Belatacept and Autoimmune Adverse Events

Abstract

Belatacept is widely used to prevent rejection in kidney transplants with its excellent tolerability profile. Here, we report a severe psoriasis manifesting in a kidney transplant recipient raising the possibility of belatacept-induced autoimmunity. Our patient was a 42-year-old man with an end-stage renal disease secondary to anti neutrophil cytoplasmic antibody-associated vasculitis. In January 2014, more than 2 years after receiving rituximab as treatment, he underwent primary renal transplantation (with 1 B mismatch). Immunosuppressive induction therapy consisted of anti-IL2R (basiliximab), whereas maintenance therapy consisted of mycophenolic acid and tacrolimus delivered at their standard regular dosages. On day 10 postoperation, a graft biopsy revealed marked thrombotic microangiopathy. Tacrolimus toxicity was suspected and tacrolimus was substituted with belatacept (5 mg/kg monthly) with an excellent result (serum creatinine, 100 μmol/L). In September 2014, physical examination revealed psoriatic plaques, confirmed by skin biopsy. Topical treatment with calcipotriol was introduced. In July 2016, because of a deterioration in his skin condition, we decided to stop mycophenolic acid and commence ciclosporin. Despite an initial improvement, the psoriasis progressively deteriorated (Figure 1). Therapeutic strategies were constrained, because in this transplant recipient, phototherapy and most biologic therapies were contraindicated. In February 2017, we decided to stop belatacept and reintroduce mycophenolic acid. A few weeks after its discontinuation, the plaques progressively disappeared, and complete resolution was finally observed.FIGURE 1: Diffuse well-demarcated psoriasis form plaques.Several factors suggest a casual association between this exposure and the development of the lesions: (i) our patient had neither a personal nor familial history of psoriasis; (ii) its onset at 7 months of costimulation blockade could be plausible (see below); (iii) rapid improvement was observed after its removal; (iv) a biological plausibility to explain this effect can be found. Psoriasis has been reported in patients with rheumatoid arthritis treated with abatacept.1 Regarding the pooled safety data of the BENEFIT trials, a similar frequency of autoimmune-related adverse events (AEs) between belatacept-treated recipients and ciclosporin-treated controls has been observed. However, psoriasis was the most common autoimmune disorder to manifest in belatacept-treated patients, whereas hyperthyroidism was the most frequent to manifest in controls. In the susceptible patient, belatacept could dysregulate immunity in different ways. First, by inhibiting regulatory T (Treg) cells either quantitatively or qualitatively.2 Indeed, abatacept and belatacept are both CTLA4-Ig fusion proteins antagonizing CD80-86, the ligand for CD28 (essential to Treg generation and maintenance) and CTLA-4 (crucial for Treg functions). Second, belatacept blocks the CTLA-4 inhibitory pathway on memory T cells. Belatacept-resistant rejection is thought to be due to alloreactive memory T cells, which are less dependent on CD28 signaling for their activation and are regulated by CTLA-4 intrinsic mechanisms.3 Krummey and Cheeseman4 demonstrated that interleukin 17-secreting T helper (Th17) cells are especially sensitive to CTLA-4 coinhibition and resistant to costimulation blockade. Psoriasis and inflammatory bowel disease, for which a belatacept-induced case has been recently reported,5 are both Th17 mediated. Pharmacovigilance in the “real life” transplant setting often yields new safety concerns about rare drug-related adverse events. Transplant community physicians should be aware that the use of belatacept after kidney transplantation may be implicated in psoriasis occurrence. Patient data were obtained from the DIVAT clinical cohort (divat.fr) ethically approved: N8CNIL 891735 version 2, August 2004.