The contributions of deleterious rare alleles in NLRP12 and inflammasome-related genes to polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a chronic inflammatory disease characterized by arthralgia and myalgia of the shoulder and hip girdles, and fever. PMR is linked to autoimmune diseases and autoinflammatory disorders. Exome sequencing has revealed the roles of rare variants in some diseases. Causative genes for monogenic autoinflammatory disorders might be candidate genes for the selective exome analysis of PMR. We investigated rare variants in the coding and boundary regions of candidate genes for PMR. Exome sequencing was performed to analyze deleterious rare variants in candidate genes, and the frequencies of the deleterious rare alleles in PMR were compared with those of Japanese population controls. Deleterious rare alleles in the NLRL12 gene were associated with PMR (P = 0.0069, Pc = 0.0415, odds ratio [OR] 4.49, 95% confidence interval [CI] 1.79-11.27). A multigene analysis demonstrated the deleterious rare allele frequency of the candidate genes for autoinflammatory disorders was also increased in PMR (P = 0.0016, OR 3.69, 95%CI 1.81-7.54). The deleterious rare allele frequencies of the candidate genes including NLRP12 were increased in PMR patients, showing links to autoinflammatory disorders in the pathogenesis of PMR.

Human leucocyte antigens and Japanese patients with polymyalgia rheumatica: the protective effect of DRB1*09:01.

OBJECTIVE: The hallmarks of the chronic inflammatory disease polymyalgia rheumatica (PMR) include pain, and morning stiffness in areas of the neck, shoulder and pelvic girdle. The human leucocyte antigen (HLA) gene was reported to be an important risk factor for PMR, but it has not been analysed precisely, especially in populations other than Europeans. METHODS: Genotyping of DRB1 and DQB1 was performed in Japanese PMR patients (n=270) and controls (n=413). Associations between allele carrier and genotype frequencies were determined for PMR. RESULTS: DRB1*04:05 was associated with a predisposition to PMR (p=0.0006, Pc=0.0193, OR 1.85, 95% CI 1.31 to 2.62). DRB1*09:01 was associated with protection against PMR (p=1.46×10-5, Pc=0.0004, OR 0.40, 95% CI 0.26 to 0.61). A shared epitope (SE) associated with PMR (p=3.07×10-6, OR 2.11, 95% CI 1.54 to 2.88). DQB1*03:03 (p=0.0010, Pc=0.0140, OR 0.52, 95% CI 0.35 to 0.77) was associated with protection against PMR and DQB1*04:01 (p=0.0009, Pc=0.0140, OR 1.82, 95% CI 1.28 to 2.58) was associated with predisposition to PMR. A gene dosage effect was observed for DRB1*09:01 and DQB1*03:03, but not for DRB1*04:05, SE or DQB1*04:01. Haplotype and logistic regression analyses suggested a protective effect for DRB1*09:01. CONCLUSION: This study is the first to demonstrate predisposing associations of DRB1*04:05, SE, and DQB1*04:01, and protective associations of DRB1*09:01 and DQB1*03:03 with PMR in Japanese patients. Our data indicate HLA has predisposing and protective effects on the pathogenesis of PMR.

Risk of venous and arterial thromboembolism in patients with giant cell arteritis and/or polymyalgia rheumatica: A Veterans Health Administration population-based study in the United States.

BACKGROUND: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are systemic inflammatory diseases that primarily affect elderly women. OBJECTIVES: To compare the risk of thromboembolic events and retinal vascular occlusions in GCA and/or PMR with that in osteoarthritis (OA), evaluating a veteran-based population. METHODS: A total of 1535 patients with GCA, 10,265 with PMR, and 1203 with overlapping disease, as well as 39,009 age- and sex-matched patients with OA were identified in this retrospective study. The incidence rate ratios (IRRs) of pulmonary embolism (PE), deep venous thrombosis (DVT), arterial thromboembolism, central retinal artery occlusion, and central retinal vein occlusion were calculated and examined over time. The cumulative incidence was plotted and hazard ratios (HRs) of thromboembolic events were calculated, adjusting for independent risk factors of thromboembolism. RESULTS: Patients with GCA and overlapping disease exhibited higher IRRs for all thromboembolic events compared to patients with OA. Patients with GCA had a higher risk of developing DVT and retinal vascular occlusions than those with overlapping disease (HR: 2.01, 95% confidence interval [CI]: 1.35-2.99, p < 0.001; HR: 2.37, 95% CI: 1.23-4.53, p = 0.009, respectively) or PMR alone (HR: 1.89, 95% CI: 1.50-2.41, p < 0.001; HR: 4.68, 95% CI: 3.10-7.07, p < 0.001, respectively). Patients with GCA had a higher risk of developing PE than those with PMR (HR: 1.55, 95% CI: 1.1-2.18, p = 0.01). CONCLUSION: The risk of thromboembolic events differs between GCA, PMR, and overlapping diseases. Our findings may help predict the risk of thromboembolic events based on disease phenotype.

The pathophysiology of polymyalgia rheumatica, small pieces of a big puzzle.

Polymyalgia rheumatica (PMR) is a frequent rheumatic condition among people over 50 years of age. Despite its frequent association with giant cell arteritis (GCA), PMR can be isolated. Its pathophysiology is poorly understood. Nevertheless, many studies are ongoing; 98 studies are currently referenced in ClinicalTrials.org involving several conventional and targeted therapies. In this review, we synthetize the current knowledge about PMR pathophysiology according to genetic and immunogenetic, immunologic, antibody and aging data. Immunogenetic data are mainly related to the HLA system and the association between the HLA-DRB1 and PMR. Few studies are also about immunogenetics of proinflammatory interleukins (i.e. IL-6). The decrease of CD8+Tcells and the strong increase of IL-6 where the main elements of PMR's pathophysiology until the recent years. The disturbance of B cell homeostasis, the search for IL-6 secretion by the innate immune system, the role of aging, are new elements revealed by recent studies. Aging might be a key element to consider as PMR occurs in patients over 50 years of age. Aging may act by the increased susceptibility to infections, by immunological modifications or hormonal disturbances. The role of the cellular infiltration around the joints remains a crucial question. Only a handful of studies described this infiltration. Finally, this review reveals the gaps in available data and suggests new leads and in-depth studies for further research on PMR pathophysiology.

Familial aggregation of longevity in giant cell arteritis and polymyalgia rheumatica.

The long-term mortality in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) is unexpectedly decreased or at least not increased regardless of several mortality risk factors that these diseases share with other chronic immune-mediated rheumatic diseases. The genetic and immunological profile of PMR/GCA patients is unique, therefore, the hypothesis that this profile provides some survival advantage to PMR/GCA patients should be considered. The longevity is a phenomenon that was demonstrated to be familial. The familial aggregation of longevity can be studied by analysis of life expectancy in family members. Here we test the hypothesis of the aggregation of an increased longevity in the families of PMR/GCA patients. We compared the age of death of 358 parents of 179 PMR and GCA patients with corresponding data retrieved from 506 parents of 253 randomly collected age and sex-matched controls. The number of nonagenarian (≥ 90-year -old) mothers of PMR/GCA patients was significantly higher (OR = 2.34, 95%CI 1.11-11.95, p < 0.0005) vs controls. Both nonagenarian parents were found in 6 patients (3.35%) and none in the control cohort (OR = 8.77, 95%CI 2.26-405.10, p = 0.003). Our data suggest the familial aggregation of nonagenarians in PMR/GCA patients.

Discovery of IL-6 and Development of Anti-IL-6R Antibody.

A series of our studies on IL-6 have revealed that it has a pleiotropic activity in various tissues and cells and its deregulated expression is responsible for several chronic inflammations and hemopoietic malignancies.Humanized antibody against 80kd IL-6R (Tocilizumab) has shown significant therapeutic effect in RA, JIA, Castleman's diseases and several other autoimmune inflammatory diseases, such as, giant cell arteritis, reactive arthritis, polymyalgia rheumatica and adult still's disease. Cytokine storm induced by CAR-T cell therapy has been shown to be controlled by Tocilizumab.Therapeutic effect of Tocilizumab confirmed that over and constitutive-production of IL-6 is responsible for the pathogenesis of autoimmune diseases.Then, the question to be asked is how is IL-6 production regulated. We identified a novel molecule called Arid5a which binds with the 3'-UTR of IL-6 mRNA and protects its degradation by competing with Regnase-1. Interestingly, this molecule is present in nuclei and inflammatory stimulation induced translocation of Arid5a from nuclei into cytoplasm and it competes with Regnase-1 for the protection of mRNA of IL-6.Our study indicates that Arid5a is one of the key molecules for inflammation as well as the development of septic shock.The results also suggest the therapeutic potential of anti-agonistic agents for Arid5a in the prevention of various inflammatory diseases and septic shock.

[A Case of Essential Thrombocythemia with a JAK2V617F Mutation andPolymyalgia Rheumatica].

A patient with polymyalgia rheumatica(PMR)had increasing thrombocytosis. CRP levels, the ESR, and serum interleukin (IL)-6 levels were slightly elevated, and the patient tested negative for RF and anti CCP antibodies. Muscle pain was ameliorated with the administration of corticosteroids. Genetic analysis of the peripheral white blood cells demonstrated the presence of a JAK2V617F mutation. The muscle pain experienced by the patient was considered to be due to essential thrombocythemia( ET)of myeloproliferative neoplasms(MPNs)along with an inflammatory reaction. Unfortunately, the patient died suddenly because of cerebral infarction.

T-786C single nucleotide polymorphism of the endothelial nitric oxide synthase gene as a risk factor for endothelial dysfunction in polymyalgia rheumatica.

OBJECTIVES: We investigated the association of the T-786C single nucleotide polymorphism (SNP) of the endothelial nitric oxide synthase gene (NOS3), which is characterised by reduced expression of the enzyme in response to shear stress or interleukin-10 stimulation and significantly associated with coronary heart disease or rheumatoid arthritis, with the occurrence of isolated polymyalgia rheumatica. METHODS: A cohort of 78 patients who had presented at a rheumatological specialist practice in Heidelberg was tested for the T-786C SNP by means of restriction fragment length polymorphism analysis, and the result was compared with the data of a control cohort (n=2061) compiled from the genotyping of umbilical cord arteries from newborns. Patients were tested for an association with the genotype and their clinical characteristics obtained at the time of the initial presentation and during the first year of treatment. RESULTS: The T-786C SNP of the NOS3 gene was significantly associated with isolated PMR (p=0.0009; OR 2.475). The C-allele frequency in patients with PMR was higher than in patients with rheumatoid arthritis, who also showed a significant association with the T-786C SNP (PMR 0.481 vs. 0.422 RA). A significant association with clinical features of the patients could not be detected. CONCLUSIONS: The T-786C SNP of the NOS3 gene, which predisposes towards the development of endothelial dysfunction, is significantly associated with polymyalgia rheumatica manifesting itself without any clinically detectable vascular involvement.

Influence of interleukin 10 promoter polymorphisms in polymyalgia rheumatica: disease susceptibility and functional consequences.

OBJECTIVES: To investigate the functional consequences of IL10 (-592C/A and -1082A/G) gene polymorphisms and their association with susceptibility to, and disease phenotype, in patients with polymyalgia rheumatica (PMR). METHODS: A total number of 168 with PMR and 124 age-matched controls were genotyped using allele-specific primers and restriction fragment length polymorphism analysis. The levels of circulating IL10 and the production of IL10 by PBMCs after in vitro stimulation were studied by Cytometric Bead Array. RESULTS: No significant differences were observed in genotype or allele frequency distribution between patients and controls. The clinical characteristics and prognosis of these patients were also unrelated to the presence of these polymorphisms. No significant differences between PMR patients with low ESR (<40 mm/hr) and classic PMR (>40 mm/hr) were found. Furthermore, we did not observe any influence of circulating IL10 with the intensity of the acute phase response. In both, PMR patients and age-matched controls, no differences in circulating IL10 levels or IL10 production were observed depending on the genotypes of the IL10 gene. CONCLUSIONS: These results do not support the impact of IL10 variants in susceptibility or clinical phenotype of PMR patients. In this aged population no functional association was found between IL10 gene variants and IL10 production.

Analysis of the rs20541 (R130Q) polymorphism in the IL-13 gene in patients with elderly-associated chronic inflammatory diseases.

OBJECTIVE: To investigate whether there is association between the rs20541 (R130Q) polymorphism in the IL-13 gene with disease susceptibility and clinical subsets in patients with elderly-associated inflammatory chronic diseases. MATERIAL AND METHODS: 78 patients with giant cell arteritis (GCA), 174 with polymyalgia rheumatica (PMR), 90 elderly-onset rheumatoid arthritis (EORA), and 465 healthy controls from the same geographic area were studied. The rs20541 (R130Q) polymorphism in the IL-13 gene was evaluated by PCR-RFLP. Circulating levels of IL-13 were measured by ELISA. RESULTS: A higher frequency of the AA genotype [2.349 (0.994-5.554)], as well as the allele A [1.589 (1.085-2.328] and the A carriers [1.656 (1.021-2.686)] (p<0.05) was observed in the GCA patients. No significant differences were observed in the PMR and EORA patients as compared with the healthy controls. Neither difference was observed among the different disease groups studied. In GCA patients, differences in the genotype were associated with a worse prognosis. In PMR patients, the AA genotype was associated with higher levels of serum IL-13 than the GA one. However, such an association was not detected for controls and the other disease groups. CONCLUSIONS: GCA is more frequent in carriers of the rs20541 (R130Q) polymorphism in the IL-13 gene. The utility of this polymorphism to predict the GCA prognosis must be confirmed in studies with a higher number of patients.

Toll-like receptor 4 gene polymorphisms in polymyalgia rheumatica and elderly-onset rheumatoid arthritis.

OBJECTIVES: Coding variants in TLR4 gene have been reported to be associated with inflammatory diseases. The aim of this study was to determine whether two of these polymorphisms (Asp299Gly and Thr399Ile) of TLR4 contribute to the genetic background of polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA). Furthermore, we have attempted to correlate the functional consequences of these polymorphisms. METHODS: 164 patients with PMR, 93 with EORA and 126 unrelated age-matched controls were genotyped. The TLR4 genotypes were determined using allele-specific primers and restriction fragment length polymorphism analysis. Association of genotypes and alleles with disease susceptibility and disease phenotypes were studied. TLR4 expression was assessed on PBMCs by flow cytometry and TLR4 function was assessed by stimulating PBMCs in vitro with LPS. RESULTS: No significant difference in allele frequency or genotype between patients with elderly-onset inflammatory conditions and controls was observed. The Thr399Ile CC genotype was associated with a higher cumulative dose of corticosteroids in patients with PMR (p=0.031). We found no association with TLR4 expression on B cells, T cells or monocytes or a distinct phenotype of TLR4 response with the Asp299Gly or Thr399Ile genotypes. CONCLUSIONS: These results do not support the association of these TLR4 variants with two age-related inflammatory conditions. The value of determining Thr399Ile genotypes for disease prognosis in PMR should be confirmed in different populations.

Can the prognosis of polymyalgia rheumatica be predicted at disease onset? Results from a 5-year prospective study.

OBJECTIVE: To identify the features of PMR that may predict the duration of steroid therapy, the occurrence of relapses and the late development of GCA. METHODS: Prospective cohort study of 176 patients with PMR, followed up for 5 years. Baseline factors associated with the duration of steroids therapy were identified using Cox regression. Predictors of relapse and the late development of GCA were identified using binary logistic regression. RESULTS: A total of 176 patients with PMR were included, of whom 124 stopped steroids within 5 years. The probability of stopping steroids within 5 years was independently reduced by an elevated plasma viscosity (PV) [hazard ratio (HR) = 0.49; 95% CI 0.29, 0.82 for a PV > or = 2.00 mPa s compared with a PV < or = 1.80 mPa s; overall P = 0.024] and by starting treatment at >15 mg prednisolone (HR = 0.63; 95% CI 0.41, 0.97; P = 0.036). Either of these independently reduced the chances of stopping steroids within a given time interval between 27 and 51%. No significant predictors of relapse were identified. Predictors of late GCA on univariable analysis were female sex [odds ratio (OR) = 8.16; 95% CI 1.06, 63.13; P = 0.044], HLA-DRB1*0101 or -*0401 alleles (OR = 4.95; 95% CI 1.05, 23.34; P = 0.043), PV > or = 2.00 mPa s compared with PV < or = 1.80 mPa s (OR = 10.64; 95% CI 1.28, 88.38; P = 0.029) and initial prednisolone dose >15 mg (OR = 4.53; 95% CI 1.61, 12.79; P = 0.004). CONCLUSION: A higher PV in PMR increases the risk of prolonged steroid therapy and late GCA. Female sex and particular HLA alleles may increase the risk of late GCA. Starting patients on >15 mg prednisolone is associated with a prolonged steroid duration.

Toll-like receptor 4 (TLR4) gene polymorphisms in giant cell arteritis.

OBJECTIVE: To investigate potential associations between toll-like receptor 4 (TLR4) gene polymorphisms and susceptibility to, and clinical features of giant cell arteritis (GCA). METHODS: A total of 155 patients with biopsy-proven GCA who were residents of Reggio Emilia, Italy, and 210 population-based controls from the same geographical area were genotyped for two coding single nucleotide polymorphisms of TLR4 (Asp299Gly and Thr399Ile) by molecular methods. The patients were subgrouped according to the presence or absence of polymyalgia rheumatica and severe ischemic complications (visual loss and/or cerebrovascular accidents). RESULTS: The distribution of allele and genotype frequencies did not differ significantly between GCA patients and healthy controls. Carriers of the -299 G allele (G/A+ G/G) [odds ratio (OR) 1.78, 95% confidence intervals (CI) 0.90-3.50)] were more frequent among GCA patients than among the controls, but the difference was not statistically significant. No significant associations were found when GCA patients with and without PMR or with and without severe ischemic complications were compared. CONCLUSION: Our data suggest that the TLR4 gene polymorphisms are not associated with susceptibility to, and clinical expression of, GCA in Italian patients.

Interleukin-12 gene polymorphisim in patients with giant cell arteritis, polymyalgia rheumatica and elderly-onset rheumatoid arthritis.

OBJECTIVE: The cytokine profile suggests that giant cell arteritis (GCA) is a Th1-driven disease, in which local IFN-gamma plays a critical role in the development of a systemic arteritis. IL-12 is a potent inducer of IFN-gamma and is critically involved in biasing an immune response towards a Th1 pathway. The purpose of this study was to investigate whether there was an association between an IL-12 gene polymorphism (-1188 A/C 3UTR) and disease susceptibility for GCA and two other age-related inflammatory conditions, such as polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA). Furthermore, we attempted to correlate such polymorphism with in vitro IL-12 production. MATERIALS AND METHODS: We analyzed genotypes at -1188 in the 3UTR of the IL-12 promoter by PCR-RFLP in 68 GCA, 138 PMR, and 72 EORA patients as well as in 465 healthy controls (HC). IL-12p70 levels in culture supernatants after stimulation with PMA+Ionomycin was assessed by ELISA. RESULTS: All groups were in Hardy-Weinberg equilibrium. Allelic and gen-omic distribution was not significantly different among the study groups. None of the genetic variants was associated with disease severity. Although the differences were not statistically significant, HC genotypes were associated with distinct IL-12 p70 production. CONCLUSIONS: The IL-12 (-1188 A/C 3UTR) gene polymorphism is not associated with disease susceptibility or severity in three age-related chronic inflammatory syndromes. The production of IL-12 p70 is dependent on the genetic background in HC, although in patients such association may be biased by other unknown factors.

Familial aggregation in giant cell arteritis and polymyalgia rheumatica: a comprehensive literature review including 4 new families.

OBJECTIVE: To review personal and published observations of giant cell (temporal) arteritis (GCA) or polymyal-gia rheumatica (PMR) with familial or conjugal aggregation and emphasise on epidemiological, clinical and genetic features of such cases. METHODS: We pooled data obtained from all cases of GCA or PMR with familial aggregation recruited in the department since 1976 and those from reports of familial or conjugal GCA or PMR published in the French-English literature since 1970. RESULTS: During the study period, we diagnosed 460 patients (128 with isolated PMR, 227 with isolated GCA, 105 with PMR/CGA). No conjugal couples were observed in the whole series. No familial cases were identified among PMR patients, whereas the prevalence of familial GCA was 1 in 83 (1 in 250 to 500 expected by chance), as we identified 4 patients (brother-brother, sister with history of affected sister, and daughter with priory affected mother). An additional pair of sisters with TA, recruited several months after diagnosis, is also presented. Pooling data from 85 patients (74 with GCA) including our patients, representing 32 families and 8 conjugal pairs, enabled us to draw the following observations: 1) partial or full agreement in the clinical picture (GCA, PMR, or GCA/PMR) was observed in 96% of the siblings pairs, suggesting a common pathogenic mechanism; 2) five kindred were described in whom at least three members were affected; 3) the lag between manifested diseases in familial or conjugal pairs averaged 5.7 years, with synchronous or close disease occurrence in only 26% of the pairs; 4) 18 of 32 assessed patients (56%) carried the DR4 antigen. CONCLUSION: Our survey on familial aggregation of GCA and PMR accumulated data pointing to a genetic predisposition. However, environmental contagious factors could have trigger synchronous disease onset in up to one-fourth of the cases.

Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions.

OBJECTIVE: In the era of genome-wide association studies, familial risks are used to estimate disease heritability and the likelihood of candidate-gene identification. This study was undertaken to estimate associations of rheumatoid arthritis (RA) with any of 33 autoimmune diseases and related conditions among parents and offspring, singleton siblings, twins, and spouses. METHODS: The Multigeneration Register in Sweden was used as a reliable source of information on Swedish families throughout the last century. Data on autoimmune diseases in individual family members were obtained through linkage to the Hospital Discharge Register. The standardized incidence ratio (SIR) was calculated as a measure of the relative risk of RA in family members of patients with RA or any of 33 other autoimmune diseases or related conditions, as compared with the relative risk of RA in those lacking an affected family member. RESULTS: Among a total of 447,704 patients, 47,361 were diagnosed as having RA. The SIRs for RA were 3.02 in offspring of affected parents, 4.64 in siblings, 9.31 in multiplex families, 6.48 in twins, and 1.17 in spouses. Significant associations with the familial risk of RA in offspring according to parental proband were observed for ankylosing spondylitis (SIR 2.96), localized scleroderma (SIR 2.40), Sjögren's syndrome (SIR 2.25), systemic lupus erythematosus (SIR 2.13), systemic sclerosis (SIR 1.65), Hashimoto thyroiditis/hypothyroidism (SIR 1.54), pernicious anemia (SIR 1.53), sarcoidosis (SIR 1.40), psoriasis (SIR 1.36), Wegener's granulomatosis (SIR 1.34), and asthma or polymyalgia rheumatica (SIR 1.32). CONCLUSION: This is the first study to compare the familial risks of RA in relation to a large number of autoimmune diseases and related conditions using data from a single population. The high discordant familial risks in this population suggest that there is extensive genetic sharing between RA and the associated diseases.