The advent of biological agents has provided further opportunities to treat resistant or relapsing rheumatic diseases, with robust data for rheumatoid arthritis and spondyloarthritis coming from randomised controlled trials. However there are data also on other rare inflammatory rheumatic diseases even if the evidence available may be heterogeneous and/or controversial. Another challenging scenario is represented by diseases that are not uncommon, but that may present with multiple manifestations and prove resistant to conventional therapies, thus requiring the use of biological agents. To assist physicians in making correct therapeutic choices in such cases, the Italian Society for Rheumatology (SIR) has developed specific recommendations for the use of biological agents in rare disease or for the off-label use of such agents in refractory inflammatory disorders.