Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases.

BACKGROUND: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs. METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.

Linear pitting and splinter haemorrhages are more commonly seen in the nails of patients with established psoriasis in comparison to psoriatic arthritis.

BACKGROUND: Recently the role of several ligament and tendon insertions around the nail matrix and nail plate have been identified as possible contributory factors that explain the higher prevalence of nail involvement in psoriatic arthritis (PsA). The purpose of this study was to determine whether such anatomical factors might also be associated with different patterns of nail involvement in skin psoriasis and PsA. METHODS: A total of 173 patients were recruited: 121 PsA cases and 52 psoriasis cases. All patients had a standardised assessment of the nails for lesions including pitting, splinter haemorrhages and onycholysis. RESULTS: The overall modified Nail Psoriasis Severity Index scores did not differ between the two groups (psoriasis mean 8.5, SD 7.1; PsA mean 8.3, SD 9.4). In the nail matrix, linear pitting appeared to be more common in skin psoriasis (OR 0.27, 95% CI 0.18-0.41). There were no significant differences in the distribution of nail plate abnormalities other than splinter haemorrhages which were more commonly seen in psoriasis cases (OR 0.23, 95% CI 0.14-0.39). CONCLUSION: The pattern of nail disease in psoriasis and PsA differed with respect to the frequency of linear pitting and splinter haemorrhages, with both features occurring more often in psoriasis.

Golimumab in refractory uveitis related to spondyloarthritis. Multicenter study of 15 patients.

OBJECTIVE: To assess the efficacy of golimumab (GLM) in refractory uveitis associated to spondyloarthritis (SpA). METHODS: Multicenter study of SpA-related uveitis refractory to at least 1 immunosuppressive drug. The main outcome variables were degree of anterior and posterior chamber inflammation, visual acuity, and macular thickness. RESULTS: A total of 15 patients (13 men/2 women; 18 affected eyes; mean age 39 ± 6 years) were evaluated. The underlying SpA subtypes were ankylosing spondylitis (n = 8), psoriatic arthritis (n = 6) and non-radiographic axial SpA (n = 1). The ocular involvement patterns were recurrent anterior uveitis in 8 patients and chronic anterior uveitis in 7. Before GLM they have received methotrexate (n = 13), sulfasalazine (n = 6), pulses of methylprednisolone (n = 4), azathioprine (n = 3), leflunomide (n = 2), and cyclosporine (n = 1). Overall, 10 of them had also been treated with TNF-α blockers; etanercept (n = 7), adalimumab (n = 7), infliximab (n = 6), and certolizumab (n = 1). GLM was given at the standard dose (50mg/sc/monthly) as monotherapy (n = 7) or in combination with conventional immunosuppressive drugs (n = 8), mainly methotrexate. Most patients had rapid and progressive improvement of intraocular inflammation parameters. The median number of cells in the anterior chamber at 2 years [0 (0-0)] was significantly reduced compared to baseline findings [1 (0-3); p = 0.04]. The mean best corrected visual acuity value also improved (0.84 ± 0.3 at 2 years versus 0.62 ± 0.3 at baseline; p = 0.03). Only minor side effects were observed after a mean follow-up of 23 ± 7 months. CONCLUSIONS: Our results indicate that GLM may be a useful therapeutic option in refractory SpA-related uveitis.

Role of PTPN22 and CSK gene polymorphisms as predictors of susceptibility and clinical heterogeneity in patients with Henoch-Schönlein purpura (IgA vasculitis).

INTRODUCTION: To determine whether the PTPN22 (protein tyrosine phosphatase nonreceptor 22)/CSK (c-src tyrosine kinase) pathway is implicated in the susceptibility and clinical heterogeneity of Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. METHODS: A set of 329 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria and 515 sex and ethnically matched controls were recruited in this study. Two well-known CSK (CSK rs34933034 and CSK rs1378942) and two functional PTPN22 (PTPN22 rs2476601 (R620W) and PTPN22 rs33996649 (R263Q)) polymorphisms, previously associated with autoimmunity, were genotyped with TaqMan single nucleotide polymorphism (SNP) genotyping assays. RESULTS: No significant differences in the genotype and allele frequencies between HSP patients and controls were observed when the CSK rs34933034, CSK rs1378942, PTPN22 rs2476601 (R620W) and PTPN22 rs33996649 (R263Q) polymorphisms were analyzed independently. In keeping with this observation, no significant differences were found when we assessed these polymorphisms combined conforming haplotypes. In addition, there were no differences in the allele or genotype frequencies when HSP patients were stratified according the age at disease onset, sex, presence of arthralgia/arthritis, nephritis or gastrointestinal manifestations. CONCLUSIONS: Our results do not support association between PTPN22/CSK and HSP.