On 7 January 2020, researchers isolated and sequenced in China from patients with severe pneumonitis a novel coronavirus, then called SARS-CoV-2, which rapidly spread worldwide, becoming a global health emergency. Typical manifestations consist of flu-like symptoms such as fever, cough, fatigue, and dyspnea. However, in about 20% of patients, the infection progresses to severe interstitial pneumonia and can induce an uncontrolled host-immune response, leading to a life-threatening condition called cytokine release syndrome (CRS). CRS represents an emergency scenario of a frequent challenge, which is the complex and interwoven link between infections and autoimmunity. Indeed, treatment of CRS involves the use of both antivirals to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Several trials, evaluating the safety and effectiveness of immunosuppressants commonly used in rheumatic diseases, are ongoing in patients with COVID-19 and CRS, some of which are achieving promising results. However, such a use should follow a multidisciplinary approach, be accompanied by close monitoring, be tailored to patient’s clinical and serological features, and be initiated at the right time to reach the best results. Autoimmune patients receiving immunosuppressants could be prone to SARS-CoV-2 infections; however, suspension of the ongoing therapy is contraindicated to avoid disease flares and a consequent increase in the infection risk.

Phosphodiesterases (PDEs) are a heterogeneous superfamily of enzymes which catalyze the degradation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Among PDEs, PDE4 is the most widely studied and characterized isoenzyme. PDE4 blocking can lead to increased levels of intracellular cAMP, which results in down-regulation of inflammatory responses by reducing the expression of tumor necrosis factor (TNF), interleukin (IL)-23, IL-17, interferon-γ, while increasing regulatory cytokines, such as IL-10. Therefore, PDE4 has been explored as a therapeutic target for the treatment of different chronic inflammatory conditions such as psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). PsA shares clinical, genetic, and pathogenic features with IBD such as ulcerative colitis (UC) and Crohn’s disease (CD), and enteropathic spondyloarthritis (eSpA) represent a frequent clinical evidence of the overlap between gut and joint diseases. Current therapeutic options in PsA patients and underlying UC are limited to synthetic immunosuppressants and anti-TNF. Apremilast is an oral PDE4 inhibitor approved for the treatment of active PsA patients with inadequate response to synthetic immunosuppressants. The efficacy and a good safety profile observed in randomized clinical trials with apremilast in PsA patients have been confirmed by few studies in a real-life scenario. In addition, apremilast led to significant improvement in clinical and endoscopic features in UC patients in a phase II RCT. By now there are no available data regarding its role in eSpA patients. In view of the above, the use of apremilast in eSpA patients is a route that deserves to be deepened.

Radiotherapy and, more recently, PARP inhibitors (PARPis) and immune-checkpoint inhibitors represent effective tools in cancer therapy. Radiotherapy exerts its effects not only by damaging DNA and inducing tumor cell death, but also stimulating anti-tumor immune responses. PARPis are known to exert their therapeutic effects by inhibiting DNA repair, and they may be used in combination with radiotherapy. Both radiotherapy and PARPis modulate inflammatory signals and stimulate type I IFN (IFN-I)-dependent immune activation. However, they can also support the development of an immunosuppressive tumor environment and upregulate PD-L1 expression on tumor cells. When provided as monotherapy, immune-checkpoint inhibitors (mainly antibodies to CTLA-4 and the PD-1/PD-L1 axis) result particularly effective only in immunogenic tumors. Combinations of immunotherapy with therapies that favor priming of the immune response to tumor-associated antigens are, therefore, suitable strategies. The widely explored association of radiotherapy and immunotherapy has confirmed this benefit for several cancers. Association with PARPis has also been investigated in clinical trials. Immunotherapy counteracts the immunosuppressive effects of radiotherapy and/or PARPis and synergies with their immunological effects, promoting and unleashing immune responses toward primary and metastatic lesions (abscopal effect). Here, we discuss the beneficial and counterproductive effects of each therapy and how they can synergize to overcome single-therapy limitations.