Current State of Precision Medicine in Primary Systemic Vasculitides

Demirkaya, Erkan; Arıcı, Zehra Serap; Romano, Micol; Berard, Roberta; Aksentijevich, Ivona

doi:10.3389/fimmu.2019.02813

Cited by 14 publications

(8 citation statements)

References 236 publications

(215 reference statements)

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“…have been many exciting developments in precision medicine approaches for autoimmune diseases (32,33). Our study demonstrated, for the first time, that precision medicine could potentially be applied to the treatment of GD.…”

Section: Discussionmentioning

confidence: 59%

Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody

et al. 2021

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BackgroundCD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves’ disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known. The aim of our study was to test the hypothesis that specific CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes are associated with clinical response of GD patients to Iscalimab.MethodsWe extracted genomic DNA from the whole blood of 13 GD patients treated with Iscalimab, and genotyped seven CD40 single nucleotide polymorphisms (SNPs) associated with autoimmunity. Additionally, we analyzed CD40 mRNA expression levels in whole blood. The patients’ CD40 SNP genotypes and mRNA levels were tested for association with clinical response to Iscalimab.ResultsThree common haplotypes, designated haplotypes A, B, and C, were identified. Haplotypes B and C were associated with higher CD40 mRNA levels and clinical response to Iscalimab (i.e., patients achieving euthyroidism without need for additional medications), while haplotype A was associated with decreased CD40 mRNA levels and no response to Iscalimab.ConclusionOur data suggest that genetic polymorphisms in the CD40 gene drive its expression levels and response to Iscalimab. Polymorphisms associated with higher CD40 levels are also associated with clinical response to CD40-targeted therapies. These results set the stage to implementing precision medicine in the therapeutic approach to GD.

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Section: Discussionmentioning

confidence: 59%

Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody

et al. 2021

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“…In multifactorial rheumatic conditions, genomic and transcriptomic analyses have been proposed for disease stratification and selection of meaningful treatments [ 16 , 17 ]. Unfortunately, pediatric patients with severe rheumatologic conditions are less likely to benefit from these studies, since the drugs available for children are much less than for adults.…”

Section: Discussionmentioning

confidence: 99%

Biological and Clinical Changes in a Pediatric Series Treated with Off-Label JAK Inhibitors

Tesser

Pastore

et al. 2020

IJMS

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Off-label use of medications is still a common practice in pediatric rheumatology. JAK inhibitors are authorized in adults in the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Although their use is not authorized yet in children, JAK inhibitors, based on their mechanism of action and on clinical experiences in small series, have been suggested to be useful in the treatment of pediatric interferon-mediated inflammation. Accordingly, an increased interferon score may help to identify those patients who might benefit of JAK inhibitors. We describe the clinical experience with JAK inhibitors in seven children affected with severe inflammatory conditions and we discuss the correlation between clinical features and transcriptomic data. Clinical improvements were recorded in all cases. A reduction of interferon signaling was recorded in three out of seven subjects at last follow-up, irrespectively from clinical improvements. Other signal pathways with significant differences between patients and controls included upregulation of DNA repair pathway and downregulation of extracellular collagen homeostasis. Two patients developed drug-related adverse events, which were considered serious in one case. In conclusion, JAK inhibitors may offer a valuable option for children with severe interferon-mediated inflammatory disorders reducing the interferon score as well as influencing other signal pathways that deserve future studies.

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“…Moreover, a multidisciplinary approach to the patient with PAN must be multidisciplinary involving rheumatologists, dermatologists, neurologists, and other specialists, which is essential to provide comprehensive care to patients with polyarteritis nodosa [ 44 , 45 , 46 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The “Viral” Form of Polyarteritis Nodosa (PAN)—A Distinct Entity: A Case Based Review

Pașa,

Popa,

Poroch

et al. 2023

Medicina

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Classic polyarteritis nodosa (PAN) is a vasculitis with systemic manifestations that is characterized by inflammatory and necrotizing lesions affecting medium and small muscular arteries, most frequently at the bifurcation of the vessels. These lesions lead to the formation of microaneurysms, hemorrhaging ruptured aneurysms, thrombosis, and, consequently, ischemia or organ infarction. Background and Objectives: We present a complex clinical case of a patient with a late diagnosis of polyarteritis nodosa with multiorgan involvement. Materials and Methods: The 44-year-old patient, in an urban environment, presented on her own in the emergency room for acute ischemia phenomena and forearm and right-hand compartment syndrome, requiring surgical decompression in the Plastic Surgery Clinic. Results: Significant inflammatory syndrome is noted, alongside severe normocytic hypochromic iron deficiency anemia, nitrogen retention syndrome, hyperkalemia, hepatic syndrome, and immunological disturbances: absence of cANCA, pANCA, anti Scl 70 Ac, antinuclear Ac, and anti dDNA Ac, as well as a low C3 fraction of the plasmatic complement system. The morphological aspect described in the right-hand skin biopsy correlated with the clinical data supports the diagnosis of PAN. Conclusions: The viral form of PAN seems to be individualized as a distinct entity, requiring early, aggressive medication.

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Current State of Precision Medicine in Primary Systemic Vasculitides

Cited by 14 publications

References 236 publications

Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody

Precision Medicine in Graves’ Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody

Biological and Clinical Changes in a Pediatric Series Treated with Off-Label JAK Inhibitors

The “Viral” Form of Polyarteritis Nodosa (PAN)—A Distinct Entity: A Case Based Review

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