In early rheumatoid arthritis, anticitrullinated peptide antibodies associate with low number of affected joints and rheumatoid factor associates with systemic inflammation.

OBJECTIVES: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis. METHODS: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline. RESULTS: Individually, all autoantibodies except immunoglobulin G (IgG) RF associated with low SJC and TJC and with high ESR. In IgM RF-negative patients, ACPA associated strictly with low number of swollen and tender joints. This association persisted in multiple regression and stratified analyses where IgM and IgA RF instead associated with inflammation expressed as ESR. Among subjects without any ACPA peptide reactivity, there was no association between RF isotypes and ESR. The effect of RF on ESR increased with the number of ACPA reactivities, especially for IgM RF. In patients fulfilling the 1987 ACR criteria without taking RF into account, associations between IgM RF and high ESR, as well as between ACPA and low joint counts, remained. CONCLUSION: Whereas ACPA associate with low counts of affected joints in early RA, RF associates with elevated measures of systemic inflammation in an ACPA-dependent manner. This latter finding corroborates in vitro models of ACPA and RF in immune complex-induced inflammation. These phenotypic associations are independent of classification criteria.

Familial autoimmunity in patients with idiopathic inflammatory myopathies.

BACKGROUND: Familial associations can be indicators of shared genetic susceptibility between two diseases. Previous data on familial autoimmunity in patients with idiopathic inflammatory myopathies (IIM) are scarce and inconsistent. OBJECTIVES: To investigate which autoimmune diseases (ADs) may share genetic susceptibility with IIM, we examined the familial associations between IIM and different ADs. METHODS: In this Swedish population-based family study, we assembled 7615 first-degree relatives (FDRs) of 1620 patients with IIM and 37,309 relatives of 7797 matched individuals without IIM. Via register linkages, we ascertained rheumatoid arthritis, other rheumatic inflammatory diseases (RIDs), multiple sclerosis, inflammatory bowel diseases (IBD), type 1 diabetes mellitus, autoimmune thyroid diseases (AITD), coeliac disease (CeD) and myasthenia gravis among the FDRs. We estimated the familial association between IIM and each AD using conditional logistic regression and performed subgroup analyses by kinship. RESULTS: Patients with IIM had significantly higher odds of having ≥1 FDR affected by other RIDs (adjusted odds ratio [aOR] = 1.40, 95% confidence interval [CI] 1.11-1.78) and greater odds of having ≥2 FDRs affected by CeD (aOR = 3.57, 95% CI 1.28-9.92) compared to the individuals without IIM. In the analyses of any FDR pairs, we observed familial associations for other RIDs (aOR = 1.34, 95% CI 1.14-1.56), IBD (aOR = 1.20, 95% CI 1.02-1.41), AITD (aOR = 1.10, 95% CI 1.02-1.19) and CeD (aOR = 1.37, 95% CI 1.08-1.74) while associations for other ADs were not statistically significant. CONCLUSION: The observed familial associations may suggest that IIM shares genetic susceptibility with various ADs, information that may be useful for clinical counselling and guiding future genetic studies of IIM.

Survival in Swedish patients with systemic sclerosis: a nationwide population-based matched cohort study.

OBJECTIVES: To conduct the first-ever nationwide, population-based cohort study investigating survival patterns of all patients with incident SSc in Sweden compared with matched individuals from the Swedish general population. METHODS: We used the National Patient Register to identify patients with incident SSc diagnosed between 2004 and 2015 and the Total Population Register to identify comparators (1:5), matched on sex, birth year and residential area. We followed them until death, emigration or the end of 2016. Follow-up of the general population comparators started the same date as their matched patients were included. We estimated all-cause survival using the Kaplan-Meier method, crude mortality rates and hazard ratios (HRs) using flexible parametric models. RESULTS: We identified 1139 incident patients with SSc and 5613 matched comparators. The median follow-up was 5.0 years in patients with SSc and 6.0 years for their comparators. During follow-up, 268 deaths occurred in patients with SSc and 554 in their comparators. The 5-year survival was 79.8% and the 10-year survival was 67.7% among patients with SSc vs 92.9% and 84.8%, respectively, for the comparators (P < 0.0001). The mortality rate in patients with SSc was 42.1 per 1000 person-years and 15.8 per 1000 person-years in their comparators, corresponding to an HR of 3.7 (95% CI 2.9, 4.7) at the end of the first year of follow-up and 2.0 (95% CI 1.4, 2.8) at the end of the follow-up period. CONCLUSION: Despite advances in understanding the disease and in diagnostic methods over the past decades, survival is still severely impacted in Swedish patients diagnosed with SSc between 2004 and 2015.

The association between autoantibodies and risk for venous thromboembolic events among patients with rheumatoid arthritis.

OBJECTIVES: To assess the association between venous thromboembolic (VTE) events and autoantibodies, following patients from RA diagnosis, measuring occurrence, levels and collective load of different autoantibodies against post-translational protein modifications, in particular recognizing citrullination (e.g. citrullinated fibrinogen) and RF by isotype. METHODS: A cohort of 2814 patients with newly diagnosed RA were followed for incident VTE through register linkages. Sera from RA diagnosis were centrally analysed for antibodies to second generation cyclic citrullinated peptides (anti-CCP2), 20 anti-citrullinated protein antibody (ACPA) fine-specificities, antibodies to additional protein modifications (carbamylation and acetylation) and RF by isotype. Association between baseline serology status and future VTE was analysed using Cox regression adjusted for age, sex and calendar period of RA diagnosis, overall and stratified by anti-CCP2 and RF positivity. RESULTS: During a median 16 years of follow-up, 213 first-ever VTE events were registered (5.0/1000 person-years). IgG anti-CCP2 (present in 65% of cohort) associated with VTE (hazard ratio [HR] = 1.33, 95% CI: 1.00, 1.78), in a dose-response manner. The risk of VTE increased with number of ACPA fine-specificities. IgM RF, but no other RF isotypes, associated with VTE (HR = 1.38, 95% CI: 1.04, 1.82). The associations were independent from smoking and HLA-DRB1 shared epitope alleles. None of the carbamylated or acetylated antibody reactivities associated with VTE. CONCLUSION: Anti-CCP2, load of ACPA fine-specificities and IgM RF at RA diagnosis are associated with an increased risk of future VTE in RA. Antibodies to citrullinated fibrinogen did not differ substantially from other ACPA fine-specificities. Autoreactivity to other post-translational modifications was not associated with VTE risk.

Genome-wide investigation of persistence to treatment with methotrexate in early rheumatoid arthritis.

OBJECTIVES: To investigate the influence of genetic factors on persistence to treatment of early rheumatoid arthritis (RA) with methotrexate (MTX) monotherapy. METHODS: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early RA patients initiating MTX in DMARD-monotherapy as their first ever DMARD. The outcome, short- and long-term persistence to this treatment, was defined as remaining on MTX at one and at three years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. RESULTS: No individual SNP reached genome-wide significance (p < 5e-8), neither for persistence at one nor at three years. The RA PRS was not significantly associated with persistence at one (RR = 0.98 (0.96-1.01)) nor three years (RR = 0.96 (0.93-1.00)). The heritability for persistence was estimated to be 0.45 (0.15-0.75) at one year and 0.14 (0-0.40) at three years. Results in seropositive RA were comparable to those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. CONCLUSIONS: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, persistence to MTX monotherapy was lower in patients with a greater genetic disposition, per the PRS, towards RA.

The familial risk and heritability of multiple sclerosis and its onset phenotypes: A case-control study.

BACKGROUND: The two main phenotypes of multiple sclerosis (MS), primary progressive (PPMS) and relapsing Onset (ROMS), show clinical and demographic differences suggesting possible differential risk mechanisms. Understanding the heritable features of these phenotypes could provide aetiological insight. OBJECTIVES: To evaluate the magnitude of familial components in PPMS and ROMS and to estimate the heritability of disease phenotypes. METHODS: We used data from 25,186 MS patients of Nordic ancestry from the Swedish MS Registry between 1987 and 2019 with known disease phenotype (1593 PPMS and 16,718 ROMS) and 251,881 matched population-based controls and 3,364,646 relatives of cases and controls. Heritability was calculated using threshold-liability models. For familial odds ratios (ORs), logistic regression with robust sandwich estimator was utilized. RESULTS: The OR of MS diagnosis in those with a first-degree family member with ROMS was 7.00 and 8.06 in those with PPMS. The corresponding ORs for having a second-degree family member with ROMS was 2.16 and 2.18 in PPMS. The additive genetic effect in ROMS was 0.54 and 0.22 in PPMS. CONCLUSION: Risk of MS increases by several folds in those with a relative with MS. The likelihood of developing either disease phenotype appears independent of genetic predisposition.

Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphenotype.

Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (Bpos-9) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(-) RA-affected case subjects separately. In CCP2(-) RA, we observed that the association between CCP2(-) RA and Bpos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10-17). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and Bpos-9 were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset.

OBJECTIVES: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. METHODS: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). RESULTS: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. CONCLUSION: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.

Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases.

BACKGROUND & AIMS: Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. METHODS: DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells. RESULTS: Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. CONCLUSIONS: In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.

Familial aggregation and heritability: a nationwide family-based study of idiopathic inflammatory myopathies.

OBJECTIVES: The magnitude of the genetic contribution to idiopathic inflammatory myopathies (IIMs) is unknown. In this project, we aimed to investigate the familial aggregation and heritability of IIM. METHODS: This is a family-based study using nationwide healthcare register data in Sweden. We matched each patient with IIM to individuals without IIM, identified their first-degree relatives and determined the IIM status among all first-degree relatives. We estimated the adjusted ORs (aORs) of familial aggregation of IIM using conditional logistic regression. In addition, we used tetrachoric correlation to estimate the heritability of IIM. RESULTS: We included 7615 first-degree relatives of 1620 patients with IIM diagnosed between 1997 and 2016 and 37 309 first-degree relatives of 7797 individuals without IIM. Compared with individuals without IIM, patients with IIM were more likely to have ≥1 first-degree relative affected by IIM (aOR=4.32, 95% CI 2.00 to 9.34). Furthermore, the aOR of familial aggregation of IIM in full siblings was 2.53 (95% CI 1.62 to 3.96). The heritability of IIM was 22% (95% CI 12% to 31%) among any first-degree relatives and 24% (95% CI 12% to 37%) among full siblings. CONCLUSIONS: IIM has a familial component with a risk of aggregation among first-degree relatives and a heritability of about 20%. This information is of importance for future aetiological studies and in clinical counselling.

Comorbidities at diagnosis of rheumatoid arthritis: a population-based case-control study.

OBJECTIVES: Comorbidities contribute to the morbidity and mortality in RA, and are thus important to capture and treat early. In contrast to the well-studied comorbidity risks in established RA, less is known about the comorbidity pattern up until diagnosis of RA. We therefore compared whether the occurrence of defined conditions, and the overall comorbidity burden at RA diagnosis, is different from that in the general population, and if it differs between seropositive and seronegative RA. METHODS: Using Swedish national clinical and demographic registers, we identified new-onset RA patients (n = 11 086), and matched (1:5) to general population controls (n = 54 813). Comorbidities prior to RA diagnosis were identified in the Patient and Prescribed Drug Registers, and compared using logistic regression. RESULTS: At diagnosis of RA, respiratory (odds ratio (OR) = 1.58, 95% CI: 1.44, 1.74), endocrine (OR = 1.39, 95% CI: 1.31, 1.47) and certain neurological diseases (OR = 1.73, 95% CI: 1.59, 1.89) were more common in RA vs controls, with a similar pattern in seropositive and seronegative RA. In contrast, psychiatric disorders (OR = 0.87, 95% CI: 0.82, 0.92) and malignancies (OR = 0.88, 95% CI: 0.79, 0.97) were less commonly diagnosed in RA vs controls. The comorbidity burden was slightly higher in RA patients compared with controls (P <0.0001). CONCLUSION: We found several differences in comorbidity prevalence between patients with new-onset seropositive and seronegative RA compared with matched controls from the general population. These findings are important both for our understanding of the evolvement of comorbidities in established RA and for early detection of these conditions.

Incidence and prevalence of systemic sclerosis globally: a comprehensive systematic review and meta-analysis.

OBJECTIVES: We aimed to conduct a systematic review and meta-analysis on the incidence and prevalence of SSc covering the entire literature. METHODS: This study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement of 2009. We conducted a systematic search in MEDLINE, Web of Science and Embase to identify articles reporting incidence and/or prevalence of SSc. Two authors conducted the search, reviewed articles for inclusion and extracted relevant data. We used random-effects models to estimate the pooled prevalence and incidence of SSc and performed subgroup analyses by sex, case definition and region to investigate heterogeneity. We explored the association between calendar period and reported estimates using meta-regression. RESULTS: Among 6983 unique records identified, we included 61 studies of prevalence and 39 studies of incidence in the systematic review. The overall pooled prevalence of SSc was 17.6 (95% CI 15.1, 20.5) per 100 000 and the overall pooled incidence rate of SSc was 1.4 (95% CI 1.1, 1.9) per 100 000 person-years. We observed significant regional variations in reported estimates; studies conducted in North America reported considerably higher estimates than other regions. The pooled incidence and prevalence in women were five times higher than in men. More recent studies reported higher estimates than older ones. CONCLUSION: In this comprehensive review of the incidence and prevalence of SSc across the world, there was large heterogeneity among estimates, which should be taken into consideration when interpreting the results.

Rheumatoid arthritis autoantibodies and their association with age and sex.

OBJECTIVES: To examine the association between individual rheumatoid arthritis (RA) autoantibodies, sex and age at RA onset. METHODS: Anti-CCP2, IgA-, IgG- and IgM-RF were analysed centrally in baseline sera from 1600 RA patients diagnosed within one year of RA symptom onset. Cut-offs for RF isotypes were determined at the 98th percentile based on RA-free controls, close to the 98.4% anti-CCP2 specificity. RESULTS: Anti-CCP2 was found in 1020 patients (64%), IgA RF in 692 (43%), IgG RF in 529 (33%) and IgM RF in 916 (57%) of the patients. When assessed one by one, anti-CCP2 and IgM RF were both associated with lower age at RA diagnosis. When assessed in one joint model, the association to IgM RF weakened and a strong association between IgA RF and higher age at RA diagnosis appeared. IgA RF and IgG RF associated with male sex, and IgM RF with female sex, with no difference for anti-CCP2. When the model was adjusted for sex, the association between IgM RF and age disappeared, whereas the strong associations between IgA RF and high age and between anti-CCP2 and low age at diagnosis remained. Further adjustments for smoking, shared epitope and inclusion year did not change the outcome. Univariate analyses stratified on anti-CCP2 and IgA RF status confirmed the findings. CONCLUSIONS: Anti-CCP associate with low, and IgA RF with high age at RA onset. RFs and anti-CCP2 display opposing association with sex. These results underscore that studies on RA phenotypes in relation to autoantibodies should accommodate age and sex.

Siblings of patients with rheumatoid arthritis are at increased risk of acute coronary syndrome.

OBJECTIVES: To investigate a potential shared susceptibility between rheumatoid arthritis (RA) and acute coronary syndrome (ACS) by estimation of the risk of ACS among full siblings of patients with RA. METHODS: By linking nation-wide Swedish registers, we identified a cohort of patients with new-onset RA 1996-2016, age- and sex-matched (5:1) general population comparator subjects, full siblings of RA and comparator subjects, and incident ACS events through 31 December 2016. We used Cox regression to estimate the HR of ACS among patients with RA and the siblings of patients with RA versus the general population, overall and stratified by RA serostatus. We explored the impact of traditional cardiovascular (CV) risk factors on the observed associations. RESULTS: We identified 8109 patients with incident RA, and 11 562 full siblings of these. Compared with the general population, the HR of ACS in RA was 1.46 (95% CI 1.28 to 1.67) and 1.22 (95% CI 1.09 to 1.38) among their siblings. The increased risks seemed confined to seropositive RA (patients: 1.52 [1.30 to 1.79], their siblings: 1.27 [1.10 to 1.46]); no significant risk increase was observed among siblings of patients with seronegative RA (HR 1.13 [95% CI 0.92 to 1.39]). Adjustment for 19 traditional CV risk factors did not appreciably alter these associations. CONCLUSION: Siblings of patients with RA are at increased risk of ACS, suggesting shared susceptibility between RA and ACS, indicating the need and potential for additional cardio-preventive measures in RA (and their siblings).

Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.

OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role. DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin. RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10-10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10-11; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis). CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.

Anticollagen type II antibodies are associated with an acute onset rheumatoid arthritis phenotype and prognosticate lower degree of inflammation during 5†years follow-up.

OBJECTIVE: Antifibrillar collagen type II (anti-CII) antibody-positive patients with rheumatoid arthritis (RA) have early but not late signs of increased inflammation and joint erosions. We wanted to replicate this in a large RA cohort, and to relate to human leukocyte antigen (HLA)-DRB1* alleles. METHODS: Anti-CII and anti-cyclic citrullinated peptide (CCP)2 were measured at baseline in 773 patients with RA from the Swedish Epidemiological Investigation in Rheumatoid Arthritis (EIRA) study with clinical follow-up data from the Swedish Rheumatology Quality Register (SRQ) registry, and 1476 with HLA-DRB1* information. Comparisons were done concerning C reactive protein (CRP), erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), Disease Activity Score encompassing 28 joints based on ESR (DAS28), DAS28CRP, pain-Visual Analogue Scale (VAS), global-VAS and Health Assessment Questionnaire Score (HAQ) at eight occasions during 5 years, and association with HLA-DRB1* alleles. RESULTS: Anti-CII associated with elevated CRP, ESR, SJC, DAS28 and DAS28CRP at diagnosis and up to 6 months, whereas anti-CCP2 associated with SJC and DAS28 from 6 months to 5 years, but not earlier. The anti-CII-associated phenotype was strong, and predominated in anti-CII/anti-CCP2 double-positive patients. Anti-CII was associated with improvements in CRP, ESR, SJC, TJC and DAS28, whereas anti-CCP2 was associated with deteriorations in SJC and DAS28 over time. Anti-CII-positive patients achieved European League Against Rheumatism good or moderate response more often than negative patients. Anti-CII was positively associated with HLA-DRB1*01 and HLA-DRB1*03, with significant interaction, and double-positive individuals had >14 times higher mean anti-CII levels than HLA double negatives. Whereas smoking was associated with elevated anti-CCP2 levels, smokers had lower anti-CII levels. CONCLUSIONS: Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse to the clinical, genetic and smoking associations described for anticitrullinated protein peptide autoantibodies. Although not diagnostically useful, early anti-CII determinations predict favourable inflammatory outcome in RA.

Similar familial risk in multiple sclerosis subgroups.

BACKGROUND: A subgroup of patients diagnosed with multiple sclerosis (MS) present with no oligoclonal bands (OCB) in the cerebrospinal fluid (CSF). Several studies report different clinical characteristics and genetic associations between the two groups. OBJECTIVE: To investigate whether the OCB negative subgroup has a distinct etiology from band positive MS. METHODS: Using nationwide registers to estimate familial risks, which reflect the genetic contribution of a disease. RESULTS: Odds ratios of MS were similar for relatives to band positive and negative patients. CONCLUSION: From the perspective of familial liability, MS without OCB is etiologically closely related to the dominant subgroup of OCB positive MS.

Age Related Multiple Sclerosis Severity Score: Disability ranked by age.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is obtained by normalising the Expanded Disability Status Scale (EDSS) score for disease duration and has been a valuable tool in cross-sectional studies. OBJECTIVE: To assess whether use of age rather than the inherently ambiguous disease duration was a feasible approach. METHOD: We pooled disability data from three population-based cohorts and developed an Age Related Multiple Sclerosis Severity (ARMSS) score by ranking EDSS scores based on the patient's age at the time of assessment. We established the power to detect a difference between groups afforded by the ARMSS score and assessed its relative consistency over time. RESULTS: The study population included 26058 patients from Sweden ( n = 11846), Canada ( n = 6179) and the United Kingdom ( n = 8033). There was a moderate correlation between EDSS and disease duration ( r = 0.46, 95% confidence interval (CI): 0.45-0.47) and between EDSS and age ( r = 0.44, 95% CI: 0.43-0.45). The ARMSS scores showed comparable power to detect disability differences between groups to the updated and original MSSS. CONCLUSION: Since age is typically unbiased and readily obtained, and the ARMSS and MSSS were comparable, the ARMSS may provide a more versatile tool and could minimise study biases and loss of statistical power caused by inaccurate or missing onset dates.