• Lupus
• Rheumatoid Arthritis
• Rheumatological Autoimmune Disorders
• Arthritis

• Lupus
• Rheumatology
• Rheumatoid Arthritis
• Rheumatological Autoimmune Disorders
• Arthritis

Rolando Cimaz, MD, University of Florence, Florence, Italy, reviewed a number of publications from the past 12 months that he considers the most important in the field of pediatric rheumatology.

Advances in technology have led to the discovery of genetic mutations that are responsible for certain rare phenotypes. A recently published case study describes a 9-month-old infant of Tunisian consanguineous parents with recurrent fevers with pericarditis, joint pain, abdominal pain, liver and spleen enlargement, and diarrhea [Melki I et al. Pediatrics 2013]. The presence of hyperpigmented, hypertichotic cutaneous patches, Rosai-Dorfman histiocytosis, and sensorineural hearing loss led the investigators to suspect a genetic mutation, and a homozygous mutation in exon 6 of the SLC29A3 gene was found. The infant failed to thrive and did not respond to any treatments (colchicine, anakinra, canakinumab, adalimumab). In another published case study, an infant of Tunisian consanguinous parents presenting with generalized pustular psoriasis did not respond to high-potency topical glucocorticoids (GC) and retinoic acid [Rossi-Semerano L et al. Pediatrics 2013]. Genetic analysis revealed a homozygous missense mutation in the interleukin (IL)-36 receptor antagonist gene, IL36RN, and the patient responded to treatment with the IL-1 inhibitor anakinra.

Two publications established a link between adenosine deaminase 2 (ADA2) deficiency and vascular disease. The first report found a link between recessive mutations in the ADA2-encoding gene CECR1 and polyarteritis nodosa vasulopathy (PNV) [Navon Elkan P et al. N Engl J Med 2014]. A pedigree of 6 families with multiple cases of systemic and cutaneous PNV indicated autosomal recessive inheritance with childhood disease onset and highly variable phenotypes. The second publication described 3 unrelated children with recurrent fever, early-onset (<5 years of age) and recurrent strokes, livedoid rash, mild immunodeficiency, hepatosplenomegaly, and systemic vasculopathy [Zhou Q. et al. N Engl J Med 2014]. They had recessively inherited CECR1 mutations and almost no active ADA2 concentrations in plasma compared with controls.

A randomized, multicenter, open-label clinical trial was conducted to determine the effects of attenuated measles-mumps-rubella (MMR) vaccine booster on juvenile idiopathic arthritis (JIA) disease activity [Heijstek MW et al. JAMA 2013]. In total, 137 patients aged 4 to 9 years with JIA were enrolled, and treatment with biologics was discontinued at 5 times their half-lives prior to vaccination. The investigators found that JIA activity was not worsened in 63 children receiving MMR boosters (Juvenile Arthritis Disease Activity Score 27 [JADAS-27], 2.8; 95% CI, 2.1 to 3.5] compared with 69 control patients who did not receive boosters (JADAS-27, 2.4; 95% CI, 1.7 to 3.1). On the basis of these data, physicians can reassure parents that vaccinations can be given to their children, that they are immunogenic, and that they will not flare disease, stated Prof. Cimaz. Key findings from other studies in JIA are presented in Table 1.

Kawasaki disease (KD) is routinely treated with intravenous immunoglobulins (IVIG). Current guidelines recommend waiting ≥6 months after IVIG treatment to administer the MMR vaccine. A retrospective study was conducted to determine the effect of IVIG infusions on the first dose of MMR vaccine in patients with KD [Tacke CE et al. J Allergy Clin Immunol 2013]. One hundred fifty-five patients were separated into 3 groups: those who were vaccinated before IVIG, those who were vaccinated after IVIG, and those who did not receive IVIG because of a delay in diagnosis. Patients vaccinated before IVIG and healthy controls had comparable immunoglobulin G concentrations and seroprotection (p<0.10 for all) to measles, mumps, and rubella. Patients vaccinated after IVIG had lower responses at 9 months. The authors therefore recommended delaying MMR vaccination until ≥9 months after IVIG treatment for KD.

Findings from a Phase 3, randomized, double-blind, placebo-controlled trial of the addition of infliximab to standard therapy for KD were recently reported [Tremoulet AH et al. Lancet 2014]. The study enrolled 196 patients but did not meet its primary endpoint of treatment resistance (11.2% for infliximab and 11.3% for placebo; p=0.81). In addition, there are preclinical data indicating that interleukin-1 is crucial for the induction of coronary artery inflammation in KD [Lee Y et al. Circulation 2012]. A study of anakinra in children with KD is planned, and Prof. Cimaz hopes results with be available next year.

Five years of follow-up data have been published regarding the treatment of childhood-onset systemic lupus erythematosus (SLE) with rituximab (RTX) and cyclophosphamide (CP) [Lehman TJ et al. Pediatr Rheumatol Online J 2014]. Twelve patients were treated with RTX (750 mg/m² up to 1 g) or CP (750 mg/m²). The initial administrations were given 2 weeks apart, followed by 1 administration 6 months later and another 18 months later. This therapy led to rapid reduction of the GC dose without disease flare, thus preventing or resolving GC-associated adverse effects. The authors concluded that this regimen led to sustained relief over 5 years while minimizing the need for GCs. In another study, protein kinase C delta (PKCδ) deficiency was reported as a new form of monogenic SLE [Belot A et al. Arthritis Rheum 2014]. This B-cell apoptotic defect results in SLE-related autoimmunity. In humans, PKCδ plays a major role in inducing B-cell tolerance and the removal of self-reactive transitional B cells.

In closing, Prof. Cimaz summarized what he considers to be the single most important publication in pediatric rheumatology from the past year. Rice and colleagues reported that neuroimmunologic features associated with an enhanced interferon state are caused by heterozygous mutations in the cytosolic double-stranded receptor gene IFIH1 (also known as MDA5) [Rice GI et al. Nat Genet 2014]. Such mutations result in a gain of function such that the mutant IFIH1 protein binds ribonucleic acid more effectively than wild-type does, leading to increased interferon signaling. Prof. Cimaz stated that these mutations provide new insights into the function of the gene, which will assist with designing treatments.

• © 2014 MD Conference Express®