–1712, 2017.
- B. L. Goldstein, L. Gedmintas, and D. J. Todd, “Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of ctla-4,” Arthritis Rheumatology, vol. 66, no. 3, pp. 768-769, 2014.
- M. Bernier, C. Guillaume, N. Leon et al., “Nivolumab causing a polymyalgia rheumatica in a patient with a squamous non-small cell lung cancer,” Journal of Immunotherapy, vol. 40, no. 4, pp. 129–131, 2017.
- A. Selva-O'Callaghan, I. Pinal-Fernandez, E. Trallero-Araguás, J. C. Milisenda, J. M. Grau-Junyent, and A. L. Mammen, “Classification and management of adult inflammatory myopathies,” The Lancet Neurology, vol. 17, no. 9, pp. 816–828, 2018.
- M. Touat, T. Maisonobe, S. Knauss et al., “Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer,” Neurology, vol. 91, no. 10, pp. 985–994, 2018.
- M. Shah, J. H. Tayar, N. Abdel-Wahab, and M. E. Suarez-Almazor, “Myositis as an adverse event of immune checkpoint blockade for cancer therapy,” Seminars in Arthritis and Rheumatism, vol. 48, no. 4, pp. 736–740, 2019.
- H. Kadota, T. Gono, Y. Shirai, Y. Okazaki, M. Takeno, and M. Kuwana, “Immune checkpoint inhibitor-induced myositis: a case report and literature review,” Current Rheumatology Reports, vol. 21, no. 4, pp. 1747–1750, 2019.
- T. Liewluck, J. C. Kao, and M. L. Mauermann, “PD-1 inhibitor-associated myopathies,” Journal of Immunotherapy, vol. 41, no. 4, pp. 208–211, 2018.
- E. L. Mitchell, P. K. H. Lau, C. Khoo et al., “Rheumatic immune-related adverse events secondary to anti-programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti- tumour response: A case series,” Europe Journal of Cancer, vol. 105, no. 10, pp. 88–102, 2018.
- S. Suzuki, N. Ishikawa, F. Konoeda et al., “Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan,” Neurology, vol. 89, no. 11, pp. 1127–1134, 2017.
- J. Narváez, P. Juarez-López, J. LLuch et al., “Rheumatic immune-related adverse events in patients on anti-PD-1 inhibitors: Fasciitis with myositis syndrome as a new complication of immunotherapy,” Autoimmunity Reviews, vol. 17, no. 10, pp. 1040–1045, 2018.
- J. Bourgeois-Vionnet, B. Joubert, E. Bernard et al., “Nivolumab-induced myositis: a case report and a literature review,” Journal of the Neurological Sciences, vol. 387, no. 10, pp. 51–53, 2018.
- G. Hunter, C. Voll, and C. A. Robinson, “Autoimmune inflammatory myopathy after treatment with ipilimumab,” The Canadian Journal of Neurological Sciences, vol. 36, no. 4, pp. 518–520, 2009.
- M. Yoshioka, N. Kambe, Y. Yamamoto, K. Suehiro, and H. Matsue, “Case of respiratory discomfort due to myositis after administration of nivolumab,” The Journal of Dermatology, vol. 42, no. 10, pp. 1008-1009, 2015.
- L. Saini and N. Chua, “Severe inflammatory myositis in a patient receiving concurrent nivolumab and azacitidine,” Leukemia Lymphoma, vol. 58, no. 8, pp. 2011–2013, 2016.
- Y. H. Chen, F. C. Liu, C. H. Hsu, and C. F. Chian, “Nivolumab induced myasthenia gravis in a patient with squamous cell lung carcinoma: case report,” Medicine, vol. 96, no. 27, article e7350, 2017.
- H. Vallet, A. Gaillet, N. Weiss et al., “Pembrolizumab-induced necrotic myositis in a patient with metastatic melanoma,” Annals of Oncology, vol. 27, no. 7, pp. 1352-1353, 2016.
- B. Koh, K. Tuite, A. Khattak, and J. M. Dyke, “Lymphocyte involvement in nivolumab-induced autoimmune myositis,” Pathology, vol. 51, no. 5, pp. 555–557, 2019.
- B. M. Warner, A. N. Baer, E. J. Lipson et al., “Sicca syndrome associated with immune checkpoint inhibitor therapy,” The Oncologist, vol. 24, no. 9, pp. 1259–1269, 2019.
- J. B. A. G. Haanen, F. Carbonnel, C. Robert et al., “Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†,” Annals of Oncology, vol. 29, no. 4, pp. 264–266, 2017.
- J. R. Brahmer, C. Lacchetti, B. J. Schneider et al., “Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline,” Journal of Clinical Oncology, vol. 36, no. 17, pp. 1714–1768, 2018.
- S. Le Burel, S. Champiat, E. Routier et al., “Onset of connective tissue disease following anti-PD1/PD-L1 cancer immunotherapy,” Annals of the Rheumatic Diseases, vol. 77, no. 3, pp. 468–470, 2018.
- E. I. Dumbrava, V. Smith, R. Alfattal, A. K. El-Naggar, M. Penas-Prado, and A. M. Tsimberidou, “Autoimmune granulomatous inflammation of lacrimal glands and axonal neuritis following treatment with ipilimumab and radiation therapy,” Journal of Immunotherapy, vol. 41, no. 7, pp. 336–339, 2018.
- F. Fadel, K. Karoui, and B. Knebelmann, “Anti-CTLA4 antibody-induced lupus nephritis,” The New England Journal of Medicine, vol. 361, no. 2, pp. 211-212, 2009.
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