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Background: Neurological manifestations and the co-occurrence of multiple sclerosis (MS) have been reported in patients with autoinflammatory diseases (AID) and variants of the NLRP3-, MEFV-, or TNFRSF1A gene. However, type and frequency of neurological involvement are widely undetermined. Methods: We assessed clinical characteristics of 151 (108 with MS) patients carrying NLRP3-, MEFV-and TNFRSF1A low-penetrance variants from the Institute of Clinical Neuroimmunology. We evaluated demographic, genetic, and clinical features with a focus on central nervous system (CNS) involvement including magnetic resonance imaging (MRI) results and cerebrospinal fluid (CSF) data. The disease course of AID patients with MS was compared to a matched MS control group without mutations. Results: The genetic distribution comprised 36 patients (23%) with NLRP3-and 66 patients (43%) with TNFRSF1A low-penetrance variants as well as 53 (34%) patients carrying pathogenic mutations or low-penetrance variants in the MEFV gene. MS patients displayed most frequently the R92Q TNFRSF1A variant (n = 51; 46%) followed by the Q703K NLRP3 variant (n = 15; 14%) and the E148Q substitution (n = 9; 8%) in the MEFV gene. The disease course of MS was not influenced by the genetic variants and did not differ from MS patients (n = 51) without mutations. AID patients without MS most frequently harbored MEFV mutations (n = 19, 43%) followed by NLRP3-(n = 17, 39%) and TNFRSF1A (n = 8, 18%) low-penetrance variants. Sixteen (36%) of them suffered from severe CNS involvement predominantly recurrent aseptic meningoencephalitis and optic neuritis accompanied by abnormal MRI and CSF results. Severe CNS inflammation was associated with the Q703K allele. Headache was a highly prevalent neurological symptom (up to 74%), irrespective of the underlying genetic variation. The NLRP3 cohort without MS more frequently exhibited affections of the cranial nerves (CN) (p = 0.0228) and motor symptoms (p = 0.0455). Elevated acute-phase reactants were detected in all patients, and fever episodes were present in up to 50%. Arthralgias were the most frequently identified constitutional symptom among all subgroups.
Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and individuals with APLAID. Remarkably, treatment with a G-CSF antibody completely reversed established disease in APLAID mice. Furthermore, excessive myelopoiesis was normalized and lymphocyte numbers rebounded. APLAID mice were also fully rescued by bone marrow transplantation from healthy donors, associated with reduced G-CSF production, predominantly from non-hematopoietic cells. In summary, we identify APLAID as a G-CSF-driven autoinflammatory disease, for which targeted therapy is feasible.
Background Pain is the clinical hallmark of patients in patients with autoinflammatory diseases (AID) caused by variants of the NLRP3-, MEFV- or TNFRSF1A gene. However, no systematical analysis of the clinical and psychological presentation of pain has been performed to date. Methods Twenty-one symptomatic patients with variants in the NLRP3-, MEFV- and TNFRSF1A gene and clinical signs suggestive of an AID were retrospectively included in this monocentric cross-sectional case-series study. Patients were examined and interviewed using the German pain questionnaire. The hospital anxiety and depression scale (HADS) was applied to screen patients for anxiety and depression. Results Twenty out of 21 AID patients (95%) reported pain at the time of examination. Mean current pain intensity in all AID patients comprised 3.6 ± 1.3 and mean maximum pain intensity was 7.0 ± 1.6 on a 11-point numeric ranging scale (NRS). In 15 patients (71%), pain was present for more than 60 months. Ten patients (48%) experienced recurrent attacks with asymptomatic intervals and 7 patients (33%) suffered from constant pain, while 4 patients (19%) experienced both. Nociceptive pain including musculoskeletal and visceral affection was the most prominent type of pain (n = 20; 95%). Pain symptoms were treated continuously with analgesic or co-analgesic drugs in 10 patients (48%). Five patients (24%) have been positively screened for concomitant depression or anxiety. Conclusions Early and prompt diagnosis is necessary to provide multimodal pain treatment and to avoid the development of chronic pain in patients with AID.
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