ISSLS PRIZE in Clinical Science 2023: comparison of degenerative MRI features of the intervertebral disc between those with and without chronic low back pain. An exploratory study of two large female populations using automated annotation.

OBJECTIVES: The relationship of degeneration to symptoms has been questioned. MRI detects apparently similar disc degeneration and degenerative changes in subjects both with and without back pain. We aimed to overcome these problems by re-annotating MRIs from asymptomatic and symptomatics groups onto the same grading system. METHODS: We analysed disc degeneration in pre-existing large MRI datasets. Their MRIs were all originally annotated on different scales. We re-annotated all MRIs independent of their initial grading system, using a verified, rapid automated MRI annotation system (SpineNet) which reported degeneration on the Pfirrmann (1-5) scale, and other degenerative features (herniation, endplate defects, marrow signs, spinal stenosis) as binary present/absent. We compared prevalence of degenerative features between symptomatics and asymptomatics. RESULTS: Pfirrmann degeneration grades in relation to age and spinal level were very similar for the two independent groups of symptomatics over all ages and spinal levels. Severe degenerative changes were significantly more prevalent in discs of symptomatics than asymptomatics in the caudal but not the rostral lumbar discs in subjects < 60 years. We found high co-existence of degenerative features in both populations. Degeneration was minimal in around 30% of symptomatics < 50 years. CONCLUSIONS: We confirmed age and disc level are significant in determining imaging differences between asymptomatic and symptomatic populations and should not be ignored. Automated analysis, by rapidly combining and comparing data from existing groups with MRIs and information on LBP, provides a way in which epidemiological and 'big data' analysis could be advanced without the expense of collecting new groups. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.

An in-depth study of the associations between osteoarthritis- and osteoporosis-related phenotypes at different skeletal locations.

The relationship between OA and osteoporosis characteristics remains controversial. This study revealed that age-adjusted hand OA is associated with lower hand/arm BMD levels. Wrist fracture occurrence is associated with increased OA hand scores and low arm BMD. Conversely, age-adjusted knee and spine OA is associated with high spine, hip, and total BMDs. INTRODUCTION: Osteoarthritis (OA) and osteoporosis are two common musculoskeletal diseases which contribute a high burden of disability, yet assessments of their relationship remains controversial. The aim of this study was to clarify the association between bone mineral densities (BMD) of the hand, arm, spine, hip, and total body, and OA of the hand and knee and lumbar disc degeneration in two different ethnic groups. METHODS: Radiographic assessments of the hand, knee, and spine were collected and coded for joint space narrowing, osteophytes, and the Kellgren-Lawrence score from Chuvashian (n = 1504) and British (n = 2280) individuals. BMD measurements of standard skeletal sites were estimated by dual X-ray absorptiometry. Age- and familial-adjusted regression analyses were conducted to determine associations. RESULTS: Knee OA affection was positively associated with elevated hip, spine, and total body BMD levels (p < 0.001). Additionally, disc degeneration phenotypes showed significant positive associations with the hip, spine, and total BMD (p < 0.001). However, increased hand OA scores was significantly negatively correlated with arm and hand BMD measurements in males and females in both samples (p < 0.001). Additionally, higher hand OA scores were significantly associated with wrist fracture. CONCLUSIONS: We discovered a clear pattern of association between hand OA and low hand and arm BMD, with increased risk of wrist fracture, as well as reproducing previous associations between knee and spine OA and elevated spine, hip, and total body BMD. It appears that hand OA manifests differently in comparison to hip and knee OA.

Twelve-year follow-up of chronic pain in twins: Changes in environmental and genetic influence over time.

BACKGROUND: While genetic influences on chronic pain have been repeatedly demonstrated, we do not know whether these effects are stable or dynamic over time. AIMS: To determine the temporal pattern of genetic and environmental effects to individual differences in chronic pain over 12 years, we use a sample of n = 961 female twins. METHODS: Data on chronic pain were collected in 2004 (T1) and 2016 (T2) using the same comprehensive body map which divides the body into 31 distinct anatomical areas. Multivariate twin analyses for repeated measures were conducted to track changes in genetic and environmental influences. RESULTS: Heritability for chronic pain was 63% at baseline and 55% at follow-up. The best-fitting AE Cholesky model revealed one genetic factor explaining 62% of variance in chronic pain at T1 and 11% at T2. No additional genetic factors explaining the variance in chronic pain at T2 could be detected. Furthermore, a unique environmental factor (E1) explaining 37% of the variance in chronic pain at T1 and 12% at T2 and an additional environmental factor (E2) explaining 77% of the variance at T2 were found. CONCLUSION: We demonstrate for the first time that the same genetic influences are operative over time and that novel environmental factors are important in pain maintenance. The findings highlight the value of more in depth exploration of these non-shared environmental influences that could provide clues to the mechanisms behind remittance and/or maintenance of chronic pain. The identification of important environmental influences could point to novel therapeutic interventions in future. SIGNIFICANCE: The variability in chronic pain is mainly explained by new environmental factors influencing incidence, aggravation and/or chronic pain remission. Integration of these findings may provide a useful conceptual framework for the treatment and prevention of pain and pain chronification.

International consensus on the definition and classification of fibrosis of the knee joint.

AIMS: The aim of this consensus was to develop a definition of post-operative fibrosis of the knee. PATIENTS AND METHODS: An international panel of experts took part in a formal consensus process composed of a discussion phase and three Delphi rounds. RESULTS: Post-operative fibrosis of the knee was defined as a limited range of movement (ROM) in flexion and/or extension, that is not attributable to an osseous or prosthetic block to movement from malaligned, malpositioned or incorrectly sized components, metal hardware, ligament reconstruction, infection (septic arthritis), pain, chronic regional pain syndrome (CRPS) or other specific causes, but due to soft-tissue fibrosis that was not present pre-operatively. Limitation of movement was graded as mild, moderate or severe according to the range of flexion (90° to 100°, 70° to 89°, < 70°) or extension deficit (5° to 10°, 11° to 20°, > 20°). Recommended investigations to support the diagnosis and a strategy for its management were also agreed. CONCLUSION: The development of standardised, accepted criteria for the diagnosis, classification and grading of the severity of post-operative fibrosis of the knee will facilitate the identification of patients for inclusion in clinical trials, the development of clinical guidelines, and eventually help to inform the management of this difficult condition. Cite this article: Bone Joint J 2016;98-B:1479-88.

Quantitative genetics of circulating Dickkopf-related protein 1 (DKK1) in community-based sample of UK twins.

UNLABELLED: Dickkopf-related protein 1 (DKK1) is a major inhibitor of Wnt signalling pathway but also plays an important role in bone formation. Its circulating levels appear to correlate significantly with plasma levels of inflammatory factors, fractalkine and IL-6. This study, using a large sample of UK twins, showed that the variation of each of these factors and correlation between them was explained by the genetic factors, and indicated possible association with DKK1 gene variants. INTRODUCTION: DKK1 is involved in the development of several inflammatory conditions related to bone and joint degradation. Our objectives were to explore the genetic contribution (heritability) to circulating DKK1 variation and its correlation with other inflammatory cytokines, interleukin 6 (IL-6) and fractalkine, and to test whether the DKK1 heritability could be attributable to single nucleotide polymorphisms (SNPs) mapped to DKK1, IL-6 and FRCT genes. METHODS: The study included a large community-based sample of 4939 women drawn from the general UK population. Plasma samples were analysed for circulating levels of DKK1, IL-6 and fractalkine (FRCT); 65 SNPs of DKK1, IL-6 and FRCT candidate genes, with MAF >0.1, were examined. We applied variance component analysis to evaluate contribution of putative genetic (including above SNPs) and environmental factors to variation of DKK1, and its correlation with IL-6 and FRCT. RESULTS: Putative genetic factors explained 42.2 ± 2 % of the total variation of circulating DKK1 levels, and were also significant for fractalkine and IL-6 variations. Most importantly, we report significant phenotypic (0.208 ± 0.006-0.459 ± 0.007) and genetic (0.338 ± 0.069-0.617 ± 0.033) correlations between these molecules. We found evidence suggestive of association between the DKK1 and its structural genes variants. CONCLUSIONS: Circulating DKK1 levels correlated significantly with levels of IL-6 and FRCT, known risk factors for several inflammatory processes suggesting a potential role of DKK1 in inflammation and tissue injury. Our results suggest the contribution of genetic factors in inter-individual variation of DKK1 levels in human population. However, further studies are required to determine genetic polymorphisms affecting DKK1 variation and its correlation with IL-6 and FRCT.

Differential methylation of the TRPA1 promoter in pain sensitivity.

Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole-blood DNA methylation was characterized at 5.2 million loci by MeDIP sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain sensitivity (pain DMRs). Nine meta-analysis pain DMRs show robust evidence for association (false discovery rate 5%) with the strongest signal in the pain gene TRPA1 (P=1.2 × 10(-13)). Several pain DMRs show longitudinal stability consistent with susceptibility effects, have similar methylation levels in the brain and altered expression in the skin. Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits.

Association between cartilage and bone biomarkers and incidence of radiographic knee osteoarthritis (RKOA) in UK females: a prospective study.

OBJECTIVE: There is a need to find biochemical markers that would identify people with increased risk of developing radiographic knee osteoarthritis (RKOA). The aim of this study was to evaluate the ability of cartilage and bone biomarkers (cartilage oligomeric matrix protein (COMP), aggrecan, cellular inhibitor of apoptosis protein (cIAP), N-telopeptide-to-helix (NTx)) to predict RKOA incidence in a 10-year follow-up of UK females from the Chingford community study. METHOD: Joint space narrowing (JSN), osteophytes (OSP) and Kellgren-Lawrence (K/L) grades were scored from radiographs of both knees at study baseline and 10 years later in 1,003 women aged 45-64. Circulating levels of biomarkers and demographic variables were measured at baseline. Statistical association analysis was conducted between the potential predictor factors measured at baseline and documentation of RKOA at 10-year follow-up. RESULTS: Age and body mass index (BMI), were significant predictors of incidence of RKOA as assessed by K/L and OSP. Considering biomarkers, independent significant association was found between COMP circulating levels and K/L scores (Odd Ratio (OR) = 2.87, 95% Confidence Interval (CI) = 1.19-6.89, P = 0.018). Significant negative association was detected between aggrecan plasma concentrations and JSN, with OR = 0.37 (95% CI 0.15-0.89), P = 0.026. CONCLUSIONS: Aggrecan and COMP circulating levels contribute to identification of phenotype-specific RKOA incidence. These data suggest potentially protective role of aggrecan in cartilage loss, as measured by JSN. High COMP levels are risk factors for development of RKOA, as assessed by K/L scores.

Neck and back pain and intervertebral disc degeneration: role of occupational factors.

Back pain is a near-universal human experience at some time during life, and neck pain is also common. The overwhelming majority of low back and cervical pain is considered to be due to unspecified mechanical factors or disc degeneration, which is a common with ageing and, hence, in people of working age. Back pain and disc disease appear to have significant heritability, based upon twin studies, but environmental factors also contribute - including physical occupational activities in some studies - although the strength of this association remains uncertain. This article examines the contribution of genetic and environmental factors to back pain and disc disease, with a specific focus on occupational exposures.

GDF5 single-nucleotide polymorphism rs143383 is associated with lumbar disc degeneration in Northern European women.

OBJECTIVE: Lumbar disc degeneration (LDD) is a serious social and medical problem which has been shown to be highly heritable. It has similarities with peripheral joint osteoarthritis (OA) in terms of both epidemiology and pathologic processes. A few known genetic variants have been identified using a candidate gene approach, but many more are thought to exist. GDF5 is a gene whose variants have been shown to play a role in skeletal height as well as predisposing to peripheral joint OA. In vitro, the gene product growth differentiation factor 5 has been shown to promote growth and repair of animal disc. This study was undertaken to investigate whether the GDF5 gene plays a role in LDD. METHODS: We investigated whether the 5' upstream single-nucleotide polymorphism (SNP) variant rs143383 was associated with LDD, using plain radiography and magnetic resonance imaging to identify disc space narrowing and osteophytes, in 5 population cohorts from Northern Europe. RESULTS: An association between LDD and the SNP rs143383 was identified in women, with the same risk allele as in knee and hip OA (odds ratio 1.72 [95% confidence interval 1.15-2.57], P = 0.008). CONCLUSION: Our findings in 5 population cohorts from Northern Europe indicate that a variant in the GDF5 gene is a risk factor for LDD in women. Many more such variants are predicted to exist, but this result highlights the growth and differentiation cellular pathway as a possible route to a better understanding of the process behind lumbar disc degeneration.

Significant differences in UK and US female bone density reference ranges.

UNLABELLED: In the United Kingdom (UK), T- and Z-scores are usually calculated using reference ranges derived from United States (US) populations. In the UK arm of a recent randomised trial (International Breast Cancer Intervention Study II (IBIS-II)), substantially, fewer women than expected were recruited into the osteopenic (-2.545 years with a typical body mass index of 28 kg m(-2) have spine and hip bone mineral density (BMD) 0.6 standard deviation higher than their US counterparts. INTRODUCTION: Dual energy X-ray absorptiometry (DXA) is widely used for the diagnosis of osteoporosis and to investigate the effect of pharmacological treatments on BMD. In both routine and research settings, it is important that DXA results are correctly interpreted. METHODS: T- and Z-scores for the first 650 UK Caucasian women enrolled in the IBIS-II study were compared with data from two independent studies of unrelated, unselected UK Caucasian women: (1) 2,382 women aged 18 to 79 recruited to the Twins UK Adult Twin Registry; (2) 431 women aged 21 to 84 with no risk factors for osteoporosis recruited at Guy's Hospital. All DXA measurements were performed on Hologic densitometers. Subjects were divided into six age bands, and T- and Z-scores were calculated using the manufacturer's US reference range for the spine and the National Health and Nutrition Examination Survey III reference range for the femoral neck and total hip. RESULTS: The overall mean Z-scores for the IBIS-II, Twin, and Guy's groups were: spine: +0.61, +0.29, +0.33; femoral neck: +0.42, +0.36, +0.45; total hip: +0.65, +0.38, +0.39 (all p<0.001 compared with the expected value of 0). The mean body weight of subjects in the three studies was 74.4, 65.5, and 65.4 kg, respectively. Analysis revealed a highly significant relationship between Z-score and weight at each BMD site with a slope of 0.03 kg(-1). CONCLUSIONS: In general, US spine and hip reference ranges are not suitable for the calculation of Z-scores in UK women. For some research study designs, the differences may significantly influence the pattern of subject recruitment.

A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-OA consortium.

To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genome-wide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81x10(-5)). The C allele conferred a reduced risk of 33% to 41% using a case-control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA.

The genetic influence on radiographic osteoarthritis is site specific at the hand, hip and knee.

OBJECTIVE: To identify whether a shared genetic influence accounts for the occurrence of OA at different skeletal sites. METHODS: Multivariate modelling of data on prevalent radiographic OA at the hand (DIP, PIP and CMC joints), hip and knee joints assessed in 992 monozygotic and dizygotic female twin participants from the TwinsUK Registry. RESULTS: OA at all the five joint sites was heritable. Genetic influences were strongly correlated among joints in the hand; however, there was little evidence of common genetic pathways to account for the co-occurrence of OA at the hand, hip and knee. CONCLUSIONS: While genetic influences are important in explaining the variation in occurrence of OA at the hand, hip and knee, there is no evidence that common or shared genetic factors determine the occurrence of disease across all these skeletal sites. The findings suggest that there are important aetiological differences in the disease that are site-specific in women. These results have implications for the design of studies examining the genetic basis of OA as well as for strategies aimed at preventing and treating the disease.

Migraine and antiphospholipid antibodies: no association found in migraine-discordant monozygotic twins.

Migraine headache (with and without aura) is common in the general population and is known to be influenced by genetic factors with heritability estimates between 34-57%. Antiphospholipid syndrome (APS) is a hypercoagulable state characterized by clinical features including venous and arterial thromboses, pregnancy loss and migraine, and by association with antiphospholipid antibodies (aPL). Numerous small studies have investigated whether aPL are associated with migraine in the general population--with contradictory results. In this study, the question was addressed by studying the prevalence of aPL in members of monozygotic (MZ) twin pairs differing in their migraine status. Such twins provide a unique natural experiment, matched as they are for age, sex and genetic factors, and allow the role of environmental factors, such as aPL, to be determined. Despite 95% power to detect a difference of 0.59 IgG units per litre in anticardiolipin antibody IgG titres, no difference in prevalence of aPL could be detected in migraine-discordant MZ twins.

Lumbar disc disease shows linkage to chromosome 19 overlapping with a QTL for hand OA.

OBJECTIVE: Cervical and lumbar degenerative disc disease (CDD and LDD, respectively) form part of the spine osteoarthritis (OA) phenotype and are known to be influenced by genetic factors. A genome-wide linkage analysis was performed to identify new chromosomal regions of interest. METHODS: Dizygotic healthy female twin volunteers (n = 348) from the TwinsUK register who had magnetic resonance imaging scans 10 years ago coded for degenerative disease, were identified. Multipoint genome-wide linkage analysis was conducted using 737 highly polymorphic markers of approximate spacing 10 cM. RESULTS: The mean age of the twins was 52 years. Significant linkage peaks (log of the odds (LOD) >3) were identified for LDD at three chromosomal regions. These included chromosome 1 (position 285 cM), chromosome 5 (position 175 cM) and chromosome 19 (position 80 cM). The peak on chromosome 19 had LOD = 4.06, and the empirical p = 6.7x10(-4) confirmed reliability of the linkage signal. It lies close to a linkage peak previously obtained by our group for hand OA. CONCLUSIONS: This genome-wide linkage study of CDD and LDD shows evidence of linkage for LDD on chromosome 19. The region of interest is likely to harbour genes that are common to LDD and hand OA.

Schmorl's nodes: common, highly heritable, and related to lumbar disc disease.

OBJECTIVE: Schmorl's nodes (SN) are common, but little is known of their relationship with degenerative change and back pain or genetic and environmental factors influencing their expression. We studied healthy female twin volunteers to determine the prevalence and clinical features associated with SN. METHODS: Serial sagittal T1- and T2-weighted magnetic resonance images of the lower thoracic and lumbar spine were analyzed in 516 healthy female twins (150 monozygotic and 366 dizygotic). The images were scored for lumbar degenerative change. Presence of SN was noted at cranial and caudal vertebral levels T9 to L5. Data on physical activity and back pain were collected by questionnaire. Heritability of SN was calculated using variance components modeling. RESULTS: SN were found in 30% of subjects. Of the 374 SN, 153 (41%) were in the lumbar spine and 221 (59%) were in the thoracic spine. SN heritability was >70%. There was a positive association between SN and lumbar disc disease (LDD). SN were more frequent in subjects with back pain (for >/=2 SN: odds ratio [OR] 2.68, 95% confidence interval [95% CI] 1.11-6.47, P = 0.03), but this was largely accounted for by the association of SN with LDD (OR 1.97, 95% CI 0.78-5.0, P = 0.15 adjusted for LDD). No independent association of SN with back pain was identified. CONCLUSION: SN are common in middle-aged women and are strongly genetically determined. They are associated with lumbar degenerative change, which is a risk factor for back pain, but are not themselves an independent risk factor for back pain.

Recent advances in the genetics of osteoporosis.

It has been known for over 20 years that osteoporosis is highly influenced by genetic factors. Bone mineral density (BMD) has also been shown to be highly heritable. Other known risk factors for osteoporotic fractures such as reduced bone quality, femoral neck geometry and bone turnover are now also known to be heritable. Susceptibility to osteoporosis is mediated, in all likelihood, by multiple genes each having small effect. Different approaches are being used currently to identify the many genes responsible. These include linkage studies in man and experimental animals as well as candidate gene studies and alterations in gene expression. Linkage studies have identified multiple quantitative trait loci (QTL) for regulation of BMD and, with twin studies, have indicated that the effects of these loci are partly site-dependent and sex-specific. On the whole, the genes responsible for BMD regulation at these QTL have not yet been isolated. Most studies have used the candidate gene approach. The vitamin D receptor gene (VDR), the collagen type I alpha 1 gene (COLIA1) and estrogen receptor gene (ER) alpha have been most widely investigated and found to play a role in regulating BMD, but the effects are modest and together probably account for less than 5% of the heritable contribution to BMD. Genes may vary in their influence of particular intermediate phenotypes, and we now know that not all genes influencing BMD will be important in fracture. In addition, the study of other diseases such as osteoarthritis and metabolic bone syndromes may prove fruitful in highlighting genes which overlap to osteoporosis as well. As large scale genetic testing becomes more cost-effective, recent findings have illustrated the potential of novel approaches. These include combining large multi-national populations for candidate gene analysis, meta-analyses, DNA pooling studies and gene expression studies.

The effect of moderate alcohol consumption on bone mineral density: a study of female twins.

BACKGROUND: Osteoporosis is associated with morbidity and mortality, particularly in postmenopausal women. The effect of moderate alcohol intake on bone mineral density (BMD) and fracture risk remains unclear. OBJECTIVE: To carry out a twin study to investigate this effect while controlling for genetic effects and other confounding variables. METHODS: BMD was determined at the hip and lumbar spine in 46 pairs of monozygotic twins discordant for alcohol consumption. Biochemical evidence of altered bone metabolism was sought. RESULTS: A positive association between alcohol consumption and BMD was shown, in contrast to the negative effect of smoking on BMD. Markers of bone turnover were not associated with alcohol or BMD. CONCLUSIONS: Moderate alcohol consumption is not harmful to bone health in women and may even be beneficial. Beneficial effects do not appear to be mediated through an action on bone metabolism.

Critical illness in systemic lupus erythematosus and the antiphospholipid syndrome.

OBJECTIVES: To investigate the causes, course, and outcome of critical illness requiring emergency admission to the intensive care unit (ICU) in patients with systemic lupus erythematosus (SLE) or the antiphospholipid syndrome (APS), or both. METHODS: Critically ill patients with SLE or APS, or both, admitted to a London teaching hospital ICU over a 15 year period were studied. Demographic, diagnostic, physiological, laboratory, and survival data were analysed. Kaplan-Meier survival curves were constructed by age, time from first diagnosis of SLE, and time from first ICU admission. The log rank test and a backwards stepwise Cox regression were used to identify factors associated with reduced survival. RESULTS: Sixty one patients with SLE alone (39%) and/or APS (61%) required 76 emergency admissions to the ICU. Patients had high severity of illness scores (median APACHE II 22 (range 8-45)) and multiorgan dysfunction. The primary diagnoses for patients admitted were infection in 31/76 (41%), renal disease in 16/76 (21%), cardiovascular disease in 12/76 (16%), and coagulopathies in 11/76 (14%). The commonest secondary diagnosis was renal dysfunction (49%). Factors associated with an increased risk of death were cyclophosphamide before admission, low white cell count, and high severity of illness score. Before adjustment for these factors renal disease had a strong adverse effect on long term survival (analysis by age at diagnosis p=0.005, analysis by time since first ICU admission, p=0.07). After adjustment, infection at admission to ICU was associated with an increased ICU mortality (p=0.02) and was the cause of death in 13/17 patients who died in the ICU. Similarly, after adjustment, APS was associated with reduced ICU survival (p=0.1) and reduced long term (p=0.03) survival. Seventeen patients (28%) died in the ICU, and 31 patients (51%) had died by the last follow up. Median time from ICU admission to death was four years. Overall five year survival from the first ICU admission was 43%. CONCLUSION: Critical illness requiring ICU admission may occur in patients with SLE and APS. In this study, ICU survival was better than previously described, but long term survival was poor. Cyclophosphamide administration, low white cell count, and high severity of illness score were associated with reduced survival. Before adjustment for these factors, only renal disease had an adverse effect on outcome but after adjustment, infection and APS reduced survival.