Rare Autoinflammatory Disease Research Articles

Chronic non-bacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO) with a focus on pamidronate therapy.

Chronic recurrent multifocal osteomyelitis (CRMO), also called chronic nonbacterial osteomyelitis (CNO) or nonbacterial osteomyelitis (NBO), is a rare autoinflammatory bone disease of unknown etiology. However, the number of patients properly diagnosed would increase with better knowledge of the disease. In this regard, whole-body magnetic resonance imaging (WB MRI) has been found to be a better predictor of active lesions than clinical examination. Importantly, the RINBO index (radiologic index for NBO) quantifies the involvement based on the WB MRI. Further, a chronic nonbacterial osteomyelitis MRI scoring (CROMRIS) has been developed as an online tool for assessing WB MRI. The therapy consists of non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates (pamidronate, zoledronate, etc.) and other drugs, including biologics. Pamidronate is an appropriate and safe therapy. The first pilot prospective randomised controlled trial (RCT) on pamidronate vs. placebo was carried out in adults. No RCT has been done in children yet. Besides RCTs, there are a number of issues to be explored in future, i.e. predictors of therapy effect, optimal therapy duration, predictors of therapy discontinuation and evaluation of optimal therapy protocol. Recently, the CNO clinical disease activity score (CDAS) was constructed and validated but the classification criteria are still being developed. As collaboration on this rare disease is essential, a prospective Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) was established to generate future comparative effectiveness research data.

A case of Schnitzler syndrome with unusual immunoglobulin Agammopathy exacerbated by COVID-19 infection.

Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by chronic urticarial rash and monoclonal immunoglobulin M (IgM) or IgG gammopathy. Viruses, including COVID-19, activate the innate immune system, therefore SchS, in which the innate immune system is improperly activated, is hypothesized to be exacerbated by viral infection. However, there were no reported SchS cases exacerbated by any viral infection. Here, we report a SchS case with an unusual IgA gammopathy manifested and exacerbated by COVID-19 infection. This report advocates the need for recognizing unusual cases of SchS with monoclonal IgA, and following up on paraprotein like IgA even when it is initially undetectable in cases with SchS symptoms. We also hypothesize that existing autoinflammatory diseases may be exacerbated by COVID-19 infection in the case of a combination of these diseases.

Time for a new approach to drug development for rare systemic autoinflammatory diseases.

Time for a new approach to drug development for rare systemic autoinflammatory diseases.

Burden of illness and unmet needs in generalized pustular psoriasis: report of four cases

Generalized pustular psoriasis (GPP), the most severe form of pustular psoriasis, is a rare autoinflammatory skin disease that manifests with the rapid and widespread eruption of small, sterile pustules and surrounding skin erythema, often accompanied by systemic symptoms. GPP is frequently painful and distressing and adversely affects patients’ quality of life. Until recently, systemic treatment for GPP in the United States mainly involved the off-label use of agents approved to treat plaque psoriasis. In September 2022, spesolimab was approved in the United States as a first-in-class treatment for GPP flares in adults, making a GPP-specific therapy available. Here, we describe 4 cases from our respective clinical practices that highlight the difficulties faced by patients with GPP in receiving an accurate diagnosis and obtaining effective treatment and demonstrate the associated physical and psychological disease burdens. The potential severity and consequences of untreated GPP necessitate a prompt diagnosis, initiation of effective treatment, and regular follow-up and monitoring of patients’ conditions. When managing GPP, a multidisciplinary approach is recommended to ensure that patients receive appropriate social and emotional support and effective medical care.

Defining the imaging diagnostic criteria for adult chronic non-bacterial osteitis.

Osteitis of the sternocostoclavicular (SCC) region, referred to as sternocostoclavicular hyperostosis (SCCH), is the clinical expression of chronic non-bacterial osteitis (CNO) in adults with this rare chronic auto-inflammatory disorder of the axial skeleton. The diagnosis is based on distinctive computerized tomography (CT) features of sclerosis and hyperostosis of the SCC region, and local increases in osteoid formation visualized by high radiopharmacon uptake on skeletal scintigraphy but clear radiologic diagnostic criteria are lacking. In a cross-sectional study, CT scans and whole-body skeletal scintigraphy images obtained in 169 patients seen at the Center for Bone Quality of the Leiden University Medical Center between 2008 and 2018 with a suspected diagnosis of CNO of the SCC region were re-evaluated by 2 skeletal radiologists and 2 nuclear physicians. The diagnosis was confirmed in 118 (70%) predominantly female patients (n= 103, 89.2%); median age at first symptoms 45years (range 20-73). The diagnosis was excluded in the remaining 51 "non-CNO" patients. Increased radiopharmacon uptake at the SCC region was observed in 82% CNO patients, with the manubrium sterni having the highest predictive ability to discriminate on both imaging modalities. The prevalence of sclerosis of the clavicles, manubrium and first ribs was significantly higher in CNO patients (P< 0.001). Hyperostosis was not observed in non-CNO patients. 46 CNO versus only 2 non-CNO patients had costoclavicular ligament calcification. Our findings identify CT scan features of sclerosis and hyperostosis of manubrium sterni, medial end of clavicles and first ribs, and calcification of costoclavicular ligaments, associated with increased tracer uptake on skeletal scintigraphy at the SCC region, specifically manubrium sterni, as well-defined imaging diagnostic criteria for adult CNO. Pitfalls encountered in the diagnosis of CNO are highlighted. These defined imaging diagnostic criteria for adult CNO should facilitate the diagnosis of this rare auto-inflammatory bone disease across the spectrum of its early to late stages.

Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome

Background and objectivesThe study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants.MethodsRNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines.ResultsTranscriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement.ConclusionOverproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.

Analysis of Anakinra Therapy for the Deficiency of Interleukin-1 Receptor Antagonist through Clinical Evidence.

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autosomal recessive autoinflammatory disease with symptoms including but not limited to osteomyelitis, periostitis, and systemic inflammation. DIRA is developed from the loss-of-function biallelic mutations of the IL1RN gene that encodes IL-1 receptor antagonist (IL-1RA), leading to the unchecked pro-inflammatory signaling and subsequent systemic inflammation. Thus, anakinra as the recombinant IL-1RA has become the primary drug to treat DIRA. Although anakinra has been effective for the complete remission of DIRA, it has also shown various side effects. To confirm the efficacy and safety issues associated with DIRA treatment, we conducted a literature review and secondary data analysis to enhance our understanding on this important topic. Through comprehensive literature search, we have identified 15 papers with 25 patients studied. The demographic, clinical, and genetic data were extracted, followed by statistical analysis to support the physiological mechanisms of anakinra treatment. Through the literature review and data analysis, it was found that 88% of patients had complete clinical remission of DIRA upon continual treatment with anakinra; patients had a mean improvement of Hemoglobin (+3.18 g/dL), Erythrocyte Sedimentation Rate (-53.4 mm/h), and C-reactive Protein (-135.45 mg/L) levels, suggesting that the improvement of hematopoietic function and inflammation is a mechanism for anakinra treatment. Various genetic variants were also identified from the patient data that cause the loss of function of IL-1RA, providing real patient genomic data to support the anakinra treatment. Considering the inconsistency and certain variations from clinical research influenced by specific conditions, this review along with the data analysis confirms the efficacy and safety of anakinra treatment for DIRA.

Stellate ganglion block in the treatment of SAPHO syndrome: a case report.

Synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare and refractory autoinflammatory disease, and there is no consensus on its treatment. Stellate ganglion block (SGB) blocks sympathetic nerves, ameliorates immune dysfunction, and alleviates stress response, which has been used to treat various chronic pain syndromes, arrhythmias, and post-traumatic stress disorder (PTSD). Also, the SGB has been reported to be successfully used to treat certain skin diseases, autoinflammatory diseases, and menopausal symptoms. In this study, over 3 years of follow-up, we found that SGB successfully intervened the symptoms of SAPHO syndrome, including sternoclavicular joint arthritis and palmoplantar pustulosis.

Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin-Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti-Interleukin-1 Therapy.

Cryopyrin-associated periodic syndromes (CAPS), also known as NLRP3-associated autoinflammatory diseases, are a spectrum of rare autoinflammatory diseases caused by gain-of-function variants in the NLRP3 gene, resulting in inflammasome hyperactivation and dysregulated release of interleukin-1β (IL-1β). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) because of cochlear autoinflammation, which may be the sole manifestation in rare cases. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting with autosomal-dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821.3:c.1784G>A p.Ser595Asn). We conducted an ex vivo functional assessment of the NLRP3 inflammasome in heterozygous individuals (n=10) and healthy family members (n=5). The assay revealed hyperactivation of the inflammasome among heterozygous individuals, supporting the hypothesis that this missense variant is a pathogenic gain-of-function variant. Administration of IL-1 receptorantagonist resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1 to 3 months of treatment. Our findings highlight the crucial role of early diagnosis and treatment with an anti-IL-1 agent in reversing cochlear damage. Furthermore, our results suggest that high- and ultrahigh-frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.

Chronic Nonbacterial Osteomyelitis in Inflammatory Bowel Disease.

Chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory bone disease primarily affecting children and adolescents. This review presents a comprehensive analysis of the intricate relationship between CNO and inflammatory bowel disease (IBD), shedding light on shared pathophysiological mechanisms and clinical management. A thorough literature review was conducted, encompassing 24 case reports involving 40 patients. The demographic distribution of patients revealed a near-equal gender ratio, with a median age of diagnosis at 12 years. The diagnosis patterns showed a higher proportion of CNO as the initial diagnosis, while Crohn's disease was more prevalent than ulcerative colitis. The time interval between the clinical presentations varied, ranging from simultaneous detection to a substantial 15-year gap. Treatment modalities included nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, aminosalicylates, and biologic agents, such as infliximab, often overlapping in their use and suggesting shared pathophysiological pathways. Both conditions displayed systemic manifestations, and patients often responded well to immunosuppressive medications. The pathophysiology of CNO involves a genetic predisposition, cytokine dysregulation, and osteoclast activation. Dysregulated innate immunity results in immune cell infiltration into bones, causing sterile bone lesions. Notably, emerging evidence hints at a potential link between the microbiome and CNO. In contrast, IBD results from imbalanced mucosal immune responses to the intestinal microbiota. Polymorphisms in the promotor region of IL-10, common cytokines, immune cells, and genetic markers indicate shared immunological and genetic factors between CNO and IBD. Both conditions also involve extraintestinal symptoms. This analysis underscores the need for clinical awareness of the co-occurrence of CNO and IBD, especially among pediatric patients. A deepened understanding of the connections between these seemingly distinct diseases could lead to more effective management and improved patient outcomes.

Аутовоспалительные заболевания в практике врача неонатолога и педиатра: клинические наблюдения

Molecular genetic analysis in the current clinical practice is a kind of must-do standard in the diagnosis of rare (orphan) diseases and syndromes in pediatric patients, which gives the opportunity for making a diagnosis at an early stage, early period of life and followed by the initiation of a targeted pathogenetic therapy, if and when needed, that in its turn is able to improve the prognosis not only for the health, but also for the quality of life and in some cases for the survival of a patient. As for now, this is an overall accessible diagnostic method the use of which is nevertheless often associated with certain difficulties, such as the need for going through the path of a complex differential diagnosis and the awareness and targeted qualification among pediatric practitioners and neonatologists. Authors presents the description of the two clinical cases of a rare autoinflammatory disease, cryopyrin-associated periodic syndrome (CAPS) in children as a demonstration of the way to verify a clinical diagnosis in childhood and the features of diagnosing orphan diseases in a Russian regional hospital. Conclusion: the presented clinical observations demonstrate the capabilities of modern medicine in making a clinical diagnosis of an orphan disease from the group of autoinflammatory diseases, CAPS in particular, starting from the neonatal period of life of a patient.

A case of cryopyrin-associated periodic syndrome due to somatic mosaic mutation complicated with recurrent circinate erythematous psoriasis.

Cryopyrin-associated periotic syndrome (CAPS) is a rare autoinflammatory disease (AID) caused by genetic variants in innate immunity genes. AIDs, including CAPS, mediate proinflammatory cytokines such as interleukin (IL)-1 and IL-18 and result in severe systemic inflammation. A gain-of-function mutation in the NLRP3 gene, which encodes the protein cryopyrin, was identified to be responsible for CAPS in 2001, and since then several additional pathogenic mutations have been found. Moreover, other phenotypes have been identified based on severity and symptomatology, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic neurologic cutaneous articular syndrome (CINCA). Prompt diagnosis of CAPS remains challenging, however, due to unspecific, extensive clinical signs, and delayed diagnosis and treatment targeting IL-1 lead to multiorgan damage. Another factor complicating diagnosis is the existence of somatic mosaic mutations in the NLRP3 gene in some cases, resulting in symptoms and clinical courses that are atypical. The frequency of somatic mosaic mutations in CAPS was estimated to be 19% in a systematic review. Psoriasis is a chronic inflammatory skin disease that affects about 3% of the global population. Although no reports have shown complication between CAPS and psoriasis, these diseases have several similarities and potential relationships, for instance activation of Th17 cells in the dermis and increased NLRP3 gene expression in psoriatic skin compared with normal skin. Here we report a case of CAPS due to a somatic mosaic mutation with recurrent circinate erythematous psoriasis.

SAPHO syndrome: current clinical, diagnostic and treatment approaches.

This review provides an overview of SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis), a rare autoinflammatory disease that primarily affects bones, skin, and joints. We conducted a search on Medline/PubMed using keywords such as SAPHO syndrome, chronic recurrent multifocal osteitis/osteomyelitis, and related terms. SAPHO syndrome is rare, with a reported frequency of 1 in 10,000 in the Caucasian population. However, the actual incidence of SAPHO syndrome is unknown, and the incidence of the disease is likely higher. The pathogenesis of SAPHO syndrome remains incompletely understood. Current evidence suggests that SAPHO results from a complex interplay between immune dysregulation, genetic susceptibility, and environmental factors. It's not clear if SAPHO syndrome is an autoimmune disease or an autoinflammatory disease, but current evidence suggests that it's more likely an autoinflammatory disease because of things like neutrophil hyperactivity, fewer natural killer (NK) cells, high levels of interleukin (IL)-1, and a good response to treatments that block IL-1. Osteo-articular (OA) involvement is a key clinical feature of SAPHO. It affects the anterior chest wall, axial skeleton, peripheral joints, mandible, long bones of the extremities, and pelvis. Dermatological involvement is a common target in SAPHO, with lesions observed in 60-90% of cases. Common skin lesions include psoriasis and acne, with hidradenitis suppurativa and neutrophilic dermatoses being less commonly seen. Other clinical findings include constitutional symptoms caused by systemic inflammation, such as fever, weight loss, and fatigue. There is no specific laboratory finding for SAPHO syndrome. However, during active disease, there may be an increase in positive acute phase markers, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement levels, mild leukocytosis, and thrombocytosis. Diagnosis is crucial for SAPHO syndrome, which lacks a specific diagnostic finding and is often underrecognized. A comprehensive evaluation of a patient's medical history and physical examination is crucial. Treatment options include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, conventional and synthetic disease-modifying agents (cDMARDs and sDMARDs), biological therapies, bisphosphonates, and antibiotics. Biological treatments have emerged as a viable alternative for SAPHO patients who do not respond to conventional treatments.

Lung Transplantation under a Janus Kinase Inhibitor in Three Patients with SAVI Syndrome.

Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a very rare autoinflammatory disease related to STING1 mutation. SAVI is mainly characterized by fever attacks and skin and respiratory manifestations such as interstitial lung disease or alveolar hemorrhage. Respiratory involvement occurs in 80% of cases and might progress to severe lung fibrosis and require lung transplantation (LT). Three patients with SAVI who underwent LT have been reported to date. Two of the three patients died months or years after LT due to multiple organ failure or sepsis. However, the diagnosis of SAVI was made after LT, thus preventing the use of targeted therapy, such as the Janus kinase 1 and 2 inhibitor (JAK1/2i) ruxolitinib, which might be beneficial for the respiratory status of these patients. We aimed to report our experience in managing three patients who were followed in three large lung transplantation centers in France and who benefited from ruxolitinib before undergoing LT. We describe posttransplant complications that occurred as well as outcomes.

A Novel LC-MS/MS Method for Therapeutic Drug Monitoring of Baricitinib in Plasma of Pediatric Patients.

Janus kinase inhibitors are antirheumatic immunosuppressive drugs that target intracellular Janus kinases (JAKs). Baricitinib is a selective and reversible orally administered JAK1/JAK2 inhibitor approved for treating rheumatoid arthritis, atopic dermatitis, and alopecia areata in adult patients. Expanded access to baricitinib has been approved for treating pediatric patients affected by rare Mendelian autoinflammatory diseases with type I interferon-mediated damage. Knowledge of the pharmacokinetic properties and target plasma levels of baricitinib in pediatric patients is limited. In this study, a novel LC-MS/MS method for measuring baricitinib in plasma, validated according to the ICH M10 guidelines, is presented. Sample preparation was performed by adding 10 µL of IS working solution (150 ng/mL) and 200 µL of MeOH to each plasma sample. Chromatographic separation was conducted using a Thermo Scientific Accucore Polar Premium column (50 mm × 2.1 mm, i.d. 2.6 m). This method was applied to 7 real anonymous plasma samples obtained from pediatric patients treated with baricitinib at IRCCS Istituto Giannina Gaslini (Genoa, Italy). Patients of both sexes had a median age of 14 years (range, 10-17 years). The LC-MS/MS method resulted linear over wide concentration ranges (1.024-100 ng/mL) and was accurate and reproducible in the absence of matrix effects, allowing for robust, specific, and rapid quantification of baricitinib from a low amount of plasma (50 µL). The plasma concentration of baricitinib in the samples of the patients, expressed as mean ± SD, was 11.25 ± 10.86 ng/mL. This novel LC-MS/MS method is suitable for the therapeutic drug monitoring of baricitinib and can help guide therapy optimization in pediatric patients.

AutoCore: A network-based definition of the core module of human autoimmunity and autoinflammation.

Although research on rare autoimmune and autoinflammatory diseases has enabled definition of nonredundant regulators of homeostasis in human immunity, because of the single gene-single disease nature of many of these diseases, contributing factors were mostly unveiled in sequential and noncoordinated individual studies. We used a network-based approach for integrating a set of 186 inborn errors of immunity with predominant autoimmunity/autoinflammation into a comprehensive map of human immune dysregulation, which we termed "AutoCore." The AutoCore is located centrally within the interactome of all protein-protein interactions, connecting and pinpointing multidisease markers for a range of common, polygenic autoimmune/autoinflammatory diseases. The AutoCore can be subdivided into 19 endotypes that correspond to molecularly and phenotypically cohesive disease subgroups, providing a molecular mechanism-based disease classification and rationale toward systematic targeting for therapeutic purposes. Our study provides a proof of concept for using network-based methods to systematically investigate the molecular relationships between individual rare diseases and address a range of conceptual, diagnostic, and therapeutic challenges.

Phenotypic and genotypic characterization of Chinese adult patients with NLRP3‑associated autoinflammatory disease with hearing loss.

Nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3-associated autoinflammatory disease (NLRP3-AID) is a rare autosomal dominant systemic autoinflammatory disease. We aimed to summarize the phenotypic and genotypic features of Chinese adult NLRP3-AID patients with hearing loss. A retrospective cohort study of twenty-one adult patients with NLRP3-AID was conducted in Peking Union Medical College Hospital between July 2015 and March 2023. All patients underwent whole exome sequencing and otorhinolaryngologic assessments. Clinical features and therapeutic data were collected and analyzed. We found that 13/21 (61.90%) of patients had hearing loss with high-frequency impairment in the majority, and most patients presented with vestibular dysfunction as a new finding. The NLRP3-AID patients with early-onset, cold or stress triggered episodes, red eyes, fatigue, hypopsia and mutations located in the NACHT domain of the NLRP3 protein were more likely to suffer from hearing loss, especially sensorineural hearing loss, perhaps as a result of pathogenic variants of high penetrance. By a series of audiological evaluations, tumor necrosis factor (TNF)-α inhibitors were confirmed to improve or reverse hearing loss. We reported the first cohort of Chinese adult NLRP3-AID patients with hearing loss and characterized vestibular dysfunction, highlighted the necessity for attention to high-frequency hearing, and provided potential alternative treatment.

Distinct NOD2 mutations reported in three families with Blau syndrome (BS) from a single center in India - Case series and review of literature

ObjectiveBlau syndrome (BS), considered a rare pediatric autoinflammatory disease, is characterised by a triad of granulomatous arthritis, dermatitis and uveitis. Here we present a tale of three families visited in our outpatient department in the last two years (2020−2022) where more than one member was affected with either skin, ophthalmological and joint involvement with either biopsy-proven granuloma or genetic mutation at NOD2 gene suggesting the diagnosis of BS. Case seriesThe first family had three affected members where the mother and her two children had skin changes, polyarthritis and a pathogenic mutation in NOD2 gene (exon 4, c.1000C > T, p.Arg334Trp) suggesting BS. The second family had two affected members where both mother and her son had uveitis, skin changes with NOD2 mutation at exon 4 with c.1147G > A (p Glu 383 Lys) variant. The son also had polyarthritis and his skin biopsy was suggestive of granulomatous inflammation. In the third family with two affected members, we found a mutation in NOD2 on exon 4 (c 1324C > T, p.Lys 442 Phe) which was described as pathogenic with only one report published till date. ConclusionThese three cases presented to us within the last two years and led to a diagnosis of BS in three other family members with discrete mutations (commonest to rarest) on the NOD2 gene in the three families.

Successful complementary therapy with traditional Chinese medicine in a patient with Qi and Jin deficiency symptoms from adult-onset Still's disease: A case report

BackgroundAdult-onset Still's disease (AOSD) is a rare yet well-documented polygenic and systemic autoinflammatory disease characterized by recurrent spiking fever, transient skin rash, arthralgia, and sore throat. Traditional Chinese medicine (TCM) holds a significant role in complementary and alternative medicine. This study presents a unique case of a female AOSD patient with concurrent Qi and fluid deficiency syndrome who received combined treatment with formulated Zhu Ye Shi Gao Decoction (ZYSGD). Case presentationIn this case, a 28-year-old female patient presented with a 15-day history of fever and skin rash accompanied by sore throat, fatigue, myalgia, and arthralgia. Additionally, leucocytosis, aminotransferase abnormalities, and elevated inflammatory factor levels were observed. Infectious diseases, solid tumors, and hematological disorders were all ruled out. Anti-infective treatments proved ineffective, leading to the final diagnosis of AOSD. Glucocorticoid therapy provided only partial relief. Consequently, formulated ZYSGD and hepatoprotective drugs were added to the glucocorticoid treatment. Subsequently, the patient's symptoms and inflammatory biomarkers showed improvement. After discharge, the patient's condition remained stable while continuing the formulated ZYSGD in combination with 4 mg of Medrolol (qd) during a 10-month follow-up period. ConclusionThis case report suggests that formulated ZYSGD could be a viable option for complementary and alternative therapy for late-stage AOSD, especially in cases involving both Qi and body fluid imbalances.

E67 Still's disease in children refractory to usual treatments: recourse to biotherapies: challenges and opportunities

Abstract Background Still's disease in children is a rare autoinflammatory disease with distinct characteristics from other forms of Juvenile Idiopathic Arthritis. A better understanding of its mechanism has led to the use of targeted therapies with a significant improvement in patient prognosis. Despite these advances, there are still subtypes of Still's disease refractory to the usual treatments with serious complications. Objective demonstrate therapeutic escalation in the Child’s Still Methods We report the case of a patient unresponsive to multiple disease-modifying antirheumatic drugs (DMARDs), who required high doses of steroids. The biological ones were an inevitable recourse to improve the vital and functional prognosis; with at the end, a therapeutic escape with anti IL1 after two years of favorable response. Case report 12-year-old girl with no particular family history, with Still's disease diagnosed at the age of nine with a typical clinical form: thermal steeple concomitant with a morbiliform and evanescent skin eruption, polyarthritis, with hepatosplenomegaly. The diagnosis was confirmed by a major biological inflammatory syndrome with raise serum ferritin, serum C-reactive protein level and sedimentation rate. Despite doses &amp;gt; 0.5 mg/kg/d of prednisone, she showed high-threshold sensitivity to corticosteroids with the appearance of deleterious effects: Cushingoid obesity, stretch marks and bilateral cataracts. Methotrexate was added at a dose of 12 m/m2/week, without clinical response. She eventually developed severe macrophage activation syndrome which was successfully treated with bolus corticosteroids. Faced with this systemic form refractory to the usual treatments; biotherapy was used. Anakinra was added to his treatment at a dose of 2 mg/kg/day. Impressive improvement in systemic and joint clinical signs occurred within the first few weeks of treatment and acute phase reactants returned to normal. Anakinra was well tolerated and no adverse effects were observed. After 24 months of follow-up and complete clinical remission, without corticosteroid therapy, she presented with a severe flare of her disease with severe inflammatory runaway (SMA) and disseminated intravascular coagulation. After controlling this acute clinical condition with intravenous corticosteroids and ciclosporin; we switched to antiIL6 with a good clinical and biological evolution. Discussion The excellent response to anakinra in this case refractory to conventional treatments suggests that IL1 inhibition could be an important therapeutic target in some patients. Nevertheless, some subtypes of Still's disease escape anakinra after a few years of good response and this has been suggested by some authors. Conclusion Pro-inflammatory cytokines such as interleukin IL1, IL6, and IL18 have been implicated in the pathogenesis of childhood Still's disease. In recent years, targeted biologics have been used with several cases of successful treatment in forms refractory to conventional drugs.