Colchicine Effectiveness and Safety in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis.

Introduction: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common fever syndrome in childhood. High disease activity (DA) dramatically impacts the health-related quality of life. Thus, effective and safe treatment is crucial. Colchicine might be effective, but data are still lacking. Study aimed to assess colchicine safety and effectiveness in PFAPA. Methods: This single center study was conducted between 03/2012 and 05/2021 in PFAPA patients without variants in genetic panel testing aged ≤ 18 years fulfilling Marshall criteria and classification criteria of Gattorno et al. Exclusion criteria were elevated liver enzymes, impaired kidney function, celiac disease, lactose intolerance, previous/ongoing biologics, known colchicine-intolerance. Demographics, clinical characteristics, treatment, DA, colchicine effectiveness and safety were recorded at baseline, first and last visit. Colchicine was started at 0.5-1.0 mg/day. DA was captured by physician (PGA) and patient/parent (PPGA) global assessment on a 10 cm visual analog scale, categorized as mild (<2), moderate (2-4), and high (≥5). Adverse event (AE) monitoring included gastrointestinal symptoms, liver enzyme/creatinine elevation, leukopenia, neutropenia. Primary outcome included response (R; composite of PPGA + PGA decrease ≥2) at last follow-up. Secondary outcomes were partial response (PR; PGA decrease = 1 + PPGA decrease ≥1), no response (NR; unchanged/worsened PGA/PPGA), colchicine safety, flare characteristics. Results: Twenty-seven PFAPA patients were included, 52% were female, median age was 5.8 years (1-10.75), median follow-up time was 13 months. At baseline, median PPGA was high; median PGA moderate. All patients had febrile flares. Median flare frequency was every 4-5 weeks; median duration 5-6 days. Nine patients were pre-treated with corticosteroids, increasing flare frequency in 8/9. Primary Outcome: 17 patients (63%) were responders. Secondary outcomes: PR was achieved in 15%; NR in 22% at last follow-up. DA decreased significantly (p <0.0001). At last follow-up, 52% reported no flares, median flare duration decreased to 1-2 days. At first follow-up, 22% reported mild abdominal pain/diarrhea. Moderate abdominal pain/diarrhea occurred with ≥1 mg/day. Mild asymptomatic liver enzyme elevation or leucopenia were rare; no severe AE or colchicine discontinuation were observed. Conclusion: Colchicine seems to be safe, well-tolerated, and effective in PFAPA patients. It can be considered in children with moderate/high DA even those without corticosteroid-benefit.

Colchicine - an effective treatment for children with a clinical diagnosis of autoinflammatory diseases without pathogenic gene variants.

BACKGROUND: Autoinflammatory diseases (AID) are rare chronic conditions with high disease burden, affecting children and adults. Clinically and genetically confirmed, AID can be effectively treated with targeted cytokine inhibition. In contrast, for patients with clinical AID symptoms without pathogenic gene variants, no treatment recommendations are available. Colchicine is approved and established as effective, safe and low-cost first-line therapy in Familial Mediterranean Fever. Up to now, efficacy data for colchicine in children with a clinical AID diagnosis without pathogenic gene variants are rare. This pilot study was performed to evaluate the effectiveness of colchicine in children with a clinical diagnosis of AID without pathogenic gene variants. METHODS: A pilot cohort study of consecutive children with active clinical AID without pathogenic gene variants treated with colchicine monotherapy was performed between 01/2009 and 12/2018. Demographics, clinical and laboratory characteristics were determined serially. Colchicine dosing and safety were documented. Physician estimate of disease activity was captured on visual analogue scales (VAS). PRIMARY OUTCOME: Complete response (PGA ≤2 plus CRP ≤0.5 mg/dL and/or SAA ≤10 mg/L) at last follow-up. SECONDARY OUTCOMES: partial/no response, flare characteristics and requirement for rescue therapies. ANALYSIS: Nonparametric comparison of disease activity measures. RESULTS: A total of 33 children were included; 39% were female. Median age at colchicine start was 3.8 years, median follow-up was 14.1 months. Clinical AID diagnoses included CAPS (24%), FMF (27%), PFAPA (43%) and unclassified AID (6%). At baseline, overall disease activity was moderate (PGA 4), inflammatory markers were elevated (CRP 12.1 mg/dL; SAA 289.2 mg/L), and 97% reported febrile flares. OUTCOME: 55% achieved complete response, 35% showed partial response and 58% had no febrile flares at last follow-up. Inflammatory markers (SAA: p < 0.0001, CRP: p < 0.005) and disease activity (p < 0.0001) decreased significantly. Overall, 93% of children experienced improvement of flare characteristics. CONCLUSION: Colchicine was found to be effective and safe in children with a clinical AID diagnosis in the absence of pathogenic gene variants. Colchicine is a low-cost treatment option for non-organ threatening AID.

Early detection of sensorineural hearing loss in Muckle-Wells-syndrome.

BACKGROUND: Muckle-Wells-syndrome (MWS) is an autoinflammatory disease characterized by systemic and organ-specific inflammation due to excessive interleukin (IL)-1 release. Inner ear inflammation results in irreversible sensorineural hearing loss, if untreated. Early recognition and therapy may prevent deafness. The aims of the study were to characterize the spectrum of hearing loss, optimize the otologic assessment for early disease and determine responsiveness to anti-IL-1-therapy regarding hearing. METHODS: A single center prospective cohort study of children and adults with MWS was performed. Standardized clinical, laboratory and otologic assessments including standard pure tone audiometry, additional high tone thresholds, vestibular organ testing, tinnitus evaluation and functional disability classes were determined serially. Pure-tone-average models were developed and evaluated. Risk factors for hearing loss and the impact of anti-IL-1 treatment were determined. RESULTS: A total of 23 patients with genetically confirmed MWS were included, of whom 63 % were females; 52 % were children. At baseline all patients had active MWS; 91 % reported clinically impaired hearing with 74 % having an abnormal standard assessment (0.5-4 kHz). In contrast, high frequency pure tone averages (HF-PTA) were abnormal in all symptomatic patients including those with early hearing loss (sensitivity 100 %). Females were at highest risk for hearing loss even after adjustment for age (p = 0.008). Treatment with IL-1 blockade resulted in improved or stable hearing in 91 % of patients. CONCLUSIONS: Early inner ear inflammation in MWS primarily affects the high frequencies, beyond the range of standard otologic assessment tools. The HF-PTA is a sensitive tool to detect imminent hearing loss and monitor treatment response.

Challenges in diagnosing Muckle-Wells syndrome: identifying two distinct phenotypes.

OBJECTIVE: The diagnosis of Muckle-Wells syndrome (MWS) remains challenging due to the clinical heterogeneity and lack of diagnostic criteria. The aims of this study were to describe key elements of the diagnostic evaluation process in MWS and compare identified variables between patients diagnosed in childhood and adulthood. METHODS: A cohort study of consecutive patients with a clinical and genetic diagnosis of MWS was conducted at 2 reference centers for autoinflammatory diseases. Demographic information, clinical presentation, access to care, and preclinical evaluation variables were captured. Presenting symptoms were compared between groups of patients diagnosed in childhood and adulthood. Prediction analysis explored variables associated with late diagnosis. Correspondence analysis identified clinical phenotypes. RESULTS: A total of 34 MWS patients were included (16 males, 18 females) and median age at diagnosis was 31.5 years (range 0.5-75 years). Patients diagnosed during childhood reported musculoskeletal symptoms (62%), rash (62%), fever (54%), and abdominal pain (31%). Those diagnosed as adults described musculoskeletal symptoms (86%), rash (67%), hearing loss (52%), and fatigue (29%). Hearing loss was associated with late diagnosis, while access-to-care variables were not predictive. Correspondence analysis identified distinct clinical phenotypes as follows: an "inflammatory phenotype" (most commonly seen in patients diagnosed in childhood and characterized by relapsing fever and abdominal pain), an intermediate phenotype, and an "organ-disease" phenotype in patients diagnosed during adulthood and characterized by fatigue and hearing loss. CONCLUSION: Distinct clinical phenotypes were identified in patients with MWS. These are closely related to age at diagnosis. The presence of these phenotypes has to be considered when developing diagnostic criteria for MWS.

Anaphylactic reaction after systemic application of aprotinin triggered by aprotinin-containing fibrin sealant.

We report a 67-yr-old male after multiple surgical procedures for treatment of arterial occlusive disease who suffered an anaphylactic reaction after administration of aprotinin (Trasylol) prior to urgent coronary artery bypass surgery. The patient had been treated with aprotinin-containing fibrin sealant in 2004 and in 2007, 2 wk before coronary artery bypass surgery. The postoperative serologic screening revealed positive results for qualitative aprotinin-specific IgG, highly elevated quantitative aprotinin-specific IgG and moderately elevated aprotinin-specific IgE antibodies.