Immunotherapy has become a cornerstone in cancer treatment offering unexpected treatment opportunities for patients with metastatic, loco-regional, or even operable tumors in melanoma, lung, urothelial, and a number of other tumoral localizations.

Two main directions of intervention are now clinically available for manipulating immune checkpoints by either targeting CTLA-4 or PD-1/PD-L1. Our current understanding of the role of these two molecules is that anti CTLA-4 is involved in the lymphocyte proliferation process after antigen specific T-cell receptor activation while anti PD-1/PD-L1 act predominantly in peripheral tissues during the effector step. However, CTLA-4 is also expressed on regulatory T lymphocytes and is thus involved in peripheral inhibition of T cell proliferation.

Despite the effectiveness of these products, two main issues arise from theoretical and practical considerations.

First not all patients respond to therapy. To date prediction of response to immune checkpoint inhibitors is difficult and available predictive markers are not optimal. Secondly cancer may be associated with a number of autoimmune manifestations either as a paraneoplastic condition (1) or as comorbidities. In experimental models, knocking-out CTLA-4 results in a massive proliferation and lymphocytic infiltration of tissues (2) while PD-1 knock-down mice are prone to autoimmune disease [reviewed in (3)]. These phenotypes can also be found in humans with CTLA-4 (4, 5) or PD-L1 (6) deficiency. Nevertheless, the mechanisms involved in antitumor immune response induced by checkpoint inhibitors may be different from those of autoimmune disease. However, it is clear that using checkpoint inhibitors to treat cancer poses the risk of a flare up of preexistent autoimmune disease and the development of new autoimmune manifestations in patients with preexisting autoimmunity even if present as a biological only manifestation (as for example positive auto antibodies).

Thus, these patients with preexisting autoimmune manifestations have been traditionally excluded from clinical trials as it was expected to have severe autoimmune manifestations which could exceed the potential benefit from tumor control. This subgroup of cancer patients harboring autoimmune manifestations is not trivial. Depending on the definition used, a large register-based analysis (SEER) including 2,10,509 patients with lung cancer identified between 13.5% (more restrictive definition) and 24.6% (more liberal definition) of cancer patients as having an autoimmune disease of any type (7). The most frequent manifestations found were rheumatoid arthritis (5.9%), psoriasis (2.8%), polymyalgia rheumatica (1.8%), Addison disease (1%), systemic lupus erythematosus (SLE-−0.9%), ulcerative colitis (0.8%), giant cell arteritis (0.8%), sicca syndrome (0.6%), regional enteritis (0.5%), and Meniere disease (0.5%). However, these autoimmune manifestations can be very broad as it has been recently reviewed for lung cancer in a series of articles curated by Jean Paul Scuiler (1, 8–11).

Thus, it is useful to perform, prior to any treatment, a careful evaluation of the possible autoimmune comorbidities in order to avoid possible harm, evaluate risk/benefit ratios, and anticipate possible complications.

In patient with lung cancer receiving checkpoint inhibitors, development of diverse IrAE is not completely random. Despite the fact that the incidence of IrAE increase with treatment duration, there is a pattern of developing specific organ manifestations in defined time frames. Thus, one can postulate that these IrAE develop in patients caring specific genotypes or having a previous immune priming predisposing for developing IrAE. Very little is known on this matter. Hasan Ali et al. (12) reported on a small series of 102 patients receiving anti PD-1/PD-L1 and anti CTLA-4 therapies, a very strong correlation between the presence of pruritus and the HLADRB1^*11:01 allele. Patient carrying these allele not only develop more pruritus than controls but also developed it earlier. Interesting, in previous investigations this specific allele has been associated with the development of atopic dermatitis in a small cohort of 185 children of Korean origin (13). The same allele has been associated with systemic sclerosis with anti-topoisomerase antibodies (14) or with the risk of developing systemic juvenile arthritis (15) or atopic dermatitis (13). The same Swiss group of Hasan Ali et al. also demonstrated an association trend between HLA DBQ1^*03:01 allele and the development of colitis. Again, this allele has been previously associated firmly with the development of inflammatory bowel disease (16). Similarly it is possible that some Single Nucleotide Polymorphism (SNP's), which are associated with a higher risk of autoimmune disease (colitis, diabetes, and allergy), positively impact the response rate to anti PD-1 therapy (17).

A systematic review of susceptible loci associated with development of IrAE's under checkpoint inhibitor therapy has been recently performed by Hoefsmit et al. (18) with a compartmentalized analysis based on affected organ and type of adverse effect. A huge number of susceptible loci, with a very variable physiologic/pathologic role, have been identified. However, these data can be hypothesis generating at most. At present time there is no sound information that can be applied to practice and there is no scientific basis to withhold checkpoint inhibitor treatment in people considered at risk based on these criteria.

Yoneshima et al. analyzed if pretreatment positive antinuclear antibodies (ANA) are associated either with IrAE or treatment response after administration of PD-1 inhibitors (19). They analyzed a group of 83 patients, of which 18 had preexisting positive serum ANA at a titer of 1:40 or higher. There was no statistical relationship between the presence of ANA and the risk of developing IrAE but there was an association trend between increasing ANA titers and the development of IrAE. Overall, response and disease control rates were similar in patients with or without ANA but there was also a higher PFS and OS in patients with negative ANA. A similar investigation was conducted by Sakakida et al. (20) which followed 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab and used a cutoff titer for positive ANA at 1:160. There was no significant difference in the development of IrAE between ANA positive and ANA negative patients with the exception of patients who developed colitis which had higher ANA titers than those who do not. Again, an elevated ANA titer was associated with a numerically lower disease control rate (37.5 and 67.5%) but this was not statistically significant (p = 0.08). Furthermore, for both series, the global numbers are rather small and the significance (both from statistical and clinical point of view) is debatable. Moreover, there are case reports of serious IrAE (i.e., fatal pneumonitis) that followed immune checkpoint administration in patients with pre-existing anti-synthetase syndrome (21).

To date, there is no sufficient data to warrant a systematic search for autoantibodies in cancer patients that are planned to receive checkpoint inhibitors. However, if knowledge of such positive finding is available, a clinical surveillance is warranted in order to identify, as early as possible, autoimmune manifestations associated with these autoantibodies.

Since these patients have been systematically excluded from clinical trials, subgroup analysis is scarcely available in the literature. Existing data originate from case reports, retrospective analyses of small series or registry data. Only one subgroup analysis of randomized trials is available but it does not cover the entire spectrum of autoimmune disease encountered in practice.

While it is difficult to aggregate such very disparate data some conclusion may still be extracted. First, patients with autoimmune disorders seems to derive the same benefit in term of tumor response compared with people without autoimmune disorders. Conflicting data exist concerning the association between autoimmunity or IrAE and tumor response, with both positive and negative investigations (76–79). Much more research is needed in this area. Thus, there is no an “a priori” reason to deny a potential effective treatment to these patients. Weather this group of patients experience more long-term benefit is still a matter of investigation.

Concerning safety, these patients seem to generate the same spectrum, number, and severity of IrAE (other than the flare up of their baseline autoimmune condition) as patients without preexisting autoimmune disease and thus need to be followed-up similarly. The question arises for the flare-up of their autoimmune condition. At least 30% to a maximum of 80% of patients, depending on series and type of baseline autoimmune disease, do not experience a flare up. In general, people with skin autoimmune disorders can be managed safely even in case of very severe flares (50). The same apply for those with thyroid dysfunction but severe hyperthyroidism can be encountered even in previously chronic hypothyroid patients (55).

Some data exist for patients with rheumatic disease, and it seems that at least 50% of them experience a disease flare. Grade 4 and 5 flare-ups seems infrequent and generally are manageable with steroids and anti-TNF medications. These patients can receive checkpoint inhibitors provided that no best option is available, they are informed on the potential disease flare and a careful follow-up is instituted.

Insufficient data exist for patients with inflammatory bowel disease. When these manifestations develop during a previous anti CTLA-4 treatment, the relapse rate under anti PD-1/PDL-1 therapy seems low and it is probable that these patients can be safely treated.

There is a need for more research in groups of patients with inflammatory bowel disease which receive checkpoint inhibitors for the first time. Their administration clearly poses some risks, but it needs to be evaluated taking into account the effectiveness of available alternatives and the patient should understand the potential benefits and harms as well as the risk -benefit ratio.

Based in SEER data, administration of immune checkpoint inhibitors do not result in excess hospitalizations compared to similar patients without autoimmune disease but the hospitalizations are strongly related to the development or flare up of autoimmune conditions. An observational trial concerning ipilimumab in patients with melanoma and underlying autoimmune diseases (80) has been performed but, to our best knowledge, results have not yet been reported.

All authors contributed to literature search, data extraction, and drafting of manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.