Hereditary auto-inflammatory disorders and biologics

Abstract

The term auto-inflammatory disorders has been coined to describe a group of conditions characterized by spontaneously relapsing and remitting bouts of systemic inflammation without apparent involvement of antigen-specific T cells or significant production of auto-antibodies. The hereditary periodic fever syndromes are considered as the prototypic auto-inflammatory diseases, and genetic studies have yielded important new insights into innate immunity. DNA analysis has greatly enhanced the clinical characterization of these conditions, and elucidation of their molecular aetiopathogenesis has suggested that therapies may be aimed at specific targets within the immune cascade. The availability of biologic response modifiers such as inhibitors of tumour necrosis factor (TNF) and interleukin-1beta has greatly improved the outlook for some of these disorders, although effective therapies remain elusive in patients with certain conditions, including hyperimmunoglobulinaemia-D with periodic fever syndrome (HIDS) and a proportion of those with TNF-receptor associated periodic syndrome (TRAPS). Indeed, outstanding challenges and the unique potential to further elucidate molecular mechanisms in innate immunity are illustrated by the dashed early hope that TNF blockade would be a panacea for TRAPS: not only is etanercept (Enbrel) ineffective in some cases, but there are anecdotal reports of this condition being greatly exacerbated by infliximab (Remicade).

Successful treatment of resistant pseudogout with anakinra

“…A small study has shown the potential for use of methotrexate in resistant pseudogout, but the response was only noted ϳ2 months after initiation of therapy (6). Anakinra has been shown to be effective in treating the hereditary autoinflammatory conditions, which are characterized by the production of IL-1␤ due to increased inflammasome activity (7)(8)(9). Recently, the pathogenesis of crystal-induced arthropathy, including gout and pseudogout, was shown to mimic that of the hereditary autoinflammatory conditions (1,10).…”

Successful Treatment with Infliximab of a Patient with Tumor Necrosis Factor-associated Periodic Syndrome (TRAPS) Who Failed to Respond to Etanercept

“…After completing the study, the patient received a second 24-week treatment cycle, which was discontinued due to declining response. He experienced a flare similar to that with infliximab when subsequently treated with adalimumab 13 . The other 3 patients with flares associated with infliximab had been described in individual case reports 9,13 .…”

“…He experienced a flare similar to that with infliximab when subsequently treated with adalimumab 13 . The other 3 patients with flares associated with infliximab had been described in individual case reports 9,13 . Two patients responded favorably to anakinra after failing anti-TNF agents 19,20 , suggesting that interleukin 1 may play a role in the pathogenesis.…”

“…Glucocorticoids, although effective for inflammatory symptoms, do not prevent future attacks and the use of escalating doses is limited by toxicity 5 . Anti-TNF agents have demonstrated variable efficacy [5][6][7][8][9][10][11][12][13][14] . We describe the case of a 48-year-old woman of Italian Catalonian descent with TRAPS who was treated successfully with infliximab.…”

Role of tumour necrosis factor (TNF)-α and TNFRSF1A R92Q mutation in the pathogenesis of TNF receptor-associated periodic syndrome and multiple sclerosis

“…The response to anti-TNF-a drugs is variable, and there are reports of response to anakinra (a recombinant IL-1 receptor antagonist) [25,29].…”