Efficacy and safety of intravitreal anti-tumour necrosis factor drugs in adults with non-infectious uveitis - a systematic review

Anti-tumour necrosis factor (TNF) drugs have been extensively used in non-infectious uveitis (NIU), when corticosteroids or conventional immunosuppressive drugs cannot adequately control inflammation or intolerable side-effects occur. However, systemic anti-TNF therapies are also associated with a myriad of side-effects. Therefore, intravitreal administration of anti-TNF biologics has been employed to minimize patient morbidity and systemic adverse effects, while maintaining therapeutic effectivity. We undertook a systematic review to determine evidence of efficacy and safety of intravitreal administration of anti-TNF drugs in adults with NIU. We conducted this systematic review according to the PRISMA guidelines. The protocol was registered with PROSPERO (CRD42016041946). We searched CENTRAL, MEDLINE and EMBASE, from inception to April 2017, as well as clinical trial registries and grey literature. The qualitative analysis included all studies of adult patients with a diagnosis of NIU and who received intravitreal anti-TNF drugs with a 4-week minimum follow-up. A total of 4840 references were considered for title and abstract screening. Seven full texts were screened, and five studies were considered for analysis. All studies were open-label, single-centre, prospective, non-randomized, interventional case series with a follow-up between 4 and 26 weeks, employing either adalimumab in two studies and infliximab in three. Three studies showed a treatment effect of anti-TNF intravitreal injections, while one study revealed short-term improvement and one study revealed no efficacy of anti-TNF intravitreal therapy. None of the studies reported ocular adverse effects but only two studies included electrophysiological assessment in the safety analysis and no study assessed systemic human anti-drug antibodies. The available evidence is not sufficiently robust to conclude about the clinical effectivity of intravitreal anti-TNF in NIU and so no recommendation can be made. In conclusion, intravitreal injection of anti-TNF antibodies remains a possible treatment option to be explored through robust clinical investigation

Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds.

Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular