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Autoinflammatory disorders
Original research
NLRP12-associated autoinflammatory disease in Chinese adult patients: a single-centre study
  1. Junke Miao1,
  2. Jingyuan Zhang1,
  3. Xin Huang1,
  4. Na Wu1,
  5. Di Wu2 and
  6. Min Shen1
  1. 1Department of Rare Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  2. 2Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  1. Correspondence to Dr Min Shen; shenmpumch{at}163.com; Dr Di Wu; med_wudi{at}sina.com

Abstract

Background NLRP12-associated autoinflammatory disease (NLRP12-AID) is an autosomal dominant autoinflammatory disorder caused by variants of NLRP12 gene. We aimed to report a cohort of Chinese adult patients with NLRP12-AID and summarised phenotypes and genotypes.

Methods Twenty patients were diagnosed with NLRP12-AID after performing whole-exome sequencing and were included in our cohort. Demographic information, clinical data and treatment response were collected and evaluated. A literature review of NLRP12-AID was performed, and the clinical features and mutated sites were summarised and compared with our cohort.

Results Among the 20 NLRP12-AID patients, the main clinical features of NLRP12-AID included fever, cutaneous rash, arthralgia/arthritis, pharyngitis/tonsillitis, lymphadenopathy, myalgia and abdominal pain/diarrhoea. Thirteen NLRP12 variants were detected as F402L, G39V, R1030X, R7G, E24A, Q90X, A218V, A259V, W581X, G729R, R859W, c.-150T>C and c.*126G>C. Glucocorticoids were used in 14 patients, immunosuppressive agents in 13, and tocilizumab in 2. Seventeen patients had good responses to therapy. When compared with 50 NLRP12-AID patients from other countries, Chinese patients had fewer variants in exon 3, higher incidences of cutaneous rash, pharyngitis/tonsillitis and lymphadenopathy. Among all these 70 NLRP12-AID patients, patients carrying non-exon-3 variants had higher frequencies of ocular involvement, pharyngitis/tonsillitis, headache and lymphadenopathy than those with exon-3 variants.

Conclusion This is the largest cohort of NLRP12-AID in the world and seven novel variants of NLRP12 were identified. Chinese adult patients of NLRP12-AID had more non-specific symptoms such as pharyngitis/tonsillitis and lymphadenopathy when compared with patients from other countries, for which the less occurrence of exon-3 variants might be one possible reason.

  • Inflammation
  • Immune System Diseases
  • Immune Complex Diseases

Data availability statement

No data are available.

Data availability statement

The original data presented in the study are included in this article. Further inquiries can be directed to the corresponding author.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2023-003598

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    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

    • NLRP12-associated autoinflammatory disease (NLRP12-AID) is an autosomal dominant autoinflammatory disorder caused by the variants of NLRP12 gene. The role of NLRP12 played in NLRP12-AID is not clear and only a few cases of NLRP12-AID patients have been reported mainly focused on the Caucasic and paediatric populations with clinical heterogeneities and incomplete penetrance of the variants.

    WHAT DOES THIS STUDY ADD

    • The phenotype, genotype and treatment responses of Chinese adult patients with NLRP12-AID were described and seven novel variants were identified. Compared with patients from other countries, Chinese adult patients of NLRP12-AID had more nonspecific symptoms such as pharyngitis/tonsillitis and lymphadenopathy and the less occurrence of exon-3 variants. The distinction of the clinical manifestations in our cohort might be related to the mutation sites.

    HOW MIGHT THIS IMPACT ON CLINICAL PRACTICE

    • We provided the clinical experiences on the treatment of NLRP12-AID adult patients in China. Our study also indicated many NLRP12-AID patients have autoimmune manifestations and a higher frequency of definite allergic histories. More clinical attentions might be needed on NLRP12-AID patients with exon 3 variants considering the phenotype–genotype interaction we found.

    Introduction

    Systemic autoinflammatory diseases (SAIDs) are a group of rare diseases caused by dysregulation of innate immune system, manifested as episodes of recurrent sterile inflammation and the lack of pathogenic autoantibodies. Monogenic SAIDs are prototypical SAID conditions, caused by the loss-of-function or gain-of-function mutations on the SAID-associated genes.1 2 NLRP12-associated autoinflammatory disease (NLRP12-AID) is an autosomal dominant SAID caused by variants of the NLRP12 gene, which encodes the NLRP12 protein, a member of nod-like receptor families as an intracellular pattern recognition receptor (PRR).3

    The main symptoms of NLRP12-AID include recurrent fever, arthralgia/arthritis, cutaneous rash and abdominal pain. It is also known as familial cold-induced autoinflammatory syndrome 2 (FCAS2) because of the similar phenotype to FCAS, the mild type of NLRP3-associated autoinflammatory disease (NLRP3-AID). The nucleotide sequence of NLRP12 also bears high similarity to NLRP3. However, the severity of NLRP12-AID is milder than NLRP3-AID in view of the less occurrence of serious complications and the less use of biological agents.4 5

    Since the first definition in 2008, only a few cases of NLRP12-AID have been reported mainly in the Caucasic and paediatric populations.6 7 There have been no established diagnostic criteria up till now, possibly because of the considerable clinical heterogeneity and the incomplete penetrance of the variants. Phenotypes and genotypes of Chinese adult-onset NLRP12-AID patients were poorly studied. Here, we reported the largest cohort of Chinese adult patients with NLRP12-AID and performed a literature review on NLRP12-AID patients from other countries that have been reported so far.

    Methods and patients

    There have not been well accepted diagnostic criteria of NLRP12-AID so far. In this study, the inclusion criteria were: (1) recurrent inflammatory signs and symptoms frequently seen in SAID patients, such as recurrent fever, arthralgia/arthritis, dermatitis, sensorineural deafness and headache with intervals free of any clinical manifestations; (2) one or more variants of NLRP12 detected by whole-exome sequencing using next-generation sequencing. Patients diagnosed with malignancies, infectious diseases, autoimmune diseases or other diseases that could explain their recurrent inflammation were excluded. This single-centre study included 20 adult patients diagnosed with NLRP12-AID at the Department of Rheumatology, Peking Union Medical College Hospital from April 2015 to June 2023. Demographic information and detailed clinical records were carefully documented and studied. The treatment responses of good, partial or no responses were defined as more than 80%, 20%–80% or less than 20% remission of clinical symptoms after the treatment. The remission of clinical symptoms referred to the decreases in the lasting time or the frequency of each episode and the severity of autoinflammatory symptoms compared with those before treatment. The families of the proband were also performed WES or Sanger sequencing to correct the mutated sites of NLRP12 if it was possible. This study was approved by the Institutional Review Board of Peking Union Medical College Hospital and was performed in accordance with the Declaration of Helsinki. Informed consents were obtained from all participants.

    A PubMed literature search for ‘NLRP12-autoinflammatory disease’ and ‘familial cold-induced autoinflammatory syndrome 2’ up to June 2023 was performed. We collected and analysed detailed information on the phenotypes and genotypes of NLRP12-AID patients from other countries reported in the English literature.

    Continuous variables were expressed as median and the range and assessed using Mann–Whiteny test. Categorical variables were described as frequency and compared using the χ2 test or Fisher’s exact test. All the statistical tests were two-sided, and the significant level of p was set as 0.05 with the analyses performed using IBM SPSS Statistics (V.26).

    Results

    Demographic data and clinical phenotypes

    The demographic and clinical features of these 20 patients were summarised in table 1. All the patients were Han Chinese with a median disease-onset age of 22 years old, ranging from several months after birth to 61 years old. The gender ratio of men to women was 11:9. Six patients (30%) had disease-onset during childhood, and 14 (70%) were adult-onset. The median time of diagnosis delay was 7.8 years (ranging from 3 months to 30 years). There were five carriers from the proband’s families (25%) who had a family history of recurrent fever or other resembling inflammation symptoms.

    View this table:
    Table 1

    Summary of the phenotypes of NLRP12-AID patients in our cohort

    Of these 20 NLRP12-AID patients, the most frequent symptoms were fever (20/20, 100%), cutaneous rash (15/20, 75%), arthralgia/arthritis (13/20, 65%), pharyngitis/tonsillitis (12/20, 60%), lymphadenopathy (10/20, 50%) and myalgia (9/20, 45%) (figure 1A,B). Abdominal pain/diarrhoea (8/20, 40%), headache (6/20, 30%) and oral ulcers (6/20, 30%) were also described. Four patients had cold-induced onsets of recurrent fever (n=1), arthralgia/arthritis (n=1) and cutaneous rash (n=2). The acute phase reactants including C reactive protein and/or erythrocyte sedimentation rate were increased in 19 patients during the episodes and returned to normal during the intervals. Autoantibodies were negative in most of the patients except for four patients, who had low-titre antinuclear antibodies (ANAs). Ten patients had a definite history of allergic reactions, including six to medicines (macrolides antibiotics, penicillin, acyclovir, ganciclovir and aminophylline), and four to pollen, alcohol, protein foods or animal hair. Four patients had elevated serum levels of immunoglobin (Ig) E.

    Figure 1
    Figure 1

    Phenotypes of the NLRP12-AID patients in our cohort. (A) Urticaria-like rash; (B) arthritis; (C) summary of the treatment response of NLRP12-AID patients (n=20). GR, good response; PR, partial response; NLRP12-AID, NLRP12-associated autoinflammatory disease; NR, no response; NSAIDs, nonsteroidal anti-inflammatory drugs.

    Genotypes

    Thirteen heterozygous NLRP12 variants were detected including F402L (n=7), G39V (n=3), R1030X (n=2), c.-150T>C, c.*126G>C, R7G, E24A, Q90X, A218V, A259V, W581X, G729R, R859W (n=1, respectively). Among them, two were compound heterozygous (A259V-F402L and R1030X-F402L) and seven were novel variants (R7G, E24A, Q90X, A218V, A259V, G729R, R859W). The minor allele frequency (MAF) and the computational prediction results of these variants are listed in table 2. According to the ACMG guideline, eight variants were categorised as VUS, three as likely benign, and the most common two variants, F402L and G39V, as benign. Among the 20 patients, families of 15 patients also performed WES or Sanger sequencing to correct the mutated sites of NLRP12 gene and all the variants were found to be inherited from their parents with no de novo variants.

    View this table:
    Table 2

    Summary of the genotypes of NLRP12-AID patients and the functional prediction of the variants

    Treatment response

    The treatment response was summarised in figure 1C. Glucocorticoids were given to 14 patients with good, partial or no response in 10, 3 or 1, respectively, among whom two were treated only at the episodes. Immunosuppressive agents were used in 13 patients combined with glucocorticoids. Methotrexate (MTX) was used in nine patients, with no relief in two, partial relief in 1 and good relief in 6. Hydroxychloroquine or thalidomide were given to five and three patients, respectively, with good responses. Tocilizumab was used in two refractory patients manifesting as relapsing arthritis and was effective. Meanwhile, tonsillectomy and colchicine were also treated for 3 and 2 patients with no effects. After a mean follow-up of 55 months, 17 patients showed good response and 2 partial responses to the treatments.

    Literature review

    Ultimately, 16 articles related to NLRP12-AID from other countries containing 50 patients were included, and their phenotypes and genotypes were compared with those from our centre.3 7–21 In terms of the clinical manifestations, patients from our cohort had higher frequencies of cutaneous rash (75% vs 48%, p=0.04), pharyngitis/tonsillitis (65% vs 6%, p<0.001) and lymphadenopathy (45% vs 18%, p=0.007) than those from other countries (figure 2). A total of 23 variants of NLRP12 were identified in NLRP12-AID patients from other countries, including F402L which was also seen in our patients (figure 3). The exon 3 of NLRP12 was the main site of the variants in NLRP12-AID, and the frequency of exon 3 variants in patients from other countries was higher than that in our cohort (84% vs 40%, p<0.001). Through literature review, 3 out of 50 patients received tumour necrosis factor inhibitors with no response in one and partial responses in two who were also diagnosed with Crohn’s disease. Eight out of 50 patients were given interleukin 1 (IL-1) antagonists with good responses in 5, partial response in 1, no response in 1 and another patient had an unknown response.

    Figure 2
    Figure 2

    Comparison of the clinical symptoms between NLRP12-AID patients in our cohort and those from other countries. NLRP12-AID, NLRP12-associated autoinflammatory disease. *p-values<0.05; ** p-values<0.01; *** p-values<0.001.

    Figure 3
    Figure 3

    Distribution of the NLRP12 variants in coding regions mentioned in NLRP12-AID patients. NLRP12-AID, NLRP12-associated autoinflammatory disease.

    Phenotype–genotype interaction

    Given the significant differences between our cohort and other studies, we speculated the distinction of the clinical manifestations might be related to the mutation sites. We, therefore, performed a comparison between the patients with and without exon 3 variants among all 70 patients from our centre and other countries. Compared with those carrying non-exon 3 variants, the frequencies of pharyngitis/tonsillitis (50% vs 10%, p=0.001), ocular involvement (30% vs 8%, p=0.027), headache (50% vs 16%, p=0.003) and lymphadenopathy (45% vs 20%, p=0.034) were higher in those carrying exon 3 variants (table 3).

    View this table:
    Table 3

    Comparison of the clinical manifestations between NLRP12-AID patients with and without exon 3 variants

    Discussion

    NLRP12, a member of NLR families as an intracellular PRR, is composed of an N-terminal pyrin domain, a central nucleotide-binding domain and a C-terminal leucine-rich repeat domain with dual functions in innate immune system.22 23 On the one hand, NLRP12 plays an anti-inflammatory role as a suppressor of canonical and non-canonical NF-κB signalling pathway under the infections of some pathogens such as Brucella abortus and Salmonella typhimurium, and it also plays a role in attenuating the colon inflammation and tumorigenesis.24–27 On the other hand, similar to other NLR proteins, NLRP12 is assembled as an inflammasome stimulated by certain conditions, including the viral and bacterial infections like herpes simplex virus type 1, Yersinia pestis, Plasmodium vivax or P. falciparum and the hypoxia-inducible factor-1α in microglial cells, leading to the formation of apoptosis-associated speck-like protein containing a CARD (ASC) speck and the cleavage of pro-caspase-1 and pro-IL-1β to control the inflammation.28–31 One recent study also indicated NLRP12 could form a PANoptosome and drive the lytic cell death called PANoptosis after sensing heme and other pathogen-associated molecular patterns (PAMPs).32 Despite its multiple biological effects, the role of NLRP12 in the pathogenesis of NLRP12-AID is still controversial. For example, NLRP12 T284X and R352C were reported to be loss-of-function variants amplifying the inflammation because of the impaired suppressive effects on NF-κB.3 9 However, NLRP12 D294E could promote the formation of ASC specks and the cleavage of pro-caspase-1, indicating a gain-of-function variant as an inflammasome.8 Considering the role of NLRP12 might be determined by the types of PAMPs, damage-associated molecular patterns and infectious pathogens, we inferred both the genetic backgrounds and environmental factors might be the risk factors of the pathogenesis of NLRP12-AID, where both the proinflammatory and anti-inflammatory effects of NLRP12 might participate simultaneously.

    In order to better understand NLRP12-AID, we reported the largest cohort of Chinese adult patients with NLRP12-AID, performed a literature review and summarised the clinical records in order to identify the difference between our cohort and patients from other countries. Apart from the common symptoms of NLRP12-AID such as cold-induced recurrent fever, cutaneous rash, arthralgia/arthritis and abdominal pain, patients in our cohort reported more uncommon symptoms like pharyngitis/tonsillitis, lymphadenopathy, oral ulcer and ocular involvement, indicating the diverse manifestations of Chinese adult NLRP12-AID patients. In addition to autoinflammation, a significant proportion of patients in our centre and others had low titers of autoantibodies such as ANAs.14 15 18 33 Intriguingly, autoimmune symptoms such as Raynaud’s phenomenon, malar erythema, morning stiffness, autoimmune haemolytic anaemia, hypothyroidism and Crohn’s disease were also reported in the literature.7 14 20 34 So, the coexistence of the dysregulations of both innate and adaptive immune systems was not rare in NLRP12-AID. The regulatory effects of NLRP12 on T cells had been well documented, such as the inhibitory effects on Th17 cell differentiation and the suppression of Th1 response by reducing interferon-γ and IL-2 production. However, the abnormalities of T cell subsets and the specific role they play in NLRP12-AID are still unknown.35 36 We hypothesised that these autoimmune manifestations were caused by the abnormal T cell responses due to genetic variants. Furthermore, we noted that half of the patients in our cohort had definite allergic histories of food or drugs or an elevation of IgE, which has also been described in other studies.7 Since the strong allergen was reported to downregulate the expression of NLRP12 and to induce the excessive maturation of IL-18, the high proportion of allergic histories in NLRP12-AID patients might be not only a causal event but also the consequence of genetic variants.37

    The main controversy on NLRP12-AID was the pathogenicity of NLRP12 in view of the uncertain significance and low penetrance of the variants. Different from other monogenic SAIDs, there were no pathogenic variants and only 7.2% (6/83) likely pathogenic variants of NLRP12 according to the Infevers database (https://infevers.umai-montpellier.fr/web/). Although most of them were VUS or even benign variants according to the ClinVar database considering the high MAF, such as F402L and G39V, they were predicted to be damaging to the protein function assessed by the bioinformatic software in silico as we mentioned in the results. Therefore, whether the variants play a modifying or a pathogenic role are still debated. The low penetrance of NLRP12 is also another feature of this disease. According to the literature review, only 24% (12/50) patients were reported to have a positive family history, similar with our data for about 25%. Meanwhile, some variants of NLRP12 could also be seen in asymptomatic relatives of the patients, patients of multiple sclerosis, stroke and psoriatic arthritis with no manifestations of FCAS2, and even healthy people.38–42 No variants in untranslated regions have been reported in NLRP12-AID except for these two patients in our centre, which might cause the disease by affecting the expression of NLRP12. Yet functional experiments should be performed to elucidate the pathogenic effects of these variants. Although many patients were adulthood onsets, mosaicism was not taken into consideration because we had adjusted the cut-off frequency to 10%–90% for heterozygosity in SAID-related genes during the bioinformatic analysis, which was able to rule out the mosaicism.

    Many Chinese adult patients with monogenic SAIDs had different phenotypes from those in other countries. Similarly, our study indicated that patients from our cohort had more infrequent symptoms, including pharyngitis/tonsillitis and lymphadenopathy. We also noticed there is a lower frequency of the variants occurring in exon 3 in our centre, where the majority of the variants in NLRP12 were reported in literature.15 Thus, we performed a separate subgroup analysis and compared the patients with and without exon 3 variants to explore whether the differences in genotype could explain the differences in phenotype. The results of our study showed that the symptoms of ocular involvement, pharyngitis/tonsillitis, headache, and lymphadenopathy were more common in patients carrying non-exon 3 variants, which implied its relationship with those aforementioned atypical symptoms. Further studies are needed to exclude the possible errors caused by the small size of the cohort.

    Based on our experience, the therapy strategy of NLRP12-AID was determined by the severity of disease. The combination of glucocorticoids and MTX was the most common choice. In general, the treatment responses were good with no severe adverse events. Interestingly, 2 out of 3 patients who didn’t have good response to treatments carried F402L variant in exon 3. Besides, two refractory patients with severe arthralgia and arthritis who eventually had satisfactory response to tocilizumab had variants in exon 3 as well, F402L and W581X. According to the literature review, 10 out of 11 patients who received biological agents also carried variants in exon 3.7 10–12 15 16 18 21 Thus, we inferred that patients carrying exon 3 variants seemed to have poor prognosis because of the more use of biological agents and the worse responses to the treatment.

    The over-production of proinflammatory cytokines in NLRP12-AID patients has been reported, providing the theoretical basis for the application of biological agents, but the choice of biological agents in refractory NLRP12-AID patients has not been well defined. IL-1 antagonists were the most common ones because of the elevation of the final concentration of IL-1 or the increased kinetics of IL-1 release in NLRP12-AID patients.43 44 Due to the unavailability of IL-1 antagonist in China, tocilizumab was given to two patients in our centre for refractory arthritis. It has been reported that there is an increased level of IL-6 in the serum of NLRP12-AID patients, indicating the possibility of tocilizumab as the treatment for NLRP12-AID, especially in those suffering from arthritis.45

    Conclusion

    In this study, we reported the largest cohort of Chinese adult patients with NLRP12-AID, and described the clinical features and the genetic backgrounds. Seven novel variants of NLRP12 gene were identified including R7G, E24A, Q90X, A218V, A259V, G729R, R859W. The phenotype of Chinese adult patients with NLRP12-AID had more atypical manifestations, which might be related to the fact that more variants occurred in non-exon 3 regions. Our study enlarged the clinical phenotypic and genotypic profiles of NLRP12-AID and indicated the possible links between phenotype and genotype. We hope these data could provide the basis for further studies on the pathogenesis of NLRP12-AID.

    Data availability statement

    No data are available.

    Data availability statement

    The original data presented in the study are included in this article. Further inquiries can be directed to the corresponding author.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Institutional Review Board of Peking Union Medical College Hospital (ZS-3272) Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    The authors would like to acknowledge the conference for the prior presentation of this study (https://acrabstracts.org/abstract/nlrp12-associated-autoinflammatory-disease-in-chinese-adult-patients-a-single-center-study/). The authors also want to acknowledge the patients for their consents to participate in the study.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors MS and DW designed the study, contributed to the disease diagnosis and revised the draft. JM was involved in the data collection and data analysis and drafted the manuscript. JZ, XH and NW also participated in the acquisition of the clinical data. All authors were involved in the revision of the draft and approved the final version to be published. MS is responsible for the overall content as the guarantor.

    • Funding This work was supported by the National High Level Hospital Clinical Research Funding (grant number 2022-PUMCH-D-002, 2022-PUMCH-B-013).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer-reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.