BACKGROUND: Lichen planus (LP) is a chronic inflammatory disease with uncertain etiology. Interleukin-18 (IL-18) is an interferon gamma (INFγ) inducing agent. It is a pro-inflammatory cytokine that was found to play a role in the pathogenesis of some autoimmune disorders.
METHODS: This study included 50 patients with classic cutaneous lichen planus (CLP) and 50 healthy volunteers serving as controls. Venous blood samples were withdrawn from the study subjects under complete aseptic precautions. Blood samples were examined for single nucleotide polymorphisms (SNPs) of IL-18 gene at promoter -137(G/C) and -656 (G/T) using polymerase chain reaction (PCR) and IL-18 level was assessed using enzyme linked immunosorbent assay (ELISA).
RESULTS: The mean level of IL-18 was significantly higher in CLP patients (31.63 ± 4.90) compared to control subjects (13.95 ± 6.82). Significantly high levels of IL-18 were found among patients with diabetes, hypertension (p < 0.01 in both). HCV positive patients and patients with both OLP and CLP also expressed higher levels of IL-18. Genotypic and allelic distribution at position -137(G/C) showed that the genotype GG was present at significantly higher frequency in cases (58%) compared to controls (28.0%). On the other hand the CC genotype at position -137 was significantly higher in the controls (28%) as compared to CLP cases (6%). Polymorphism of IL-18 at position -656(G/T) showed no significant difference between cases and controls. No significant difference could be detected in IL-18 level between different genotypic variants at position -137(G/C) and -656(G/T).
CONCLUSIONS: IL-18 may play important role in pathogenesis of LP. Elevated IL-18 levels could be part of the pro-inflammatory autoimmune process in LP. The presence of OLP, HCV, diabetes and hypertension is associated with higher production of IL-18. IL-18 promotor region -137(G/C) polymorphism might be a factor that increase the risk of development of lichen planus in Egyptian patients.

Chronic infantile neurological cutaneous articular (CINCA) syndrome is an autoinflammatory disease encompassed in the group of cryopyrin-associated periodic syndromes (CAPS). Patients suffering from CINCA have an elevated risk of developing chronic sequelae, including deforming arthropathy, chronic meningitis, neurodevelopmental delay, and neurosensorial hearing loss. The diagnosis of CINCA presents several difficulties, as the clinical phenotype could be difficult to recognize, and almost half of the patients have negative genetic testing. In this paper, we describe the case of a patient presenting with the typical phenotype of neonatal-onset CINCA who resulted negative for NLRP3 mutations. Based on the clinical judgment, the patient underwent treatment with anti-interleukin-1 (IL-1) agents (anakinra and, later, canakinumab) resulting in a complete clinical and laboratory response that allowed confirmation of the diagnosis. Additional genetic investigations performed after the introduction of anti-IL-1 therapy revealed a pathogenic mosaicism in the NLRP3 gene. After a 12-year follow-up, the patient has not experienced chronic complications. Although genetics is rapidly progressing, this case highlights the importance of early diagnosis of CINCA patients when the clinical and laboratory picture is highly suggestive in order to start the appropriate anti-cytokine treatment even in the absence of a genetic confirmation.

Bi-allelic pathogenic variants in the MVK gene, which encodes mevalonate kinase (MK), an essential enzyme in isoprenoid biosynthesis, cause the autoinflammatory metabolic disorder mevalonate kinase deficiency (MKD). We generated and characterized MK-deficient monocytic THP-1 cells to identify molecular and cellular mechanisms that contribute to the pro-inflammatory phenotype of MKD.
Using CRISPR/Cas9 genome editing, we generated THP-1 cells with different MK deficiencies mimicking the severe (MKD-MA) and mild end (MKD-HIDS) of the MKD disease spectrum. Following confirmation of previously established disease-specific biochemical hallmarks, we studied the consequences of the different MK deficiencies on LPS-stimulated cytokine release, glycolysis versus oxidative phosphorylation rates, cellular chemotaxis and protein kinase activity.
Similar to MKD patients\' cells, MK deficiency in the THP-1 cells caused a pro-inflammatory phenotype with a severity correlating with the residual MK protein levels. In the MKD-MA THP-1 cells, MK protein levels were barely detectable, which affected protein prenylation and was accompanied by a profound pro-inflammatory phenotype. This included a markedly increased LPS-stimulated release of pro-inflammatory cytokines and a metabolic switch from oxidative phosphorylation towards glycolysis. We also observed increased activity of protein kinases that are involved in cell migration and proliferation, and in innate and adaptive immune responses. The MKD-HIDS THP-1 cells had approximately 20% residual MK activity and showed a milder phenotype, which manifested mainly upon LPS stimulation or exposure to elevated temperatures.
MK-deficient THP-1 cells show the biochemical and pro-inflammatory phenotype of MKD and are a good model to study underlying disease mechanisms and therapeutic options of this autoinflammatory disorder.

UNASSIGNED: The blockade of interleukine-1 (anakinra and canakinumab) is a well-known highly effective tool for monogenic autoinflammatory diseases (AIDs), such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinaemia D syndrome, and cryopyrin-associated periodic syndrome, but this treatment has not been assessed for patients with undifferentiated AIDs (uAIDs). Our study aimed to assess the safety and efficacy of canakinumab for patients with uAIDs.
UNASSIGNED: Information on 32 patients with uAIDs was retrospectively collected and analyzed. Next-generation sequencing and Federici criteria were used for the exclusion of the known monogenic AID.
UNASSIGNED: The median age of the first episode was 2.5 years (IQR: 1.3; 5.5), that of the disease diagnosis was 5.7 years (IQR: 2.5;12.7), and that of diagnostic delay was 1.1 years (IQR: 0.4; 6.1). Patients had variations in the following genes: IL10, NLRP12, STAT2, C8B, LPIN2, NLRC4, PSMB8, PRF1, CARD14, IFIH1, LYST, NFAT5, PLCG2, COPA, IL23R, STXBP2, IL36RN, JAK1, DDX58, LACC1, LRBA, TNFRSF11A, PTHR1, STAT4, TNFRSF1B, TNFAIP3, TREX1, and SLC7A7. The main clinical features were fever (100%), rash (91%; maculopapular predominantly), joint involvement (72%), splenomegaly (66%), hepatomegaly (59%), lymphadenopathy (50%), myalgia (28%), heart involvement (31%), intestinal involvement (19%); eye involvement (9%), pleuritis (16%), ascites (6%), deafness, hydrocephalia (3%), and failure to thrive (25%). Initial treatment before canakinumab consisted of non-biologic therapies: non-steroidal anti-inflammatory drugs (NSAID) (91%), corticosteroids (88%), methotrexate (38%), intravenous immunoglobulin (IVIG) (34%), cyclosporine A (25%), colchicine (6%) cyclophosphamide (6%), sulfasalazine (3%), mycophenolate mofetil (3%), hydroxychloroquine (3%), and biologic drugs: tocilizumab (62%), sarilumab, etanercept, adalimumab, rituximab, and infliximab (all 3%). Canakinumab induced complete remission in 27 patients (84%) and partial remission in one patient (3%). Two patients (6%) were primary non-responders, and two patients (6%) further developed secondary inefficacy. All patients with partial efficacy or inefficacy were switched to tocilizumab (n = 4) and sarilumab (n = 1). The total duration of canakinumab treatment was 3.6 (0.1; 8.7) years. During the study, there were no reported Serious Adverse Events (SAEs). The patients experienced non-frequent mild respiratory infections at a rate that is similar as before canakinumab is administered. Additionally, one patient developed leucopenia, but it was not necessary to stop canakinumab for this patient.
UNASSIGNED: The treatment of patients with uAIDs using canakinumab was safe and effective. Further randomized clinical trials are required to confirm the efficacy and safety.

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Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is an autoinflammatory disorder that primarily affects young children, and typically gives rise to fever episodes that recur monthly for several years. This study investigated the impact of PFAPA syndrome on the families of affected children, the health-related quality of life (HRQOL) of children with the syndrome, and how these factors were influenced by tonsillectomy.
This prospective cohort study included 24 children with typical PFAPA syndrome that were referred for tonsillectomy, of whom 20 underwent the procedure. The control group consisted of randomly selected children from the general population. Family impact and HRQOL were measured using the standardized, validated questionnaires Pediatric Quality of Life Inventory™ (PedsQL™) Family Impact Module (FIM) and PedsQL™ 4.0 Generic Core Scales (GCS). Parents to children with PFAPA completed the questionnaires before and 6 months after their child underwent tonsillectomy, and HRQOL was measured both between and during PFAPA episodes. The Wilcoxon signed-rank test was used to compare data before and after tonsillectomy in the patient group, while the Mann-Whitney test was used for comparison of the patient and control groups.
Before tonsillectomy, children with PFAPA had significantly lower scores than the control group on the PedsQL™ FIM and the PedsQL™ 4.0 GCS during fever episodes. After tonsillectomy, all patients improved with diminished febrile episodes, which resulted in significantly higher scores regarding both family impact and HRQOL at the time of follow-up. HRQOL of in children with PFAPA improved after tonsillectomy even when compared to afebrile intervals before the procedure. The differences between PFAPA patients and controls were eliminated after tonsillectomy.
PFAPA syndrome has a profound negative impact on the families of affected children. Tonsillectomy that leads to cessation or reduction of fever episodes eases the impact of the disease on the family. HRQOL in children with PFAPA is low during febrile episodes and similar to healthy controls in between episodes. The improvement of HRQOL in patients with PFAPA after tonsillectomy compared to the afebrile intervals before tonsillectomy highlights that the constantly recurring fevers may affect the children\'s well-being even between fever episodes.

Interleukin-1 (IL-1)-blocking therapies are effective in reducing disease severity and inflammation in Schnitzler syndrome. Here, we present a patient with Schnitzler syndrome treated successfully using canakinumab for over 10 years. Complete clinical response was associated with a decrease in dermal neutrophil number and expression of the pro-inflammatory cytokines IL-1β, IL-8, and IL-17 as assessed by immunohistochemical studies.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease primarily affecting the gastrointestinal (GI) tract and other organs. In this article, we provide a comprehensive review of IBD, particularly in the context of enteropathic arthritis and its therapeutic advances. Patients with IBD present with intestinal and extraintestinal manifestations (EIMs). Enteropathic arthritis or arthritis associated with IBD (Crohn\'s disease [CD] and ulcerative colitis [UC]) is the most common EIM and can involve both peripheral and axial joints with some overlaps. Furthermore, peripheral arthritis can be divided into two subcategories. Due to its varied inflammatory presentations and association with NOD2 mutations, CD can mimic other autoimmune and autoinflammatory diseases. Differential diagnosis should be extended to include another NOD2-associated disease, Yao syndrome. Therapy for IBD entails a myriad of medications and procedures, including various biologics targeting different pathways and Janus kinase (JAK) inhibitors. A better understanding of the therapeutic efficacy and mechanism of each drug aids in proper selection of more effective treatment for IBD and its associated inflammatory arthritis.

The International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) reports here the 2022 updated phenotypic classification, which accompanies and complements the most-recent genotypic classification. This phenotypic classification is aimed for clinicians at the bedside and focuses on clinical features and laboratory phenotypes of specific IEI. In this classification, 485 IEI underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity and auto-inflammation are described, including 55 novel monogenic defects and 1 autoimmune phenocopy. Therefore, all 485 diseases of the genetic classification are presented in this paper in the form of colored tables with essential clinical or immunological phenotype entries.