Living with autoinflammatory diseases: identifying unmet needs of children,adolescents and adults

Background

Autoinflammatory diseases (AIDs) illnesses of the innate immunity resulting in clinical signs and symptoms of systemic inflammation and loss of organ functions. While pathophysiological mechanisms are heavily studied and increasingly well understood, psychosocial needs are much less explored. The disease impact on the everyday life of patients including school and work is poorly studied. The purpose of the study was to identify the spectrum of unmet needs of children, adolescents and adults living with autoinflammatory disease and their families, to define key unmet needs and strategies and to develop and evaluate a pilot intervention addressing the unmet need “school”.

Methods

A single-center, mixed-method study of AID patients and their families was conducted. Consecutive patients ages ≥4?years and their families were included. Expert consulting, focus groups and questionnaires explored the patient perspective of “unmet needs in AID”. Quantitative and qualitative content analyses were performed and informed the development of a framework of unmet needs. A targeted pilot multimodular intervention for the unmet need “school” was developed and tested. Health-related Quality of Life (HRQoL) was evaluated using DISABKIDS-questionnaires and psychosocial impact evaluations.

Results

The study included 83 patients and their families. These were 14 children, 9 adolescents and 25 adults with AID and 35 family members; patients’ median age was 19?years (5–78). Expert consultations: 110 AID patients with 320 visits/year; 99 (90%) were children and adolescents. 78 patients and family members (94%) participated in 10 groups. Qualitative content analysis delineated 9 domains of unmet needs, the most relevant being school, health care system and public institutions. The pilot intervention“school” included 18 participants; median age was 9?years (7–16). HRQoL improved with the intervention including “understanding” by 53%, however improvement was not sustained over time.

Conclusion

Unmet needs of AID patients and families affect all areas of life. Accessible networks increasing knowledge and empowering patients, strategies supporting academic and workplace environments to ensure successful participation and integrated concepts addressing psychosocial needs are urgently needed.

     

Risk factors for severe Muckle‐Wells syndrome

Objective

Muckle‐Wells syndrome (MWS) is an inherited autoinflammatory disease resulting in excessive interleukin‐1 release. It is unknown whether demographic, clinical, or laboratory characteristics at the time of diagnosis may identify patients who are at high risk for severe disease activity. This study was undertaken to analyze clinical and laboratory features of MWS, compare genetically defined subcohorts, and identify risk factors for severe MWS.

Methods

A multicenter cohort study of consecutive MWS patients was performed. Parameters assessed included clinical features, MWS Disease Activity Score (MWS‐DAS), inflammation markers, and cytokine levels. E311K mutation–positive patients were compared with E311K mutation–negative patients. Putative risk factors for severe MWS (defined as an MWS‐DAS score of ≥10) were assessed in univariate analyses, and significant predictors were entered into a multivariate model.

Results

Thirty‐two patients (15 male and 17 female) were studied. The most frequent organ manifestations were musculoskeletal symptoms and eye and skin disorders. Renal disease and hearing loss were seen in >50% of the patients. Genetically defined subcohorts had distinct phenotypes. Severe disease activity was documented in 19 patients (59%). Predictors of severe MWS identified at the time of diagnosis were female sex, hearing loss, musculoskeletal disease, increased erythrocyte sedimentation rate, and low hemoglobin level. Female sex and hearing loss remained significant after adjustment for age in a multivariate model (relative risk 1.8 and 2.6, respectively).

Conclusion

MWS patients at high risk for severe disease can be identified at the time of diagnosis. Female patients presenting with hearing loss have the highest likelihood of manifesting severe MWS and should be considered a high‐risk group.

     

Marked changes of the hepatic sinusoid in a transgenic mouse model of acute immune-mediated hepatitis

BACKGROUND/AIMS: The liver sinusoidal endothelial cell (LSEC) is increasingly recognized as having an important role in hepatic immunity. However, the responses of LSECs and the hepatic sinusoid in immune-mediated hepatitis are poorly described. METHODS: We studied a transgenic mouse model of acute immune-mediated hepatitis: Met-Kb mice injected with T cells from Des-TCR mice. RESULTS: Hepatitis was characterized by lymphocyte infiltrates causing severe but transient liver damage. There were marked changes in the ultrastructure of the LSEC five days after injection of the T cells that coincided with the peak of the hepatitis. The porosity of fenestrations in the LSEC decreased and the endothelium became thickened. LSECs appeared to be markedly activated. These changes were associated with narrowing of the space of Disse, loss of hepatocellular microvilli and deposition of basal lamina. Lymphocytes were seen passing through fenestrations. Loss of fenestration in the LSEC prevented hepatitis induced by a second injection of lymphocytes on day 5. CONCLUSIONS: Structural changes in the LSEC occur during the peak of a mouse model of immune-mediated hepatitis. These changes were associated with attenuation of subsequent liver damage, suggesting that they may influence immunological responses mediated by LSECs or the passage of lymphocytes through LSEC fenestrations.     

MSC-based therapies in solid organ transplantation

Immunomodulatory cell therapy as a complement to standard pharmacotherapy represents a novel approach to solid organ allograft acceptance. This methodology may allow for a reduced dose of immunosuppressive drug to be administered and thus attenuate the severe side effects associated with long-term immunosuppression such as drug-related impairment of renal function, increased risk from opportunistic infections and malignancies. Mesenchymal stem cells (MSCs) have been shown to possess both immune modulatory and regenerative properties in vitro and in preclinical models. Encouraging results have been reported from studies examining the safety and efficacy of MSCs as a treatment for acute graft-versus-host disease. MSCs represent a promising candidate cell therapy to supplement immunosuppression in recipients of solid organs, and initial reports on the clinical use of MSCs in kidney transplantation have been recently published (Tan et al. in J Am Med Assoc 307:1169–1177, 2012; Reinders et al. in Stem Cells Transl Med 2:107–111, 2013; Perico et al. in Transpl Int 26:867–878, 2013; Perico et al. in Clin J Am Soc Nephrol 6:412–422, 2011). An area of even greater interest might be the application of MSCs in clinical liver transplantation as graft survival is closely associated with overall patient survival. Here, we present preclinical findings and discuss their possible impact on clinical liver transplantation. Then we discuss clinical studies designed to investigate how MSCs may be distributed and act in solid organ transplantation.     

The New Histopathologic Classification of ANCA-Associated GN and Its Association with Renal Outcomes in Childhood

Background and objectives

A proposed histopathologic classification for ANCA-associated GN is predictive of long-term renal outcome in adult populations. This study sought to validate this system in a pediatric cohort.

Design, setting, participants, & measurements

This was a retrospective, single-center, cohort study of 40 children diagnosed and followed until their transition to adult care at one institution between 1987 and 2012. Renal biopsy specimens were reviewed by a pathologist blinded to patient outcome and were classified using the new histopathologic classification system of focal, crescentic, mixed, and sclerotic groups. Time to the composite outcome of CKD stages 3 and 4 (determined by eGFR with repeated creatinine measures using the Schwartz equation) or ESRD (defined as dialysis dependence or transplantation) were ascertained.

Results

The study population consisted of 40 children (70% female), followed for a median of 2.4 years. The biopsy specimens were categorized as focal in 13 patients (32.5%), crescentic in 20 (50%), mixed in two (5%), and sclerotic in five (12.5%). Mixed and crescentic were combined for analyses. Survival analysis of time to the composite renal endpoint of at least 3 months of eGFR<60 ml/min per 1.73 m² or ESRD differed significantly among the three biopsy groups log-rank P<0.001), with an adjusted hazard ratio of 3.14 (95% confidence interval, 0.68 to 14.4) in the crescentic/mixed group and 23.6 (95% confidence interval, 3.9 to 144.2) in the sclerotic category compared with the focal category. The probability of having an eGFR>60 ml/min per 1.73 m² at 2 years was 100% for the focal, 56.5% for the crescentic/mixed, and 0% for the sclerotic biopsy categories.

Conclusions

This study showed the clinical utility of this histopathologic classification system and its ability to discriminate renal outcomes among children with ANCA GN.     

Hearing loss in Muckle‐Wells syndrome

Objective

Muckle‐Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fevers, rashes, arthralgia, conjunctivitis, and sensorineural hearing loss. In MWS, NLRP3 gene mutations are associated with excessive interleukin‐1 release. The aims of this study were to determine the otologic characteristics of MWS, define trajectories of hearing loss, and explore the association with distinct NLRP3 genotypes.

Methods

A prospective observational cohort study of children and adults diagnosed as having MWS was conducted at a single center. NLRP3 gene mutations were determined. Patients underwent standardized clinical, laboratory, and otologic assessments, including pure tone audiometry, vestibular organ testing, and tinnitus evaluation. Trajectories of hearing loss were defined for each genotype. The genotype‐specific risk of progression of hearing loss was determined.

Results

A total of 33 patients ages 3–75 years who were members of 5 families with 4 different NLRP3 gene mutations were included. The majority of patients (67%) experienced bilateral sensorineural hearing loss. Even in cases of profound hearing loss vestibular reactivity remained normal. Fourteen adult patients reported nondebilitating tinnitus. Overall, hearing impairment progressed with age. Patients with the T348M mutation were at highest risk of rapid progression of sensorineural hearing loss.

Conclusion

Patients with MWS are at risk of developing progressive sensorineural hearing loss without vestibular involvement. Hearing impairment starts at high frequencies and can subsequently progress to profound hearing loss. Progression is age dependent. Patients with different NLRP3 mutations had distinctly different trajectories of hearing loss, suggesting a mutation‐specific risk that should be considered when making treatment decisions.