Do you have any hesitations for combining belimumab with any of the DMARDs in patients with SLE/RA overlap?

The only disease-modifying agents for rheumatic diseases (DMARDs) that I would not use with Benlysta are the Janus kinase inhibitors (tofacitinib, baricitinib, and upadacitinib), which are considered “targeted synthetic DMARDs” (Harrington). We all know these agents to be as strong as biologics. Most of us would be hesitant to use them with a biologic, such as belimumab, unless studies come along in the future demonstrating efficacy and safety.

However, in your question, I suspect you mean the “conventional DMARDs” (such as methotrexate, azathioprine, etc.). The phase-III clinical trials for belimumab (Benlysta in BLISS-52, BLISS-76, and BLISS-SC) used belimumab on top of “standard of care,” which included antimalarials, methotrexate, azathioprine, and mycophenolate (Stohl).

Interestingly, a GlaxoSmithKline (GSK)-sponsored clinical trial using rituximab in tandem with belimumab called the BLISS-BELIEVE trial utilized these two B-cell inhibitors. In addition to the DMARDs listed in the previous paragraph, patients were allowed to take other DMARDs like leflunomide, calcineurin inhibitors, and others (Teng) along with belimumab. The study’s endpoints were not to assess safety/efficacy with the individual DMARDs with belimumab, yet it speaks to the study sponsor (GSK) thinking it safe to use these combinations.

I have personally used belimumab combined with all the above, including leflunomide and voclosporin, with excellent results.

I would like to point out that belimumab was even used with cyclophosphamide in the BLISS-LN trial, demonstrating efficacy and safety for lupus nephritis (Furie).

The only classic DMARD that I suspect has not been studied with belimumab, which we use for rheumatoid arthritis, would be sulfasalazine (SSZ). Since we commonly use SSZ with the B-cell depleter rituximab, I would not hesitate to use SSZ along with belimumab.

REFERENCES:

Harrington et al., PMID 32982367

Stohl et al., PMID 28118533

Teng et al., PMID 30898822

Furie et al., PMID 32937045

I agree with Dr. @Dr. First Last.

I have used belimumab in combination with most DMARDs (Methotrexate, Mycophenolate, Azathioprine, Hydroxychloroquine) without any safety signals (except an increase in UTI and bronchitis rates in my experience). I have avoided combining belimumab with other biologics except for rituxan.

Belimumab has of course been extensively studied in SLE and has been safely combined with cyclophosphamide, mycophenolate, azathioprine among others, and is regarded as a safe option.

It has interestingly been studied in RA as well (Stohl et al., PMID 23547209) with modest effect (ACR20 belimumab 1 mg/kg: 34.7% vs placebo 15.9%). In this study, it was combined with MTX (most patients), leflunomide, sulfasalazine, and hydroxychloroquine. It was tolerated in general well. There was a decrease in Ig levels but no frank severe hypogammaglobulinemia. 

In conclusion, I would say that belimumab can be safely combined with conventional DMARDs bearing in mind that infection rates can increase. In that case, I do screen for hypogammaglobulinemia and may adjust therapy.