A Look Back at a Decade of Therapeutic Advances in Rheumatology

The past 10 years have been marked “an explosion” of new therapies for use across the spectrum of rheumatic diseases, some with outstanding success, others, not so. The November issue of Nature Reviews Rheumatology, which marks the 10th anniversary of the publication, includes a collection of articles that focus on the major advances in rheumatology throughout the past decade. In a review of new therapeutics for rheumatoid arthritis, psoriatic arthritis, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), systemic sclerosis, systemic lupus erythematosus, juvenile idiopathic arthritis and ankylosing spondylitis, John D. Isaacs, of Newcastle University in the United Kingdom, sums up the most significant therapeutic advances of the last 10 years. Rheumatoid Arthritis The major advance in new treatments for rheumatoid arthritis:  Orally bioavailable small molecule inhibitors of signaling proteins. Tofacitinib, the first of this class of drugs now used in rheumatoid arthritis, inhibits the Janus-associated kinase (JAK) signaling pathways downstream of various cytokine and growth factor receptors. A phase III trial showed that tofacitinib had a safety and efficacy profile similar to disease-modifying antirheumatic drugs (DMARDs). Psoriatic Arthritis No group of rheumatology patients has needed new treatments more than patients afflicted with psoriatic arthritis (PsA), Isaacs writes. If DMARDs failed in this group, the only other alternative was TNF blockade, until recently with the licensure of new oral and biologic therapies. Apremilast, an oral phosphodiesterase 4 inhibitor that indirectly reduces proinflammatory cytokine production, is now used before biologic therapies for patients who do not respond to DMARDs. Ustekinumab has been shown to have similar efficacy to TNF blockade and now provides an additional option for patients with PsA refractory to DMARDs.  In addition, although less effective than ustekinumab and TNF blockade, apremilast is well-tolerated. Systemic Lupus Erythematosus Belimumab is the first new therapy to be licensed for use in systemic lupus erythematosus (SLE) in more than 50 years, but it was a tough road getting there. It’s development was marked by two failed phase II trials, but the endpoints in two phase 3 studies of belimumab were achieved, but only with modest improvements over placebo. Belimumab is currently licensed as an addition to conventional therapy in patients with active, seropositive SLE, Isaacs writes. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) Rituximab has “gained a foothold” in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). “It proved non-inferior to daily oral cyclophosphamide in achieving glucocorticoid-free remission in patients with newly-diagnosed or relapsing disease.” This offers an important alternative to traditional cytotoxic and immunosuppressive medications for these patients. Rituximab has also been shown to be superior to azathioprine in sustaining remission after treatment with cyclophosphamide and glucocorticoids, which remain an important part of therapy, Isaacs writes. Systemic Sclerosis Unfortunately, there are no new treatments to slow the progression of systemic sclerosis, which remains one of the most refractory connective tissue diseases. However, there may be a new treatment for ulcers associated with systemic sclerosis. Bosentan has been licensed to treat severe digital ulcers secondary to poor digital circulation.  “These ulcers are a particularly painful and debilitating symptom of systemic sclerosis, and endothelin‑1 inhibition (bosentan) has provided new hope for patients with this unrelenting condition.” Juvenile Idiopathic Arthritis  In juvenile idiopathic arthritis (JIA), the IL‑6-receptor blockade tocilizumab was shown to be highly effective in children with active systemic or polyarticular-course JIA. “It's effectiveness was particularly welcome in systemic JIA, previously a condition with limited therapeutic options, a situation that resulted in dependency on growth-inhibiting glucocorticoids.” Ankylosing Spondylitis There remains few treatment options for ankylosing spondylitis (AS). The standard treatment currently includes NSAIDs, physiotherapy and TNF blockade. “Ustekinumab trials in patients with PsA suggested benefits for spinal inflammation, and the biology of AS strongly implicates the IL‑23–IL‑17 axis.” “Secukinumab, an anti-IL‑17 mAb, was shown to rapidly improve the signs and symptoms of AS, with positive changes assessed in parallel by use of imaging techniques.” New therapies are in development that target the IL-17 pathway. Conclusion “By reviewing these therapeutic advances, it is satisfying to see that the majority are targeted therapies are aimed at pivotal pathogenetic pathways. What lies ahead for the next decade? In RA, a continuing trend towards earlier treatment is clear, and trials are underway in ‘pre-RA’ focused on individuals with autoantibodies, but without joint inflammation symptoms,” Isaacs writes. 

References:

John D. Isaacs. "10 years of therapeutic advances in the rheumatic diseases,"

Nature Reviews Rheumatology.

VOLUME 11 | NOVEMBER 2015. doi:10.31038/nrrheum.2015.138 Published online 13 October 2015