A 65-year-old man with non-small cell lung cancer (NSCLC) and no history of joint disease presented with a 1-week history of arthralgia in his knees after having received five doses of pembrolizumab (anti-programmed death 1 [PD-1] antibody). He developed pain and swelling in both knees and had difficulty walking. A physical examination revealed tenderness in both knees with a small to moderate degree of effusion. Laboratory studies revealed an elevated erythrocyte sedimentation rate (ESR) of 74 mm/hr (normal range, 0 to 15) and a C-reactive protein (CRP) level of 4.62 mg/dL (normal range, 0.01 to 0.3). Rheumatoid factor (RF), anti-cyclic citrullinated antibodies, and anti-nuclear antibodies (ANA) were negative. How should this patient’s case be managed?

Immune checkpoint inhibitors (ICIs) have recently led to a paradigm shift in various cancer treatments. ICIs against cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and PD-1 have shown clinically significant anti-cancer effects in various cancer types, including melanoma, NSCLC, urothelial cancers, gastrointestinal cancers, and genitourinary cancers [1-4]. The outstanding benefit of ICIs is that they can lead to long-term survival in some subsets of advanced metastatic cancer patients [1,3,5]. This long-term survival benefit is quite rare in the field of cytotoxic chemotherapy and molecular targeted therapy for advanced solid cancers. ICIs revitalize exhausted T-cells by reversing immune tolerance to the cancer cells.

Antigen presenting cells normally elicit an immune response by presenting diverse cancer cell antigens to T-cells. Naïve T-cells are stimulated to convert to cytotoxic T-cells by recognizing tumor antigens with the help of various co-stimulatory ligands and immune cytokines [6]. However, this immune surveillance is jeopardized by immune checkpoints. Immune checkpoints inhibit the overreaction of the immune system that leads to T-cell anergy, exhaustion, and death, so-called immune tolerance [7]. Immune checkpoint (inhibitory) signals play an important role in self-tolerance under normal conditions to prevent hyper-reactive autoimmune responses. Immune tolerance (mediated by immune checkpoints) becomes pathologically predominant in patients with advanced metastatic cancer, resulting in cancer cell proliferation and survival. The major immune checkpoint is CTLA-4 at the antigen presentation stage in dendritic cells (DCs) and PD-1 at the T-cell activation stage. ICIs upregulate immune surveillance against cancer cells by reinvigorating cytotoxic T-cells, resulting in a robust anti-tumor response in advanced solid cancer patients [8]. Despite their considerable anti-cancer effects, ICIs can induce profound inflammatory and immune-related adverse events (irAEs) [9], which can be severe and present challenges for their clinical application. IrAEs can affect almost any organ system, including the endocrine, pulmonary, gastrointestinal, and skin systems (Table 1) [10]. The pattern of these auto-inflammatory and autoimmune toxic effects appears to differ considerably from the side effects of conventional chemotherapeutic agents [2,11], which usually present immune suppressive side effects due to neutropenia.

Of the irAEs, rheumatic irAEs are commonly underestimated because they present less fatal complications; however, they significantly affect the quality of life of cancer patients and limit the use of ICIs [12]. In this review, the mechanisms of ICIs and irAEs are described, with a special focus on rheumatologic irAEs in terms of their prevalence, clinical characteristics, diagnosis, and treatment.

Immune surveillance, a natural defense mechanism between cancer and the immune system resulting in the elimination of cancer, is a widely accepted phenomenon [13]. Cancer cells initially induce an immune response resulting in the destruction of malignant cells, a process known as immune surveillance. However, immune surveillance fails to recognize the ‘edited’ tumor cells that have escaped surveillance. Immunoediting leads to pro-tumor immunity that blocks anti-tumor adaptive and innate responses and promotes cancer progression. Cancer immunoediting from immune surveillance to immune escape is one of the key phenomena underlying why tumors evade surveillance [14]. Chronic stimulation by malignant cells exhausts T-cells, which are referred to as ‘exhausted T-cells.’ Both innate and adaptive immunity have negative and positive effects on cancer, either by promoting cancer cell survival or by destroying cancer cells. As a result, the immune system has the potential to either promote cancer cell proliferation or cell death. CD8+ T-cells are the principal effector cells of adaptive immunity and immunotherapy, activating and revitalizing these cytotoxic effector T-cells [15]. Increased understanding of immune tolerance by immunoediting will be the foundation for cancer immunotherapy.

ICIs act at two stages of immune checkpoints: T-cell unresponsiveness at the time of activation of naïve T-cells (early stage) and T-cell downregulation and programmed cell death at the effector stage (late stage) [8]. The first immune checkpoint is the CTLA-4 T-cell, which binds the B7 ligand, blocking the costimulatory CD28-B7 interaction during antigen presentation by DCs. CTLA-4 blocks the costimulatory signal leading to T-cell unresponsiveness despite the presentation of tumor antigens [16]. The CTLA-4 inhibitor, an important early ICI, prevents T-cell unresponsiveness and results in T-cell activation [17]. The second immune checkpoint is PD-1, an already activated effector of cytotoxic T-cells [18]. PD-1 binds to programmed death ligand 1 (PD-L1) or programmed death ligand 2 (PD-L2), which are frequently expressed on cancer cells, leading to T-cell exhaustion, anergy, and apoptosis, the main mechanisms of immune escape by cancer cells [19]. Anti-PD-1 or anti-PD-L1 inhibitors act at this second stage, interrupting immune tolerance and leading to T-cell revitalization and stimulation of the ability of T-cells to attack the tumor cells [14,15]. Fig. 1 graphically showed the mechanism of immune check point inhibitors.

Several ICIs have been approved by the U.S. Food and Drug Administration (FDA) and the Korean FDA: Ipilimumab (Yervoy, Bristol-Myers Squibb, New York, NY, USA) an anti-CTLA-4 antibody, the first agent approved for treatment of advanced melanoma, and pembrolizumab (Keytruda, Merck, Kenilworth, NJ, USA) plus nivolumab (Opdivo, Bristol-Myers Squibb), which are anti-PD-1 antibodies that have been approved for melanoma, metastatic NSCLC, head and neck squamous cell carcinoma, urothelial cancer, gastric adenocarcinoma, mismatch-repair-deficient solid tumors, and classic Hodgkin’s lymphoma. Nivolumab has also been approved for hepatocellular carcinoma and renal cell carcinoma. Pembrolizumab has been approved for PD-L1 positive cholangiocarcinoma, ovarian cancer, and thymic carcinoma. The combination of ipilimumab and nivolumab for advanced melanoma has also received US FDA approval. The PD-L1 antibodies atezolizumab (Tecentriq, Genentech Inc., South San Francisco, CA, USA), durvalumab (Imfinzi, AstraZeneca, Cambridge, UK), and avelumab (Bavencio, Pfizer, New York, NY, USA) have also received approval in the United States. These ICIs, which block CTLA-4, PD-1, and PD-L1, are being rapidly approved for various types of cancer; their indicated use has been extended in Korea and other countries [20]. The field of immuno-oncology is evolving rapidly. Table 2 summarizes the available ICIs and the corresponding types of cancer for which they have been approved according to target site.

The irAE mechanisms of ICIs can be grouped into three categories: (1) The tumor antigen itself is a self-antigen, so the ICIs attack not only cancer cells but also normal cells. (2) Epitope spreading (determinant spreading); cancer cells secrete both tumor-associated antigens (neo-antigens) and self-antigens. The initial immune response attacks tumor-associated antigens (initial dominant epitope), after which it broadens and diversifies immunity to self-antigens (secondary endogenous epitope), resulting in an auto-inflammatory response to self-antigen-containing normal cells, which is another important mechanism of chronic autoimmune or inflammatory responses [21]. (3) The anti-CTLA-4 antibody downregulates regulatory T-cells (Treg), leading to immune revitalization and attack of normal self-cells [22-24]. However, the exact irAE mechanisms have not been fully elucidated. Although ICIs are usually less toxic than traditional chemotherapy, the toxicology profile of immuno-oncological drugs differs considerably from traditional chemotherapy immunosuppressive complications, especially neutropenic infections, and these drugs display a new spectrum of adverse events of autoimmune or auto-inflammatory origin—the so-called irAEs [9,13]. It is imperative that clinicians are aware of the unique toxicity profiles of ICIs with rapidly increasing use. IrAEs have been reported in almost every organ system, including the gastrointestinal, endocrine, respiratory, skin, rheumatic, renal, and neural systems. Table 1 summarizes the irAEs reported in each organ. IrAEs can occur in a single organ or in several organs by the process of immune activation [11].

The onset time of irAEs is within 3 months from the start of ICI use. However, irAEs can occur even 1 year after the discontinuation of immuno-oncology therapy [10]. Although there is no specific role for the pathologic diagnosis by biopsy when diagnosing irAEs, accurate diagnoses are necessary to select appropriate treatment strategies for Grades 3 and 4 severe cutaneous, gastrointestinal, renal, and pulmonary irAEs. Careful patient selection, baseline assessment of underlying autoimmune disease, and collection of family history are necessary before initiating treatment with ICIs. Awareness and early diagnosis are essential for the management of irAEs, including cessation of ICIs and timely use of glucocorticoid treatment [25]. High-dose steroids, tumor necrosis factor-α (TNF-α) blockers, mycophenolate, and tacrolimus should be considered to manage irAEs depending on the grade and organ involvement. A meta-analysis revealed that the prevalence of irAEs is up to 75% for anti-CTLA-4 [26] and close to 30% for anti-PD-1 and/or anti-PD-L1 therapies [27]. Some patterns of toxicity are associated with specific immunotherapy drugs or cancer types. Anti-CTLA-4 antibodies are associated with more severe toxicities than anti-PD-1/PD-L1 antibodies: up to 43% of patients treated with ipilimumab (anti-CTLA-4 antibody) suffer from Grade 3 or more toxic events, compared with less than 20% of patients treated with anti-PD-1 or anti-PD-L1 antibodies. Although most irAEs are mild to moderate, fatal complications can occur in up to 2% of patients, mostly caused by severe pneumonitis, fulminant bowel disease, and more rarely by myocarditis, encephalitis, toxic epidermal necrolysis, and type 1 diabetes with acute ketoacidosis. Of the irAEs, rheumatic complications are common, but are difficult to diagnose and have quite distinct characteristics from irAEs of other organ systems, in terms of variable onset time and capacity to persist even after cessation of ICIs [12,28]. This review considers the prevalence, clinical characteristics, and treatment approaches for rheumatic irAEs.

Musculoskeletal symptoms, such as arthralgia and myalgia, are likely to occur in 5% to 16% of cancer patients undergoing treatment with ICIs [29], whereas severe or life-threatening musculoskeletal irAEs are rare. Clinician awareness of musculoskeletal irAEs is relatively poor, but musculoskeletal irAEs can have a significant effect on functional activities, leading to a reduced quality of life. This review focuses on the epidemiology, clinical manifestations, and management of the most frequent musculoskeletal irAEs, which are inflammatory arthritis, myositis, and polymyalgia rheumatica (PMR)-like syndrome [28].

The development of irAEs during ICI treatment suggests shifting from the exhausted T-cell phenotype to an active effector T-cell phenotype. However, the question of the relationship between the occurrence of irAEs and the anti-tumor response to ICI treatment remains unanswered. A prospective cohort study from a single center found that patients experiencing rheumatic or other type of irAEs had a higher response rate to ICI treatment compared to those without [35]. However, two retrospective studies yielded conflicting results. One study found an association between cutaneous irAEs and overall survival in melanoma patients treated with nivolumab [58], while the other found that overall survival was not affected by occurrence of irAEs in melanoma patients treated with ipilimumab [12]. Further studies are needed to clarify the association between irAEs and the tumor response to ICIs.

Data on the safety of ICIs in patients with cancer and underlying autoimmune diseases are limited, and guidelines or recommendations for these patients are missing. Patients with preexisting autoimmune diseases were excluded from the initial clinical trials for FDA approval of ICIs [12]. Several retrospective studies found that 6.25% to 55% patients with autoimmune diseases who were treated with ICIs, experienced disease flares, and another 16% to 22% developed new irAEs while receiving ICI therapy. Most of these irAEs were mild to moderate (CTCAE Grades 1 to 2) and were treated with glucocorticoids. The reported incidence of irAEs ≥ 3 ranges from 10% to 33%, yet most of these severe irAEs were also treated by discontinuing ICIs and glucocorticoid ± immunosuppressant agents [59-63]. Overall survival or tumor response to ICIs did not differ significantly in patients with pre-existing autoimmune diseases [62,63]. Recent retrospective studies have provided evidence for the feasibility of ICIs for patients with pre-existing autoimmune diseases. Largescale prospective studies are required to validate these findings and establish evidence based on guidelines for ICI therapy in patients with coexisting cancer and autoimmune diseases.

In the vignette, we described a man with Grade 2 inflammatory oligo-arthritis involving large joints as irAEs, who presented at our institution. Imaging studies were performed. Plain X-rays of the knee joints revealed no radiographic joint damage. Ultrasound revealed joint effusion and synovial hypertrophy with an increased power Doppler signal. Subsequently, arthrocentesis was performed for the differential diagnosis, such as crystal-induced arthritis and septic arthritis. The synovial fluid was inflammatory (white blood cell count was 25,900/mL, neutrophils 76%, lymphocytes 5%) with no evidence of crystals, and the culture results were negative. Without initiating prednisolone or discontinuing the ICI, inflammatory arthritis improved with intra-articular corticosteroid injections and NSAIDs for 2 weeks. After 10 doses of pembrolizumab, inflammatory arthritis recurred in his elbows, which subsequently responded to 10 mg/day prednisolone with intra-articular corticosteroid injections. The arthritis improved significantly 2 weeks later. The patient remains in durable stable disease without a flare of inflammatory arthritis 12 months after initiating pembrolizumab.

The development of immuno-oncology drugs such as anti-PD-1 and anti-CTLA-4 inhibitors has led to a paradigm shift in the treatment of cancer patients. The revolutionary anti-cancer effects and the wide spectrum of indications of ICIs, regardless of cancer type, have increased their use exponentially. As their utilization expands, there is a great likelihood of an increase in the frequency of irAEs, which have been relatively underestimated. The mechanism, clinical characteristics, and pattern of management are quite different from managing the adverse events of cytotoxic chemotherapy. The occurrence of various irAEs can limit the use of ICIs and lead to fatal cancer progression. Timely screening and early detection of irAEs are critical to manage irAEs and long-term use of immune oncology drugs. Rheumatic irAEs are some of the most frequently encountered irAEs and could be severe and life-threatening. Awareness of rheumatic irAEs is an important first step, and a multidisciplinary approach is vital for their management.