Statin-associated immune-mediated necrotising myopathy: a New Zealand case series showing possible overrepresentation in Pacific Islanders.

BACKGROUND: Statin-associated immmune-mediated necrotising myopathy (IMNM) is an emerging entity. Being an uncommon condition, our knowledge and understanding is largely based on case series. AIM: To review incident cases of statin-associated IMNM associated with anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) antibodies in a single New Zealand centre over a 2-year period. METHODS: Four incident cases of statin-associated IMNM were seen between 2014 and 2016. Their presentation, investigation, treatment and current response to treatment are summarised. Two of the four patients were Pacific Islanders despite a small Pacific Island population in the southern district health board. A literature search was performed focusing on the presentation, investigation and treatment of statin-associated IMNM and also genetic associations with this entity to determine whether Pacific Islanders may be at increased risk RESULTS: All four patients presented with profound weakness and recent exposure to atorvastatin. All proceeded to muscle biopsy. Two biopsies showed typical IMNM. One biopsy had mild changes, reported as possibly being compatible with anti-HMGCR antibodies. The final biopsy had features consistent with IMNM, with some features suggestive of polymyositis. Two recent studies have shown an association between anti-HMGCR antibodies and the HLA-DRB1*11:01 haplotype. Interestingly, HLA-DRB1 alleles (including HLA-DRB1*11:01) were observed to be among the most frequent alleles in a Pacific Island population study. CONCLUSION: This is the first case series of statin-associated IMNM with a focus on Pacific Islanders and raises the possibility that Pacific Islanders exposed to statins may be at increased risk of developing an immune-mediated myopathy.

Expression of the genes facilitating methotrexate action within subcutaneous rheumatoid nodules.

OBJECTIVES: We sought further understanding of the association between methotrexate (MTX) therapy and accelerated development of subcutaneous rheumatoid nodules. The objective was to establish expression of genes involved in the transport, metabolism, and mechanism of action of MTX within nodule tissue. We also examined for differences in gene expression between nodules from patients actively receiving MTX compared to those not receiving MTX. METHODS: Subcutaneous nodule tissues (n=23) were obtained from 21 patients with RA, undergoing elective surgery. Expression of genes important to the transport (SLC19A1, ABCB1, ABCC1, ABCG2), metabolism (FPGS, GGH), and mechanism of action (TYMS, MTR, MTRR) of MTX, including for the adenosine receptors ADORA1, ADORA2A, ADORA2B, ADORA3 and ADORA3variant were quantitated by real-time PCR in each nodule sample. RESULTS: Transcripts for all genes were found in all nodules. Expression of MTR was significantly reduced in nodules from patients receiving MTX therapy. Patterns of gene expression differed, with those metabolising MTX more prominent in nodules from patients receiving MTX when compared to nodules from those not receiving MTX, where genes involved in MTX transport were more prominent. CONCLUSIONS: Genes involved in MTX handling are expressed in rheumatoid nodules, providing further evidence that metabolism of MTX within nodules could exert a local effect. Furthermore the profile of gene expression in nodules differed from that previously observed in rheumatoid synovial membrane. The significant reduction of MTR expression in nodules has implications for MTR- and MTRR-mediated re-methylation reactions. Our data suggest that in contrast to synovium, downstream methylation reactions involving methionine and the biosynthesis of S-adenosylmethionine (SAM) could be reduced in nodule tissue. This could help explain differing responses to MTX in rheumatoid nodules and synovium and warrants further investigation.

Sugar-sweetened beverage consumption: a risk factor for prevalent gout with SLC2A9 genotype-specific effects on serum urate and risk of gout.

OBJECTIVE: Consumption of high fructose corn syrup (HFCS)-sweetened beverages increases serum urate and risk of incident gout. Genetic variants in SLC2A9, that exchanges uric acid for glucose and fructose, associate with gout. We tested association between sugar (sucrose)-sweetened beverage (SSB) consumption and prevalent gout. We also tested the hypothesis that SLC2A9 genotype and SSB consumption interact to determine gout risk. METHODS: Participants were 1634 New Zealand (NZ) European Caucasian, Ma¯ori and Pacific Island people and 7075 European Caucasians from the Atherosclerosis Risk in Communities (ARIC) study. NZ samples were genotyped for rs11942223 and ARIC for rs6449173. Effect estimates were multivariate adjusted. RESULTS: SSB consumption increased gout risk. The OR for four drinks/day relative to zero was 6.89 (p=0.045), 5.19 (p=0.010) and 2.84 (p=0.043) for European Caucasian, Ma¯ori and Pacific Islanders, respectively. With each extra daily SSB serving, carriage of the gout-protective allele of SLC2A9 associated with a 15% increase in risk (p=0.078), compared with a 12% increase in non-carriers (p=0.002). The interaction term was significant in pooled (pInteraction=0.01) but not meta-analysed (pInteraction=0.99) data. In ARIC, with each extra daily serving, a greater increase in serum urate protective allele carriers (0.005 (p=8.7×10(-5)) compared with 0.002 (p=0.016) mmol/L) supported the gout data (pInteraction=0.062). CONCLUSIONS: Association of SSB consumption with prevalent gout supports reduction of SSB in management. The interaction data suggest that SLC2A9-mediated renal uric acid excretion is physiologically influenced by intake of simple sugars derived from SSB, with SSB exposure negating the gout risk discrimination of SLC2A9.

Hospital admissions associated with gout and their comorbidities in New Zealand and England 1999-2009.

OBJECTIVES: To describe the national demographics, comorbidities and mortality of admissions associated with gout in New Zealand (NZ) from 1999 to 2009 and compare this with English gout admission data from the same period. METHODS: The characteristics of all admissions due to or complicated by gout in NZ from 1999 to 2009 were analysed. These findings were then compared with the wider NZ population and the English National Health Service (NHS) gout admission rates from 1999 to 2009. RESULTS: There were 10 241 admissions due to gout (group A) and 34 318 admissions complicated by gout (group B) in NZ from 1999 to 2009. There were 32 741 admissions due to gout in England over the same period. Gout admissions rose at 5.5% per year in NZ and at 7.2% per year in England over the study period. NZ gout patients admitted to hospital were more likely to be Maori or a Pacific Islander and had 3-7 comorbidities. Multiple admissions were common with 1479 NZ gout patients admitted more than once. Comorbidities varied between the NZ groups A and B: hypertension (19-39%), renal disease (16-27%) and diabetes mellitus (20-27%) were common. Heart failure (27.6%) and cardiovascular disease (39.1%) were common in those who had gout complicating their hospital admission. This group also had poorer survival compared with those admitted primarily for gout. CONCLUSION: This is the first study to describe the epidemiology of admissions associated with gout across an entire country. Admissions are rising in both countries studied and those admitted in NZ have a high rate of comorbidity and re-admission.

A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not Maori, case and control sample sets.

Genetic variation in ABCG2 (rs2231142, Q141K), encoding a uric acid transporter, is associated with gout in diverse populations. The aim of this study was to examine a role for ABCG2 in gout susceptibility in New Zealand Maori, Pacific Island and Caucasian samples. Patients (n = 185, 173 and 214, for Maori, Pacific Island and Caucasian, respectively) satisfied the American College of Rheumatology gout classification criteria. The comparison samples comprised 284, 129 and 562 individuals, respectively, without gout. rs2231142 was genotyped and stratification accounted for using genomic control markers. Association of the minor allele of rs2231142 with gout was observed in the Pacific Island samples (OR = 2.80, P(STRAT) < 0.001 after accounting for effects of population structure), but not in the Maori samples (OR = 1.08, P(STRAT)= 0.70), with heterogeneity in association evident between the Maori and Pacific Island datasets (P(HET) = 0.001). A similar dichotomy in association was observed when samples were stratified into Western (Tonga, Samoa, Niue, Tokelau) versus Eastern Polynesian (Maori, Cook Island) origin (OR = 2.59, P(STRAT) < 0.001; OR = 1.12, P(STRAT)= 0.48, respectively; P(HET) = 0.005). Association with gout was observed in the Caucasian samples (OR = 2.20, P = 3.2 × 10(-8)). Unlike SLC2A9, which is a strong risk factor for gout in both Maori and Pacific Island people, ABCG2 rs2231142 has a strong effect only in people of Western Polynesian ancestry. Our results emphasize the need to account for sub-population differences when undertaking biomedical genetic research in a group defined by a geographical region and shared ancestry but characterized by migratory events that create bottlenecks and altered genetic structure in the founder populations.

Validation of the Dudley Inflammatory Bowel Symptom Questionnaire for the assessment of bowel symptoms in axial SpA: prevalence of clinically relevant bowel symptoms and association with disease activity.

OBJECTIVES: To validate the Dudley Inflammatory Bowel Disease Questionnaire (DISQ) for determining the presence and severity of bowel symptoms in axial SpA. METHODS: Seventy-seven SpA patients were assessed for disease activity using the BASDAI. All participants, including 32 healthy controls and 29 patients with Crohn's Disease (CD), completed the DISQ and an assessment of stool form and frequency. Validation of the DISQ was undertaken in accordance with OMERACT criteria. RESULTS: Validity of the DISQ for measuring bowel symptoms in SpA was confirmed (Cronbach's α 0.79). Mean DISQ scores (s.d.) were: controls 2.6 (2.6), SpA 8.7 (6.1) and CD 17.1 (10.2). Differences were significant between controls and SpA, and SpA and CD, and correlated with disease activity (ρ 0.27, P = 0.02). In SpA, DISQ scores of those taking NSAIDs (n = 59) did not differ from those not taking NSAIDs (n = 18) (P = 0.31). Stool form and frequency differed significantly between SpA patients and healthy controls (P < 0.001). Using the DISQ the prevalence of clinically relevant bowel symptoms in SpA is 31%, and 7.8% experience bowel symptoms equivalent to active CD. CONCLUSION: The DISQ is a valid measure of bowel symptoms in SpA. Bowel symptoms are prevalent in SpA and correlate with disease activity. Symptoms do not relate to treatment with NSAIDs. We conclude that bowel symptoms should be included as a domain in the clinical assessment of patients with SpA and that the DISQ has potential as an outcome measure in clinical trials.

Cell-specific expression of TLR9 isoforms in inflammation.

Toll-like receptors (TLRs) are key pattern recognition receptors during an immune response. With five isoforms of human TLR9 described, we hypothesised that differential expression of TLR9 isoforms in different cell types would result in variable contributions to the overall input from TLR9 during inflammation. We assessed the molecular expression of the TLR9 isoforms, TLR9-A, -C and -D. In normal peripheral blood mononuclear cells, B-lymphocytes express ∼100-fold more TLR9-A transcript than monocytes or T-lymphocytes, which predominantly express the TLR9-C transcript. Switches in isoform predominance accompany B-lymphocyte development. TLR9 protein expression in rheumatoid inflammatory lesions reflected the TLR9 isoform expression by immune cells. Herein we suggest that B-lymphocytes and plasmacytoid dendritic cells contribute the ∼3-fold higher TLR9-A transcript levels observed in inflamed synovium when compared to subcutaneous rheumatoid nodules. In contrast, macrophages and T-lymphocytes contribute the ∼4-fold higher TLR9-C transcript levels seen in nodules, compared to synovia. From protein sequence, predictions of subcellular localisation suggest TLR9-B may locate to the mitochondria, whereas TLR9-D adopts an opposing orientation in the endoplasmic reticulum. Consistent with this, structure models raise the possibility of alternative ligands for the TLR9-B and TLR9-D variants. Our results highlight differences in the expression of human TLR9 isoforms in normal and inflamed tissues, with differing contributions to inflammation.

Methotrexate pneumonitis in rheumatoid arthritis: increased prevalence with increasing latitude: an epidemiological study of trends in new zealand.

BACKGROUND: There is an association between increasing prevalence and increasing latitude for some autoimmune diseases, including rheumatoid arthritis (RA). Furthermore, in RA patients, a geographical variation in methotrexate pneumonitis has been suggested at a regional level in New Zealand. OBJECTIVE: The objective of the study was to determine if there is an increased incidence of methotrexate pneumonitis with increasing latitude in New Zealand. METHODS: A search was conducted using the NZ Ministry of Health's National Minimum Data Set for patients with discharge codes for RA (M05, M06) or history of RA and drug-induced lung disease (J702, J703, J704) or other (J189, J680, J90, J984) and methotrexate (Y431), for the period July 1, 1999, to June 30, 2008. Anonymous data were provided by the Ministry of Health for the 43 patients fulfilling these coding criteria and also the latitude and population of each domicile code. A Poisson regression analysis was undertaken with latitude as a continuous variable, adjusting for the total population at different latitudes. RESULTS: The incidence rate ratio for methotrexate pneumonitis shows a 16% increase per 1 degree of latitude (95% confidence interval, 7%-27%; P = 0.02). CONCLUSIONS: There was a latitudinal gradient seen in the rate of patient discharges for methotrexate pneumonitis, in the defined period. This supports the hypothesis that there is a latitude-dependent risk factor for this disorder and raises questions regarding possible environmental cofactors. It also supports the growing pool of evidence that certain immune-mediated conditions are more common at higher latitudes.

Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples.

OBJECTIVE: There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiology of rheumatoid arthritis (RA), the authors hypothesised that FCGR3B gene dosage influences susceptibility to RA. METHODS: FCGR3B CN was measured in 643 cases of RA and 461 controls from New Zealand (NZ), with follow-up analysis in 768 cases and 702 controls from the Netherlands and 250 cases and 211 controls from the UK. All subjects were of Caucasian ancestry. RESULTS: Significant evidence for an association between CN <2 and RA was observed in the Dutch cohort (OR 2.01 (95% CI 1.37 to 2.94), p=3 x 10-4) but not in the two smaller cohorts (OR 1.45 (95% CI 0.92 to 2.26), p=0.11 and OR 1.33 (95% CI 0.58 to 3.02), p=0.50 for the NZ and UK populations, respectively). The association was evident in a meta-analysis which included a previously published Caucasian sample set (OR 1.67 (95% CI 1.28 to 2.17), p=1.2 x 10-4). CONCLUSIONS: One possible mechanism to explain the association between reduced FCGR3B CN and RA is the reduced clearance of immune complex during inflammation. However, it is not known whether the association between RA and FCGR3B CN is aetiological or acts as a proxy marker for another biologically relevant variant. More detailed examination of genetic variation within the FCGR gene cluster is required.

A comparison of fatigue correlates in rheumatoid arthritis and osteoarthritis: disparity in associations with disability, anxiety and sleep disturbance.

OBJECTIVES: To investigate correlates of fatigue among individuals with RA and OA, including mood, sleep, disease activity and radiographic damage. METHODS: Fatigue was assessed using the Multidimensional Assessment of Fatigue-Global Fatigue Index (MAF-GFI) in 103 patients with RA and 103 with OA. Sleep disturbance and pain were assessed using a visual analogue scale anxiety and depression using the Hospital Anxiety and Depression scale and disability using the HAQ. In the RA cohort, the disease activity score-28 joint count (DAS-28) and the Van der Heijde modified Sharp score were calculated, and in the OA cohort, the Kellgren-Lawrence score and the WOMAC score calculated. RESULTS: The MAF-GFI scores were higher in the OA cohort (P = 0.02). This was not significant after controlling for disability (P = 0.59). OA participants reported greater pain, disability, depression and sleeplessness than those with RA (all P < 0.01). The strongest correlates of fatigue in the RA cohort were depression (P < 0.001) and anxiety (P < 0.001). There was no significant association with pain (P = 0.43), DAS-28 (P = 0.07), HAQ (P = 0.10) or Sharp score (P = 0.78). In OA, the correlates of fatigue were older age (P = 0.02), sleep disturbance (P = 0.03), depression (P = 0.04), disability (P = 0.04) and lower CRP (P = 0.001). CONCLUSIONS: Fatigue is common and severe in both RA and OA. In RA, fatigue had no significant association with pain, disease activity, disability or erosions, but was associated with depression and anxiety. The disparity in correlates indicates that generalizing the experience of fatigue between OA and RA is not appropriate. Fatigue is an important domain in the assessment of disease impact.

Co-expression of CD21L and IL17A defines a subset of rheumatoid synovia, characterised by large lymphoid aggregates and high inflammation.

OBJECTIVE: To determine whether the expression of IL17A and CD21L genes in inflamed rheumatoid synovia is associated with the neogenesis of ectopic lymphoid follicle-like structures (ELS), and if this aids the stratification of rheumatoid inflammation and thereby distinguishes patients with rheumatoid arthritis that might be responsive to specific targeted biologic therapies. METHODS: Expression of IL17A and CD21L genes was assessed by RT-PCR, qRT-PCR and dPCR in synovia from 54 patients with rheumatoid arthritis. A subset of synovia (n = 30) was assessed by immunohistology for the presence of CD20+ B-lymphocytes and size of CD20+ B-lymphocyte aggregates as indicated by maximum radial cell count. The molecular profiles of six IL17A+/CD21L+ and six IL17A-/CD21L- synovia were determined by complementary DNA microarray analysis. RESULTS: By RT-PCR, 26% of synovia expressed IL17A and 52% expressed CD21L. This provided the basis for distinguishing four subgroups of rheumatoid synovia: IL17A+/CD21L+ (18.5% of synovia), IL17A+/CD21L- (7.5%), IL17A-/CD21L+ (33.3%) and IL17A-/CD21L- (40.7%). While the subgroups did not predict clinical outcome measures, comparisons between the synovial subgroups revealed the IL17A+/CD21L+ subgroup had significantly larger CD20+ B-lymphocyte aggregates (P = 0.007) and a gene expression profile skewed toward B-cell- and antibody-mediated immunity. In contrast, genes associated with bone and cartilage remodelling were prominent in IL17A-/CD21L- synovia. CONCLUSIONS: Rheumatoid synovia can be subdivided on the basis of IL17A and CD21L gene expression. Ensuing molecular subgroups do not predict clinical outcome for patients but highlight high inflammation and the predominance of B-lymphocyte mediated mechanisms operating in IL17A+/CD21L+ synovia. This may provide a rationale for more refined therapeutic selection due to the distinct molecular profiles associated with IL17A+/CD21L+ and IL17A-/CD21L- rheumatoid synovia.

Association of Crohn's disease-related chromosome 1q32 with ankylosing spondylitis is independent of bowel symptoms and faecal calprotectin.

BACKGROUND: Genome-wide association studies have identified a plethora of risk genes for both Crohn's disease (CD) and ankylosing spondylitis (AS). A subset of genes found to be risk factors for CD have also been found to be risk factors for AS. The objective of our study was to assess whether CD risk genes were associated with non-invasive clinical markers of gut inflammation in patients with AS, indicating a potential subset of patients with clinical as well as genetic overlap. METHODS: A total of 308 Caucasian patients who fulfilled the modified New York Criteria for AS, were assessed for bowel symptoms using the Dudley Inflammatory Bowel Symptom Questionnaire (DISQ). Of these patients, 157 also had faecal calprotectin measured. All AS patients and 568 healthy controls were genotyped for 10 CD risk loci using predesigned single nucleotide polymorphism (SNP) genotyping assays. Chi-square analysis was used to test for association between genotype and DISQ score and faecal calprotectin level. RESULTS: The minor allele of two SNPs, one in chromosome region 1q32 SNP (rs11584383), and one in the gene coding for IL23R (rs11209026) conferred protection against AS. Only the association of 1q32 remained significant after Bonferroni correction for multiple testing. Stratification by DISQ score and faecal calprotectin did not influence the association of 1q32 with AS. CONCLUSION: In patients with AS, the association of the CD 1q32 SNP was independent of non-invasive markers of bowel inflammation. Other CD related SNPs were not found have a significant association with AS.

Multicentric carpal-tarsal osteolysis with nephropathy treated successfully with cyclosporine A: a case report and literature review.

Multicentric carpal-tarsal osteolysis is a rare skeletal disorder characterized by osteolysis of the metacarpal, carpal, and tarsal bones and leading to crippling joint deformities. Progressive nephropathy occurs in more than half the cases. All previously reported series with renal biopsies showed only end-stage renal disease on histological examination because of the late presentation to nephrologists. Accurate diagnosis of the underlying renal pathological state therefore has not been possible. We report the first case in which early and sequential renal biopsies were performed. These show the renal lesion to be focal and segmental glomerulosclerosis, which was treated successfully with cyclosporine A.

Coronary artery stenting in acute coronary syndrome associated with giant cell arteritis.

Coronary vasculitis is a rare but devastating complication of giant cell arteritis, otherwise known as temporal arteritis. Originally named for its propensity to attack the superficial temporal arteries, it is now recognized that it commonly involves a number of medium and large arteries throughout the body. Here we describe two cases of giant cell arteritis affecting the coronary arteries, one discovered at post-mortem and one which was successfully treated with immunosuppressive therapy and drug-eluting coronary stents. .

The deleted in colorectal carcinoma (DCC) gene 201 R --> G polymorphism: no evidence for genetic association with autoimmune disease.

The product of the deleted in colorectal carcinoma (DCC) gene has a role in apoptosis and is a positional candidate for IDDM6, the putative chromosome 18q12-q23 autoimmune disease locus. We hypothesised that a nonconservative substitution (DCC 201 R --> G; nucleotide (nt) 601 C --> G), located in an extracellular immunoglobulin-like domain of DCC, is an aetiological determinant of autoimmunity. We tested this hypothesis by genetically testing the nt 601 C --> G polymorphism for association with three autoimmune phenotypes in a large population-based case-control study. There was no evidence for association of DCC nt 601 C --> G with autoimmune disease in cohorts comprising 2253 subjects with rheumatoid arthritis, type I diabetes and Graves' disease, and 2225 control subjects, from New Zealand and the United Kingdom. Furthermore, using the transmission disequilibrium test, there was no significant evidence for biased transmission of the nt 601 C --> G polymorphism to probands within a 382 family type I diabetes affected sibpair cohort from the United Kingdom. Thus, the DCC 201 R --> G polymorphism does not appreciably influence risk of developing the autoimmune diseases tested.