Clinical and Genetic Findings of the First Report of PAPA Syndrome in Brazil

Background. PAPA syndrome (MIM #604416) is a rare monogenic autoinflammatory disease genetically transmitted in an autosomal dominant trait that results from missense mutations in the proline-serine-threonine phosphatase-interactive protein 1 (PSTPIP1) gene located on chromosome 15 and is characterized by sterile pyogenic arthritis, pyoderma gangrenosum, and cystic acne. We describe the clinical and molecular findings of two related Brazilian patients with PAPA syndrome. Case Presentation. A 7-year-and-3-month-old boy with nonconsanguineous parents had had recurrent pyoarthritis since the age of 5 years and 8 months. During his last and long hospitalization, the lack of improvement with antibiotics, evidence of increased inflammatory activity, repeated arthrotomies, draining purulent fluid that had negative cultures, and the history of trauma, all on in a clinical background of pyoarthritis, led to the suspicion of an autoinflammatory syndrome. This was confirmed by the good clinical response to corticotherapy. Genetic sequencing confirmed the diagnosis of PAPA syndrome, with the pathogenic mutation c.688 G > A (p. Ala230Thr) in the PSTPIP1 gene present in the patient and in the mother. Conclusions. This case illustrates that in children with recurrent/recalcitrant sterile recurrent pyogenic arthritis/osteomyelitis, the possibility of an underlying immunological condition should be considered. In both, recurrent infections or recurrent inflammation, many genes involved in the inborn errors of immunity can be associated, and a correct and precocious diagnosis is necessary to avoid mobility and mortality. To the best of our knowledge, this is the first report of PAPA syndrome in Brazil.

Risk Factors for Secondary Glaucoma in Patients with Vogt-Koyanagi-Harada Disease

Background: To identify the prevalence and risk factors for secondary glaucoma among Mexican-mestizo patients with Vogt-Koyanagi-Harada Disease (VKH). A retrospective cohort study was conducted to identify the risk factors for developing secondary glaucoma based on demographic, clinical, and epidemiological variables of VKH Mexican-mestizo patients. Risk estimates were calculated using a Cox proportional hazards regression model. Main text: One hundred eyes of 50 patients, 44 (88%) women and 6 men (12%) with a median age of 35.5 years (IQR 29 – 46), and a median follow-up time of 72 months (IQR 13.7 – 126.7) were included for analysis. The prevalence of glaucoma was 20%, with angle-closure glaucoma accounting for 70% of all cases. Significant clinical risk factors for glaucoma development were a chronic recurrent stage at presentation (RR 2.88 95% CI 1.11 – 12.63, p=0.037), more than two episodes of recurrent anterior uveitis (RR 8.52 95% CI 2.02 – 35.92, p<0.001), angle-closure disease (ACD, RR 7.08 95% CI 2.44 – 20.48, p<0.001), iris bombé (RR 5.0 95% CI 2.10 – 11.90, p<0.001), and peripapillary atrophy (RR 3.56 95% CI 1.43 – 8.85, p<0.001). Exposure to prednisone for more than 24 months (RR 9.33 95% CI 2.21 – 39.28, p<0.001) or topical corticosteroid drops for more than 12 months (RR 3.88 95% CI 1.31 – 11.46, p=0.007) were associated with an increased likelihood for secondary glaucoma development. Conclusions: Glaucoma is a frequent complication in patients with VKH, often attributed to mixed pathogenic mechanisms. Chronic disease at presentation, recurrent inflammation, angle-closure mechanisms, iris bombé, and peripapillary atrophy represent clinically significant risk factors for secondary glaucoma development. Prompt and aggressive steroid-spearing immunosuppressive therapy for reaching adequate control of inflammation may lower the risk of glaucoma in VKH patients.

Co-occurrence of Relapsing Polychondoritis and Autoimmune Thyroid Diseases

Background: Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent inflammation and destruction of cartilageous tissues. RP has characteristics of autoimmune disease and some reports have noted co-occurrence with autoimmune thyroid disease (AITD), consisting of Graves’ disease (GD) and Hashimoto thyroiditis (HT). However there have been no detailed studies on the co-occurrence of RP and AITD. In this study, we aimed to determine whether patients with RP tend to be complicated with AITD. We also analyzed clinical and genetic profiles of patients in whom these diseases co-occur.Methods: We recruited 117 patients with RP and reviewed their medical records. Furthermore, we genotyped Human Leucocyte Antigen (HLA)-A, B Cw, DRB1, DQB1 and DPB1 alleles for 93 of the 117 patients. The prevalence of AITD among the patients with RP was compared with that among the general Japanese population. We also analyzed the clinical and genetic features of the patients with both RP and AITD.Results: The prevalence of GD among the patients with RP was 4.3% (5 among 117 patients), significantly higher than that among Japanese (0.11%) (p=2.44×10-7, binomial test). RP patients with GD tended to have nasal involvement (p=0.023) (odds ratio (OR) 2.58) and HLA-DPB1*02:02 (p=0.035, OR 10.41). We did not find significant enrichment of HT in patients with RP.Conclusions: Patients with RP appear to be at elevated risk of GD. Nasal involvement and HLA-DPB1*02:02 may characterize the subset of RP patients with GD, which may guide attempts to characterize distinct subtype of RP for precision medicine.

In Vivo Biofilm Formation of Pathogenic Leptospira spp. in the Vitreous Humor of Horses with Recurrent Uveitis

Equine recurrent uveitis (ERU) causes painful inflammatory attacks and oftentimes blindness in the affected eyes. The disease is considered a late sequela of systemic leptospirosis. The most effective therapy is the surgical removal of the vitreous (vitrectomy), which is not only therapeutic, but provides vitreous material that can be assessed diagnostically. For example, the lipL32 gene, culturable Leptospira spp., and anti-Leptospira antibodies have all been detected in vitreous samples obtained from eyes with chronic ERU. Despite this clear evidence of leptospiral involvement, the systemic administration of antibiotics in infected horses is ineffective at resolving ERU. This syndrome of chronic recurrent inflammation, which is unresponsive to antibiotic therapy, combined with apparent bacteria evading the immune response, is consistent with a biofilm-associated infection. The purpose of this study, therefore, was to detect the in vivo biofilm formation of Leptospira spp. in vitreous samples collected during vitrectomy and examined using a Warthin-Starry silver stain and immunohistochemistry. All known steps of biofilm formation were visualized in these samples, including individual Leptospira spp., leptospiral microcolonies and dense roundish accumulations of Leptospira spp. In many instances spirochetes were surrounded by an extracellular substance. Taken together, data from the present study show that ERU is a biofilm-associated intraocular leptospiral infection, which best explains the typical clinical course.

Subglottic Stenosis as an Isolated Clinical Manifestation in Relapsing Polychondritis – A Case Report

Relapsing Polychondritis is a rare, multisystem autoimmune disease still of unknown origin, characterized by recurrent inflammation of the hyaline cartilages. The involvement of Laryngotracheal cartilages in polychondritis is one of the most serious known complications, observed in 50% of patientswith worse prognosis. Among the causesof death, laryngotracheal stenosis associated with pneumonia or severe respiratory failure stands out, and may be found in 10% to 50% of patients with the disorder. We describe a case of relapsing polychondritis in a female patient, with dyspnea as an initial manifestation, in which Grade III Cotton-Myer Laryngotracheal Stenosis was later confirmed. During the 10 years of investigation, clinical treatment stabilized the disease, but the respiratory distress persisted, which prompted the patient to be submittedto surgical correction of laryngotracheal stenosis.

Rare Autoinflammatory Diseases: A Single Center Experience of 47 Patients

Autoinflammatory diseases include a group disease characterized by recurrent systemic inflammatory attacks due to failure in the regulation of the innate immune system. The beginning time of autoinflammatory disease are the most commonly in childhood. Autoinflammatory disease which having different clinical forms are rare, therefore diagnosis is often delayed. To determine the clinical, laboratory and radiological characteristics of children with rare autoinflammatory diseases and in which patients to consider autoinflammatory disease. Forty seven patients diagnosed with rare autoinflammatory diseases between 2010 and 2020 were analyzed retrospectively. Demographic characteristics, clinical courses, laboratory and imaging findings of the patients were recorded. Forty-seven with rare autoinflammatory patients evaluated. Twenty-three patients had Chronic Nonbacterial Osteomyelitis (CNO), seven patients had Mevalonate Kinase Deficiency (MKD), six patients had Blau Syndrome / Early-Onset Sarcoidosis (BS/EOS) Syndrome, three patients had Cryopyrin-associated periodic fever syndrome (CAPS), three patients had Autoinflammatory Vasculitis, one patient had Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) syndrome, one patient had Neonatal Onset Pancytopenia, Autoinflammation, Rash and Episodic HLH (NOARCH) syndrome. Three of our patients were being followed up with a diagnosis of undiferantiated systemic autoinflammatory disease (uSAID).Autoinflammatory diseases may have different presentations. Steril and recurrent inflammation should be warning clinicians.

Berberine-Loaded Carboxylmethyl Chitosan Nanoparticles Ameliorate DSS-Induced Colitis and Remodel Gut Microbiota in Mice

Inflammatory bowel disease (IBD) is a refractory disorder characterized by chronic and recurrent inflammation. The progression and pathogenesis of IBD is closely related to oxidative stress and irregularly high concentrations of reactive oxygen species (ROS). A new oxidation-responsive nano prodrug was constructed from a phenylboronic esters-modified carboxylmethyl chitosan (OC-B) conjugated with berberine (BBR) that degrades selectively in response to ROS. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. OC-B-BBR micelles could effectively encapsulate the anti-inflammatory drug berberine and exhibit ideal H2O2-triggered release behavior as confirmed by in vitro drug loading and release studies. The in vivo anti-inflammatory effect and regulation of gut microbiota caused by it were explored in mice with colitis induced by dextran sodium sulfate (DSS). The results showed that OC-B-BBR significantly ameliorated colitis symptoms and colon damage by regulating the expression levels of IL-6 and remodeling gut microbiota. In summary, this study exhibited a novel BBR-loaded Carboxylmethyl Chitosan nano delivery system which may represent a promising approach for improving IBD treatment.

Utilizing dexamethasone intravitreal implant to control postoperative inflammation in refractory uveitis undergoing cataract surgery

AIM: To report the effectiveness of intravitreal implantation of dexamethasone implant (Ozurdex) after phacoemulsification and intraocular lens implantation in refractory uveitis patients. METHODS: This single-center retrospective study conducted for refractory pan-uveitis patients who underwent cataract surgery combined with intravitreal Ozurdex implantation. The main outcome measurements were best-corrected visual acuity (BCVA), central retinal thickness (CRT), grade of anterior chamber cell (AAC), intraocular pressure (IOP), and systemic/ocular adverse events. RESULTS: Ten eyes of 7 patients were included. BCVA showed significant improvement at 1mo (P=0.004), 3mo (P=0.0004), and 6mo (P=0.001) post operation. There were no statistically significant differences in the postoperative CRT among follow-up groups (P>0.05). No significant differences were observed in the baseline IOP when compared to 1, 3, and 6mo (all P>0.05) post operation. One patient developed a transient elevated IOP post injection. Two eyes (20%) developed posterior capsular opacifications and underwent neodymium-doped yttrium aluminum garnet (Nd:YAG) laser capsulotomy. In six patients (8 eyes, 71.4%), the systemic steroid usage was reduced to below 10 mg/d. The patients experienced a mean of 1.4±0.52 recurrences of inflammation in the 6mo before operation and 0.7±0.48 in the 6mon post operation. The mean recurrence time was 13±0.58wk (range 12-14wk) post operation. In five of seven patients (7 out of 10 eyes), inflammation relapse was developed postoperatively. Only one patient (2 eyes) needed increased amounts of oral corticosteroids. Intraocular inflammation recurrence in the remaining patients was controlled by topical steroids. CONCLUSION: Ozurdex is considered a safe and effective approach to control postoperative inflammation in cataract surgery for patients with refractory uveitis in our study. After the disappearance of Ozurdex’s anti-inflammatory effects over time, in most cases the recurrent inflammation can be controlled by topical steroids.