Systemic Sclerosis Association with Malignancy

Among all SSc clinical and serological features, some SSc-specific autoantibodies have been demonstrated to increase the risk for cancer development suggesting a molecular link between autoimmunity and neoplasm. To identify risk factors is essential both to stratify patients into more clinically relevant subsets and to follow-up SSc patients with personalized cancer screening recommendations [62].

In this context, since several years a certain association between anti-RNA Pol III antibodies and an increased risk cancer with a close temporal gap between SSc and neoplasm have been reported [19, 57, 63‐65]. In 2014, Moinzadeh et al. [66] reported 154 cancers (7.1%) among 2.177 enrolled patients and confirmed a significant association between anti-RNA Pol III antibodies and a close cancer occurrence (36 months within SSc onset). The incidence of neoplasms was higher in anti-RNA Pol III patients than in those with anti-topo I or anticentromere antibodies (ACA) positivity (14.2% vs 6.3% and vs 6.8% respectively). In this study, breast cancer was reported as more frequent in patients with anti-RNA Pol III antibodies and these antibodies were reported as the only ones that significantly increased the risk of cancer. Comparing to SSc patients negative for anti-RNA Pol III antibodies, those positive were reported to present nearly six times increased risk of developing cancer within 3 years and 19 times more likely to present breast cancer within 36 months of onset of SSc when compared to patients with ACA [66]. Out of 2.383 SSc enrolled patients, Igusa et al. [62] reported neoplasm in 8.6% of patients. Authors did not demonstrate that a diffuse disease subset associated with anti-RNA Pol III antibodies significantly increased the risk of cancer development. Evaluating the risk of neoplasm within the first 3 years of SSc onset, patients with dcSSc were at major risk to develop cancer compared to the general population, and this risk further increased if they presented anti-RNA Pol III abs positivity. Therefore, data from this study also suggested that the risk of malignancy may differ among anti-RNA Pol III patients according to their cutaneous subset: dcSSc anti-RNA Pol III patients were reported to have a higher risk of breast cancer and lcSSc anti-RNA Pol III patients an increased risk of lung cancer. However, this last result was uncertain, given the small numbers of patients with lung malignancy in the enrolled population. Authors also showed a decreased cancer risk in patients with ACA positivity and an increased risk, particularly for breast cancer and melanoma, in patients with limited subset (lcSSc) and “triple negative”, that is lacking ACA, anti-topo-I, and anti-RNA Pol III [62]. Similar findings were already reported by a previous study on 23 SSc patients with cancer demonstrating a difference in SSc median duration at neoplasm onset between patients positive for anti-RNA Pol I/III and those with anti-topo I or ACA positivity. In the first group, a close temporal relationship between cancer and SSc was shown reporting SSc onset within 2 years of malignancy diagnosis. A similar close temporal association with cancer and “triple negative” SSc patients was also shown [63]. In this study, authors investigated the expression of RNA polymerase I and III in cancer tissues reporting an increased nucleolar expression of RNA polymerase III in tumor cells from patients with anti-RNA Pol III antibodies compared to those negative for these antibodies. According to this finding, an association between tumor antigen expression and SSc-specific autoantibody responses may be suggested, advancing the hypothesis of a close relationship between cancer, immune response, and SSc occurrence. Although requiring further validations, according to these data, anti-RNA Pol III antibodies could be considered a marker of malignancy [63]. In 2015, a study reported 168/1.044 (16.1%) SSc patients with cancer and confirmed the higher frequency of cancers in anti-RNA Pol III patients (20.9%) compared to those with ACA (16%), anti-topo I (13.6%), and to SSc subjects negative for these three antibodies (14.9%) [67]. Comparing the two populations, SSc patients with cancers vs SSc subjects without, a significant higher frequency of white race, older age, and anti-RNA Pol III positivity were observed in the first group. The older age at SSc onset was a risk factor both for cancer development and for its occurrence in close temporal relationship with SSc beginning and this last datum was particularly confirmed in patients with anti-topo I positivity and in those negative for anti-RNAP III, anti-topo I, and ACAs. In addition, in this study the close temporal association between cancer occurrence and SSc has been again reported in anti-RNA Pol III patients [67]. A case–control study that collects data from 13 EUSTAR centres confirmed a higher overall rate of cancers in anti-RNA Pol III positive patients compared to controls (anti-RNA Pol III negative) (17.7% vs 9.0%, p = 0.015) with a higher incidence of neoplasms synchronous with SSc (OR: 7.38%). Regarding cancer types, the incidence of solid neoplasm, in particular breast malignancy, was higher in anti-RNA Pol III positive patients. Furthermore, authors reported a greater proportion of men among patients diagnosed with non-breast synchronous cancer [68]. More recently, Lertphanichkul and Smith [57] confirmed the significant higher incidence of cancers in patients with anti-RNA Pol III antibodies compared to anti-topo I and ACA positive patients. In the study of Morrisroe et al. [19] the association between anti-RNA Pol III antibodies and cancer was again demonstrated and, when diagnosed within 5 years of SSc onset, cancer was more likely to occur in older and anti-RNA Pol III positive patients, particularly regarding breast cancer [19]. In the case–control study on 2.431 SSc patients and 12.710 control subjects, Watad et al. [69] showed an increased risk of cancer in patients with anti-topo I and anti-RNA Pol III abs [69]. In addition, the study suggested that humoral autoimmunity represented by autoantibodies status may impact survival in SSc patients with cancer. Particularly, antinuclear antibodies (ANA) negativity, anti-topo I and anti-RNP positivity appeared to be associated with a less favourable outcome, although the hazard ratio for death was significant only for ANA and anti-topo I antibodies. In addition, among SSc patients positive for anti-topo I, those with cancer were reported to have an increased risk of death compared to those without [69]. The significant higher prevalence of cancer in anti-RNA Pol III positive subjects has not been confirmed by all studies [70‐72]. Comparing SSc patients with anti-RNA Pol III positivity and those without, a recent study did not observe a significant different prevalence in cancer occurrence between the two groups of subjects [72]. All together data about anti-RNA Pol III antibodies reported a higher incidence of cancer in patients with these antibodies with a close temporal relationship between malignancy occurrence and SSc onset. These findings lead to obvious implications in clinical practice, suggesting regular screening and follow-up for patients with anti-RNA Pol III antibodies [68]. In addition, the close temporal relationship between SSc and cancer may lead to consider SSc as a paraneoplastic manifestation. In this context, Joseph et al. [73] found that out of 16 SSc patients with cancer, 8 were positive for anti-RNA Pol III antibodies. In 5/8 cases, cancer occurred before SSc onset and in the remaining 3 patients it developed within the 2.5 years of SSc onset. Authors confirmed a major temporal gap between SSc beginning and cancer in patients with anti-topo I and ACA positivity. Authors analysed neoplastic tissue and reported somatic genetic alterations of the POLR3A locus, encoding polymerase III, in 6/8 patients with anti-RNA Pol III antibodies and none in TOP1 or CENPB. Alterations in POLR3A were not found in patients without anti-RNA Pol III antibodies. According to these findings, the gene mutations located in tumor cells could trigger an immune response with the exposure of new self-antigens leading to the production of autoantibodies that started a humoral and cellular response typical of autoimmune rheumatic disease as SSc [73].

Concerning the risk of cancer, the role of SSc-specific antibodies other than anti-RNA Pol III still remains uncertain and debated [69, 74]. As above reported, also anti-topo I antibodies positivity seems to be associated with a higher frequency of cancer among SSc patients [34] and these antibodies have been suggested to be a hallmark for the occurrence of malignancy in SSc [33, 75]. Already in 1996, Kuwana et al. reported an increased levels of anti-topo I antibodies in two SSc patients after the diagnosis of lung adenocarcinoma. In addition, sera obtained from patients after cancer diagnosis, recognized some novel and/or different epitopes of the entire topoisomerase I molecule suggesting that autoantibodies specificities may change after malignancy occurrence [76].

As previously mentioned, another autoantibody subset that has been associated with cancer occurrence is the “triple negativity” [67, 77, 78]. In patients without neither anti-RNA Pol III nor anti-topo I nor ACA, a certain increased frequency of cancer occurrence has been reported. As already described, Igusa et al. [62] reported an increased risk of melanoma and breast cancer among these patients and older age has been demonstrated to represent a risk factor for malignancy development particularly in these SSc subjects [62, 67]. In contrast with these results, findings from a recent study suggested a protective role of SSc-specific antibodies negativity on the occurrence of haematological cancers by the multivariable logistic regression analysis [19]. However, most studies seem to be in accordance suggesting an association of triple negativity and cancer and this datum does not refute the suspected relationship between autoimmunity and cancer, rather it might bring to suspect the presence of another unknown autoantibodies subset predisposing cancer occurrence [79].

Among SSc-antibodies identifying patient subgroups at major risk to develop cancer, also anti-PM/Scl antibodies seem to be associated with an increased occurrence of neoplasia. Bernal-Bello et al. [71] showed presence of cancer in 53/432 SSc enrolled patients describing a more frequency of anti-PM/Scl in patients with cancer and a significant increased risk of neoplasm in patients with these antibodies (OR = 3.9; 95% CI 1.31–11.61; p = 0.014) [71]. However, this datum has not been confirmed by all studies, and for example the analysis on 46/305 SSc patients with cancers showed a similar prevalence of anti-PM/Scl antibodies in SSc patients with and without neoplasm (6.5% vs 6.9%, p = 0.916) [80].

Data regarding the relationship of ACA and anti-Th/To antibodies suggested a decreased frequency of cancers in patients with these autoantibodies, compared with general population. ACA positivity is generally reported to be associated with a lower frequency of cancer occurrence and also in oncological patients without rheumatic diseases, the presence of ACA positivity is shown to correlate with a good prognosis. In this context, Atalay et al. [81] evaluated a population of 55 patients with breast cancer and without diagnosis of connective tissue disease and suggested anti-centromere protein (CENP)-B antibodies positivity as a prognostic factor for disease-free survival and overall survival [81]. Morrisroe et al. suggested a protective role of ACA positivity in lung cancer occurrence with an OR of 0.22 (p = 0.023) [19].

A protective role of anti-Th/To for cancer development among SSc patients has also been suggested. In the recent study of Mecoli et al. [82] a negative association between the positivity for each Th/To antibody specificity (hPOP1, RPP25, RPP30, and RPP40) and cancer was demonstrated. In addition, authors also suggested a possible protective effect of anti-Th/To antibodies that seemed able to modify cancer risk given by anti-RNA Pol III positivity; however, this finding requires additional analysis on larger populations as in this study only 9 patients presented both anti-Th/To and anti-RNA Pol III antibodies [82].

Table 2 summarizes the most relevant data on cancer risk associated to SSc-specific autoantibodies.

Several immunosuppressive therapies have been approved for the treatment of patients with SSc [83] and such agents might play a role in the development of malignancy, although data are contradictory and often derived from studies on other rheumatic and non-rheumatic diseases.

Cyclophosphamide, an alkylating agent, is the cornerstone of the treatment of SSc, in particular of ILD and skin involvement related to SSc [84, 85]. As above mentioned, long-term treatment with cyclophosphamide is associated with an increased risk of developing transitional cell bladder carcinoma [56] and haematological malignancies [86]. The risk of developing malignancy is dose-dependent, and the benefit from cyclophosphamide treatment must be weighed against the risk of long-term AEs [87].

Mycophenolate mofetil (MMF) has been shown to have comparable efficacy to cyclophosphamide with a better toxicity profile [85, 88] particularly in treatment of SSc lung involvement. Cancer risk data related to MMF are mostly derived from transplant patients, with contradictory results on the increased risk of lymphoproliferative and non-melanoma skin cancer [89‐92]. However, no conclusions can be drawn on the risk of cancer-related to the use of MMF, because many of the transplant patients receive multiple immunosuppressive treatments.

Methotrexate is mainly used for forms with widespread skin involvement and in patients with arthritis [84] and it is associated with an increased risk of non-melanoma skin cancer, although these data come from a study on patients with RA or psoriasis [93].

The use of azathioprine appears to be associated with an increased risk of non-melanoma skin cancer [94, 95], but with conflicting results: a meta-analysis of 5 studies of patients receiving long-term treatment for myasthenia gravis did not show an increased risk of neoplasms [96]. However, no data are available on the risk of cancer for patients with SSc treated with aziathioprine.

A recent study on an Italian cohort of SSc patients treated with immunosuppressants confirmed an increased incidence of neoplasms in SSc patients without finding an association between cancer risk and exposure to immunosuppressive drugs commonly used for the treatment of SSc [97].

Data on the new biologic disease-modifying drugs are contradictory and derive from studies on their use in other rheumatic diseases. Some studies have shown an increased risk of invasive melanoma [98, 99], and an increased risk of squamous cells skin cancer in patients treated with abatacept [100].

Tocilizumab, a humanized anti-interleukin-6 receptor antibody that might preserve lung function in patients with early SSc-ILD [101], does not seem to increase cancer risk. In a large Swedish cohort study of rheumatoid arthritis (RA) patients, the overall cancer risk was not increased by tocilizumab [100]. Furthermore, data from a large European collaborative project do not show an increased risk of invasive melanoma in patients treated with tocilizumab for RA [99]. Longer follow-up data on tocilizumab use for SSc-ILD could clarify whether there is an increased risk of cancer.

Further prospective studies in SSc patients are needed to define cancer risk related to these drugs; in the meantime, the choice of the best treatment must be guided by the balance of risks and benefits, and adequate monitoring of patients is recommended in order to diagnose neoplasms early.

On the other hand, drugs used for the treatment of SSc can also have an antineoplastic effect. This is the case of nintedanib, a tyrosine kinase inhibitor, that when used in the SSc-ILD reduces the rate of decline in forced vital capacity [102]. In combination with docetaxel, nintedanib demonstrated an advantage in progression-free survival and overall survival in patients with lung adenocarcinoma, when used as second-line therapy [103].

The immune system plays a role in both the development and treatment of cancer. The most pivotal shift in use of the immune system in the fight against cancer came with the discovery of ICIs. Malignant tumors take advantage of the inhibitory programmed cell PD-1/PD-L1 or CTLA-4 pathways to evade the immune system [20]. The development of drugs promoting the disruption of this axis by blocking monoclonal antibodies allowed durable remissions in different types of cancer that previously were considered incurable. Indeed, substantial improvements in terms of survival have been documented in patients with metastatic cancer suggesting the ground‑breaking impact of immune modulation across different tumors [133‐135].

Since 2011 the Food and Drugs Administration (FDA) approved an antibody against CTLA-4 (ipilimumab), two antibodies against PD-1 (pembrolizumab and nivolumab), and against PD-1 ligand 1 (atezolizumab and durvalumab) for cancer treatment. The combination of anti-PD-1 and anti-CTLA-4‑agents further improves clinical response rates compared with single‑agent activities in some types of cancers [136]. The superiority of combination therapy is most likely due to the different and non-redundant mechanism by which CTLA-4 and PD-1 inhibit T cells. In fact, CTLA-4 is expressed by activated T cells and competes with CD28 for costimulatory ligands attenuating the early activation of naive and memory T cells [137]. The use of CTLA-4 inhibitors causes an increase in T cell infiltration into tumors and reduces it at the level of the tumor microenvironment, preventing the suppression of cytotoxic T cell activity [138]. PD-1 directly interferes with the T cell receptor signalling at the effector stage within tissues by inhibiting and causing depletion [139]. Tumors expressing PD-1 ligands thus protect themselves from T cell–mediated killing [140]. However, additional checkpoint‑blocking approaches such as V‑type immunoglobulin domain‑containing suppressor of T cell activation (VISTA) or T cell immunoreceptor with Ig and ITIM domains (TIGIT) blocking for the treatment of human cancer are expected to demonstrate efficacy in some kind of solid tumors.

Although ICIs have a beneficial role in the activation of T cells directed against the tumor antigen, they can also lead to aberrant activation of T cells reactive to autoantigens, resulting in side effects that resemble autoimmune diseases. In fact, both CTLA-4 and PD-1 block are associated with side effects known as immune-related adverse events (irAEs), whose underlying mechanisms still remain unclear. These irAEs can affect any organ, but typically the skin, intestines, liver, and endocrine organs, as in autoimmune diseases [141]. Although some irAEs have been well‐documented, there is a little knowledge of rheumatic irAEs, including arthralgia, arthritis, myositis, polymyalgia–rheumatica‐like (PMR‐like) syndrome, sicca syndrome, vasculitis, and scleroderma. In general, the incidence and severity of irAEs are more marked among patients treated with anti-CTLA-4 or combination of anti-CTLA-4 and anti-PD-1, than in those treated with anti-PD-1 or anti-PDL-1 alone [141]. This could be attributed to the difference in the T cell activation process. In fact, the use of anti-CTLA-4 unblocks T cells at an earlier stage of their development compared to PD-1 inhibitors with a consequent increase in the frequency of autoreactive T cells. This difference could also explain the further increase in the severity of the irAEs observed among patients treated with combination therapies [141, 142]. The most frequent adverse manifestations within the first few weeks of treatment include rash and/or pruritus on the patient’s trunk and extremities [143]. Gastrointestinal irAEs are common and usually first occur 4–6 weeks after initiation of treatment [141]; hepatic irAEs are observed less frequently and occur in approximately 5% of patients treated with CTLA-4 and PD-L1 block. The most common endocrine disorders include CTLA-4 blocking hypophysitis and anti-PD-1-induced hypothyroidism, affecting approximately 10% of patients. Although most irAEs are reported as moderate and relatively simple to treat with temporary interruption of the therapy or mild immunosuppressive treatment as systemic corticosteroids, in some cases, irAEs are fatal, as reported in organizing inflammatory pneumonia and myasthenia gravis [144, 145]. Since ICIs treatment can induce a lasting response in metastatic disease, unlike traditional chemotherapy, it is important to be aware that in patients experiencing serious side effects, the discontinuation of treatment can lead to a reduction of efficacy and to a treatment failure. Because of this, availability of effective therapies against irAEs is expected, and this concept emphasizes the fact of the strong connection between cancer immunotherapy and autoimmune disease.

As stated above, ICIs are associated with a broad spectrum of immune AEs which appear more pronounced in patients with pre-existing autoimmune diseases (PADs). In this context, the use of ipilimumab is reported to cause exacerbation in approximately one quarter of patients with pre-existing autoimmune disorders [146]. In these patients, ICI activation of the immune system may result in more severe irAEs due to their underlying abnormal immune response to self-antigens. For this reason, patients with PAD were excluded from large randomized controlled trials evaluating the efficacy and safety of ICIs and only limited data from case series/case reports are available [147‐149]. Also patients with only specific autoimmune autoantibodies are reported to be more likely to develop irAE if treated with anti-PD-1 antibody [147, 148, 150].

A systematic review of 123 pre-existing cancer and autoimmune diseases patients treated with ICI reported exacerbation of PAD, development of irAE, or both events in 75% of patients. Of these, 41% had recurrence or worsening of previous manifestations, 25% developed de novo irAE, and 9% had both. Patients with PAD on active treatment at the time of initiation of ICI therapy had fewer AEs than those who were not receiving treatment (59% vs 83%) [151]. In a prospective study by Danlos et al., irAEs developed more frequently and more rapidly in patients with PAD than in patients without PAD (44% versus 24%) [152]. Similarly, in a retrospective study by Cortellini et al., the incidence of any grade irAEs was higher among patients with PAD than in patients without PAD (66% vs 40%), with no difference in the incidence of grade 3–4 irAE among these groups (9.4% vs 8.8%) [153]. Another retrospective study of patients with PAD treated with ICIs reported the irAEs development in 38% of patients who required glucocorticoids and discontinuation of ICIs. 63% had previously received a disease-modifying anti-rheumatic drugs (DMARDs), but only 2 patients were on active systemic treatment at the time of ICI initiation. A longer survival was observed in patients who experienced irAEs than those who did not have an irAE [154]. Leonardi et al. conducted a retrospective study in patients with PAD (with active symptoms and on immunosuppressant or immunomodulatory agents) treated with a PD-1/PD-L1 inhibitor. Grade 1-2 exacerbations of underlying PAD occurred in 23% of patients and were more frequent in patients with rheumatologic disorders compared with other PAD. Treatment included supportive care and steroids. Partial responses (PR) and stable disease (SD) were recorded in 22% and 31%, respectively [155].

Recently, 27 patients with PAD and cancer who reported exacerbations of disease during antiPD-1 immunotherapy were evaluated in a national case series from the Canadian Research Group of Rheumatology in Immune-Oncology (CanRIO) [156]. Nearly 80% of patients developed at least one irAE, usually mild and manageable, but required ICI to be discontinued in one third of cases. The most observed PADs were RA, psoriasis/psoriatic arthritis, immune bowel disease, and axial spondyloarthritis while, for tumors, lung cancer and melanoma. Exacerbations were more frequent and/or severe in patients requiring more intensive pre-ICI systemic therapy and occurred despite the preventive use of immunosuppressive drugs prior to ICI treatment. As for the efficacy outcome, more than 40% of patients with PAD vs 15% without PAD presented tumor progression at a median follow-up of 11 and 17 months, respectively [156]. The irAEs were more frequent in patients without tumor progression confirming the positive predictive role of irAE on the antitumor response as already previously reported [157]. Tumor progression was not associated with exposure to immunosuppressive drugs before or after the onset of ICI. Furthermore, the rate of severe irAEs leading to ICI discontinuation was lower in patients with PAD (33% vs 52%) thus not explaining the higher rate of progression observed in these patients [158]. Contrarily, another study observed a shorter median progression-free survival among patients with PAD who received immunosuppression at the onset of ICI in a multivariate analysis adjusted for gender, age, cancer type, and ICI type [159]. Likewise, Menzies et al. [160] reported, in an analysis adjusted for cancer stage, brain metastases, performance status, and/or LDH, lower response rates among immunosuppressed patients at the onset of ICI (15% vs. 44%). Steroid use at prednisone-equivalent doses of ≥ 10 mg at the time of ICI initiation has also been associated with poor cancer outcomes [161, 162]. Thus, although data on ICI therapy in patients with PAD and cancer are still debated, guidelines from the National Comprehensive Cancer Network (NCCN) recommend considering ICI in patients with low or no immunosuppression and a good control of PAD, avoiding them, if possible, in life threatening or poorly controlled PAD or in patients requiring high levels of immunosuppression [163].

The experience of cancer treatment with ICIs and the study of related irAEs have provided an interesting opportunity to study the early biology of autoimmune diseases and to design new treatment options for these conditions. Considering the principle on which immune therapy in cancer is based and the role that ICIs play in autoimmune rheumatic diseases, all inhibitory receptors could represent potential targets for therapeutic interventions in autoimmune diseases. To date, multiple approaches are available for targeting immune checkpoints for the treatment of autoimmune rheumatic diseases, including soluble inhibitory receptor-Fc fusion proteins, ligand-Fc fusion proteins, artificial ligands, agonistic antibodies, and bispecific antibodies, which bind an inhibitory receptor and activator (Fig. 1). Abatacept, a CTLA-4-Fc fusion protein, is the first checkpoint targeted drug approved for the treatment of rheumatic diseases. CTLA-4-Fc binds in the same way as CTLA-4 to the high affinity costimulatory ligands CD80 and CD86 preventing their costimulatory signalling [164]. It is currently used in patients with RA and juvenile idiopathic arthritis (JIA), although CTLA-4-Fc clinical efficacy is being tested on other autoimmune rheumatic diseases such as SSc [165]. Several other inhibitory receptors that modulate T cell activation have been explored as potential therapeutic targets in autoimmune diseases. Among these, TIGIT which is expressed by T cells and natural killer cells and binds CD155 on dendritic cells (DCs), macrophages with high affinity and CD112 with lower affinity [166, 167]. The binding with its ligand on DC results in an increase in the secretion of IL10 by DCs and a decrease in the proliferation of T cells. The blockade of TIGIT determines a powerful antitumor immune action [168‐170]. Co-blockade of TIGIT and PD-1 pathways elicits tumor rejection in preclinical murine models. TIGIT is also involved in autoimmune diseases and appears to inhibit pro-inflammatory immune responses that drive organ-specific autoimmunity as demonstrated in a preclinical study where administration of soluble TIGIT or anti-TIGIT agonist antibodies in mice with collagen-induced arthritis reduced the severity of the disease [171]. The PD-1 pathway appears to be negatively linked with the development of several autoimmune diseases [172‐174] and several targeted treatment approaches have been studied in mouse models [175]. Depletion of PD-1 positive cells appears to lead to the improvement of autoimmune diseases including type I diabetes and experimental autoimmune encephalomyelitis [176]. Therefore, targeting PD-1 could be a promising strategy for treating these diseases. VISTA could represent another potential target for T cell inhibition in autoimmune rheumatic diseases. It binds non-better characterized inhibitory receptor expressed on T cells causing its inhibition. The presence of VISTA-Fc patterns in vitro resulted in inhibition of T cell proliferation and cytokine production, while blocking VISTA and failure to bind to T cells improved T cell responses [177]. Therefore, targeting different inhibitory receptors alternately or simultaneously could aid the successful treatment of patients with autoimmune rheumatic diseases, even in those unresponsive to certain targeted checkpoint therapies. Finally, an alternative approach to fight autoimmune rheumatic diseases could be the targeting of inhibitory receptors expressed on immune cells other than T cells belonging to both the innate and the adaptive arm of the immune system. An interesting candidate seems to be FcγRIIB, an inhibitory receptor linked to rheumatic diseases whose block by bispecific antibodies has shown improvement in autoimmune diseases in preclinical studies [178].

In conclusion, although the available evidence for the use of ICI in patients with pre-existing autoimmune diseases is limited and derived from retrospective analysis, for the majority of the PAD, the use of ICIs appears to be safe and effective. Therefore, the treatment with ICI should be considered for patients with severe PAD including those with an active disease. However, special consideration should be given to patients receiving high levels of immunosuppression for PAD control because the immunosuppression might compromise efficacy of ICIs. Moreover, multidisciplinary approach with the involvement of an autoimmune disease’s specialist and a good assessment of the PAD activity and organ impairment before the starting of an ICI should be recommended. Moreover, a multidisciplinary approach to every irAE in patients with PAD could facilitate the management of potential fatal irAEs [179‐181]. In fact, the exacerbation of the underlying condition if not adequately controlled can lead to a potential life-threatening event or to the definitive interruption of treatment with a strong impact on survival.