Biologics in Rheumatology: Revolution & Perspectives

ACR CONVERGENCE 2020—Gerd Burmester, MD, professor of medicine at Charité, University Medicine, Berlin, gave this year’s Phillip Hench, MD, Memorial Lecture and used the opportunity to review the evolution of the treatment of rheumatic diseases with a focus on biologics.

Dr. Burmester described four milestones in treatment evolution, starting by outlining how glucocorticoids, one of the first drugs used to treat rheumatic disease, continue to play an important role in rheumatology. Glucocorticoids not only help with pain relief, but also modify disease in early rheumatoid arthritis (RA) and are immunosuppressive in vasculitides and systemic lupus erythematosus (SLE). Patients are more likely to experience adverse effects with longer use and higher doses of glucocorticoids.

The next milestone, methotrexate, joined glucocorticoids as a treatment for RA when rheumatologists prescribed it to reduce disease activity. Methotrexate’s dramatic effect on the lives of patients has made it the most popular drug worldwide for the treatment of RA. Low-dose methotrexate administered weekly can be used as a monotherapy and, for some patients, can be as effective as the newer biologics, especially in combination with glucocorticoids. Although methotrexate monotherapy may reduce radiographic progression in RA, some patients experience this positive effect, which can potentially abolish radiologic changes, only when methotrexate is combined with biologic therapies.

These biologic therapies, or biologics, have taken a prominent place in the RA treatment arsenal. The numerous current therapies include B cell inhibitors, interleukin (IL) 1 blockers, IL-6 blockers and, most notably, tumor necrosis factor (TNF) inhibitors. Initially, rheumatologists recognized CD4-positive cells are important in the pathophysiology of disease, and thus, the first biologic to be used for the treatment of RA was anti-CD4.

In 1991, Dr. Burmester and colleagues published the results of a series of 10 patients with severe intractable RA treated with a monoclonal antibody (known as 16H5) against the CD4 antigen present on T helper cells.¹ In the open trial, they infused the monoclonal antibody and documented its clinical benefits. They noted in their paper that it remained to be determined whether long-term remission could be induced with this therapeutic approach.

A few years later, investigators created a chimeric CD4 monoclonal antibody called cM-T412 and evaluated its use in RA patients. In initial results, patients tended to demonstrate a favorable clinical response; however, a subsequent controlled clinical trial did not show a benefit.

Alemtuzumab (CAMPATH-IH) was among the first humanized, therapeutic, monoclonal antibodies and, thus, the first of many targeted immunomodulatory therapies that have revolutionized the treatment of autoimmune diseases. Alemtuzumab depletes cells expressing CD52 (T and B cells, monocytes and natural killer cells). In the early 1990s, alemtuzumab was successfully used to treat patients with refractory RA. Unfortunately, however, many patients experienced profound lymphopenia, especially in the CD4+ compartment, and alemtuzumab fell out of favor as a treatment for RA.