Polly J. Ferguson

Membranoproliferative glomerulonephritis (MPGN) is among the most challenging glomerulonephritides to diagnose and manage, given its clinico-immunopathologic heterogeneity. Although recent advances have introduced new therapies for complement-mediated and immune-complex MPGN, a substantial subset of cases remains poorly understood and lacks effective treatment. We report a pediatric case of biopsy-confirmed C3-dominant MPGN without evidence of complement dysregulation, with disease flares triggered by febrile episodes. Genetic testing identified underlying hyper-IgD syndrome (HIDS), a rare autoinflammatory disorder characterized by recurrent fevers and immune dysregulation. The patient’s MPGN was refractory to conventional immunosuppressive therapy but achieved remission with IL-1β blockade that targets HIDS. This case highlights the importance of considering alternative etiologies—including autoinflammatory diseases—in patients with MPGN when complement dysregulation is not evident.

Background: The ChRonic nonbacterial Osteomyelitis Magnetic Resonance Imaging Scoring (CROMRIS) tool was developed to assess specific characteristics of bone and soft tissue inflammation on MR images of patients with CNO; however, this tool was labor intensive to utilize. We aimed (1) to refine and adapt this scoring method, (2) to assess the usability of this web-based CROMRIS system among radiologists and (3) to evaluate the absolute agreement of the components and summary CROMRIS scores at each body site, and the interrater reliability. Methods: We used a qualitative, user-centered design approach involving software developers, rheumatologists, radiologists, and a patient artist to adapt the paper-based scoring system to a web-based prototype that was further refined by monthly meetings between the group members. A clickable-schematic-based CROMRIS system was developed to include all body regions: head (skull/mandible), spine, torso (clavicle, sternum, and ribs), pelvis, hands, feet, arms, and legs. Readers scored individual bone units to indicate the presence of bone marrow hyperintensity on STIR images (score 0–1), soft tissue/periosteal hyperintensity of surrounding tissue (score 0–1), and bony expansion (score 0–1), and quantified the signal size of the CNO lesion (scores 1–3 defined as < 25%, 25–50%, or > 50% of the estimated volume, respectively). The sum of these parameters for lesions detected on fluid-sensitive sequences was the CROMIS Activity Index (maximum score 720). Feedback for usability was reported with descriptive content analysis and continuous variables as means and categorical variables as percentages. Interrater reliability was assessed by free-marginal kappa (k) statistics and the intraclass correlation coefficient (ICC). Results: The mean system usability score increased from 64.5 (below average) to 75 (above average) after user feedback. Interrater reliability for the CROMRIS Activity Index was excellent for clavicle, tibia, cervical and lumbar spines (> 0.9) and good to moderate for the remainder of the body regions. The mean kappa of each category of bones was > 0.6 demonstrating substantial interrater reliability among radiologists for the bone sites most affected by CNO, namely the long bones and clavicle. Conclusion: The web-based CROMRIS portal developed was usable and showed substantial-moderate agreement in the total CROMRIS Activity Index total scores among experienced radiologists after self-guided learning of the atlas and video. This tool can potentially be used in future clinical trials after calibration.

Objective: The health effects of SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome and chronic nonbacterial osteomyelitis (CNO) have not been well studied. We assessed health-related quality of life (HRQOL) in adults with SAPHO-CNO and performed a review of EQ-5D questionnaire outcomes among similar chronic rheumatic and inflammatory diseases. Methods: We enrolled patients in the first US-based SAPHO-CNO prospective registry and assessed their HRQOL using the EQ-5D index and EQ-5D visual analog scale (VAS). A focused scoping review was performed of EQ-5D–related outcomes among disease cohorts with phenotypic similarities to SAPHO-CNO. Results: In the 138 participants with SAPHO-CNO, mean age was 37.7 (SD 15.0) years with a mean disease duration of 6.4 (SD 6.2) years. All subjects had musculoskeletal involvement (with 43% having spine involvement) and 46% had skin involvement. Mean 5-level EQ-5D index value was 0.75 (SD 0.16) and mean EQ-VAS was 63.0 (SD 21.0). Most patients were affected by pain/discomfort (86%), difficulty in carrying out usual activities (65%), and anxiety/depression (54%); over one-third reported problems in all 5 EQ-5D domains. These adults with SAPHO-CNO had similarly reduced EQ-5D and VAS values, and similar high proportion of perceived problems, as in other inflammatory disease cohorts. Conclusion: The HRQOL among adults with SAPHO-CNO is low, with more than half of patients experiencing greater impact on perceived pain, difficulty performing usual activities, and feelings of anxiety or depression. Future therapies should address the multidimensional nature of SAPHO-CNO, targeting HRQOL as a major outcome.

Gestational hypertension (GH) is prevalent, with life-long health burdens for mothers and their children exposed in utero. We analyzed the nation-wide Epic Cosmos dataset and found significantly higher rates of seizures in children of mothers with GH than in children of normotensive mothers. Complementary studies of nested Iowa and Stanford cohorts and a large Taiwanese cohort also revealed significantly increased seizure risk after covariate adjustments. We modeled this association in an angiotensin (ANG) II mouse model of GH. Maternal ANG II significantly increased seizure grade and deaths elicited by pilocarpine among male but not female offspring. Electrical stimulation increased seizure grade and death across sexes in offspring from ANG II–treated dams. Proinflammatory and microglial gene expression in the brain were upregulated only in male offspring from ANG II–treated dams. Chronic phenylephrine, a GH model lacking the maternal proinflammatory aspects of ANG II, induced similar offspring seizure phenotypes. PLX5622-induced depletion of microglia or antiinflammatory pentoxifylline abolished this sensitized seizure response and lowered mortality in the ANG II model. These results suggest that GH programs offspring risk for seizures in a sex-dependent manner in humans and mice. Neuroinflammatory mechanisms may contribute to the elevated sensitivity and mortality from seizures elicited by GH exposure in utero.

Purpose of review: To review recent trends in treatment and recent progress in developing outcome measures needed for chronic nonbacterial osteomyelitis (CNO) clinical trials. Recent findings: CNO is an autoinflammatory bone disease. In a minority of patients, the disease is genetically driven, and diagnosis can be made by DNA sequencing. However, for nonsyndromic CNO there is no diagnostic test. The number of children with CNO appears to be increasing and damage is common. Increases in CNO diagnosis is due to raised awareness, increased availability of whole-body magnetic resonance imaging and rising incidence. Treatment remains empiric and it is unclear which second line treatment is superior. Tumor necrosis factor inhibitors (TNFi) and bisphosphonates continue to be used as second line agents for nonsteroidal anti-inflammatory drugs (NSAID) refractory CNO; newer immune modulatory medications are used if this fails. Validated classification criteria, clinical outcome measures and imaging scoring standards are needed for successful clinical trials. Summary: Best treatment for NSAID refractory CNO remains unclear. Classification criteria, clinical outcomes measures and standardized imaging scoring have been developed or are near completion. This will facilitate robust clinical trials in CNO with the goal of having approved medications for this painful disease.

Chronic pain and itch afflict millions of patients, and current treatments are largely ineffective. The neural control of pain and itch are not fully elucidated, and this limits the development of therapies targeting the underlying neural circuitry. Sensory information is transmitted from peripheral nerves, to the spinal cord, and up to the brain (“bottom up” pathway), but may be modulated by “top-down” projections from the brain to the spinal cord. However, the neurons mediating top-down inhibition of pain are not fully elucidated, nor has any such pathway been identified for itch sensation. Here we identify a novel population of GABAergic neurons in the ventral brainstem, distinguished by prodynorphin expression. We named the neurons LJA5 to describe their location in the lateral pons, juxta the A5 cell group. LJA5 neurons provides the only known inhibitory projection to the spinal cord selectively targeting lamina I, which exclusively transmits pain, temperature, and itch information up to the brain. Through this work, we sought to investigate the role of LJA5 neurons in sensation. The first set up experiments were designed to more fully characterize LJA5 neurons. We first identified the gene expression pattern in mouse, and then we looked to identify these neurons in human brains. We then fully explored the input and output connections of LJA5 neurons in mouse using anterograde and retrograde tracers. These neurons demonstrate the first inhibitory projection specifically targeting lamina I of the spinal cord. This finding, along with projections to other sensory regions in the brainstem, suggested that LJA5 neurons directly inhibit noxious sensory information. Furthermore, we show that LJA5 neurons receive input from forebrain structures implicated in stress and sensory detection.In the second set of experiments, we tested the function of LJA5 neurons through chemogenetic activation during behavioral tests. We knew that LJA5 neurons projected to many known sensory regions including lamina I of the spinal cord, so we hypothesized that LJA5 neurons could modulate itch, pain, or temperature sensations. Chemogenetically activating LJA5 neurons reduced capsaicin-induced pain and histamine-induced itch. Together, our findings identify and characterize a novel nucleus in the brainstem with the first described inhibitory projection specifically targeting lamina I of the spinal cord. Additionally, this is the first identified descending projection that reduces both pain and itch. This new top-down pathway updates current sensory models and opens new treatment opportunities for refractory pain and pruritis.

The molecular interactions underlying vitreoretinopathy are poorly understood. Mutations in calpain-5 (CAPN5) were identified as the cause of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). CAPN5 is a member of the calcium-activated cysteine protease family referred to as calpains, which modulate the function of their targets through limited proteolysis. Although increases in calpain activity are associated with many different diseases, ADNIV-causing mutations in CAPN5 are the first reported intrinsically hyperactive case of a calpain. Although ADNIV is relatively rare, it shares overlapping phenotypes with multiple, more common ocular diseases, including diabetic retinopathy. This provides an unprecedented starting point for investigating the substantial gap in our understanding of the molecular basis of vitreoretinopathy. In this thesis, the expression patterns of CAPN5 in the eye and brain are reported (Chapters 2 and 3). I discuss the identification and validation of a CAPN5 substrate and its role in ADNIV. This association is extended as an underlying mechanism in diabetic retinopathy. Utilizing this information, I identify the proteolysis site and alter it to create the first CAPN5-specific and ADNIV-causing-mutation specific inhibitors (Chapter 4). Insights gained from these studies may be used to design therapies for ADNIV, diabetic retinopathy, and other calpain-associated pathologies. Lastly, in an attempt to better understand how increased calpain activity contributes to a myriad of diseases, we created a mouse model in which we express a synthetic hyperactive calpain protein (Chapter 5).

From the first description in 1972 as “subacute and chronic recurrent osteomyelitis” to the currently recognized chronic recurrent multifocal osteomyelitis (CRMO) or chronic nonbacterial osteitis (CNO), diagnosis and monitoring of patients with this disease has been and continues to be a challenge^1,2. While the most common presenting symptom is focal bone pain, its waxing and waning nature tends to contribute to the diagnostic odyssey that many patients must endure.

Majeed syndrome is a multi-system inflammatory disorder affecting humans that presents with chronic multifocal osteomyelitis, congenital dyserythropoietic anemia, with or without a neutrophilic dermatosis. The disease is an autosomal recessive disorder caused by mutations in LPIN2, the gene encoding the phosphatidic acid phosphatase LIPIN2. It is exceedingly rare. There are only 24 individuals from 10 families with genetically confirmed Majeed syndrome reported in the literature. The early descriptions of Majeed syndrome reported severely affected children with recurrent fevers, severe multifocal osteomyelitis, failure to thrive, and marked elevations of blood inflammatory markers. As more affected families have been identified, it has become clear that there is significant phenotypic variability. Data supports that disruption of the phosphatidic acid phosphatase activity in LIPIN2 results in immune dysregulation due to aberrant activation of the NLRP3 inflammasome and overproduction of proinflammatory cytokines including IL-1β, however, these findings did not explain the bone phenotype. Recent studies demonstrate that LPIN2 deficiency drives pro-inflammatory M2-macrophages and enhances osteoclastogenesis which suggest a critical role of lipin-2 in controlling homeostasis at the growth plate in an inflammasome-independent manner. While there are no approved medications for Majeed syndrome, pharmacologic blockade of the interleukin-1 pathway has been associated with rapid clinical improvement.