Patient-reported Outcomes and Clinical Response in Patients with Moderate-to-severe Plaque Psoriasis Treated with Tonsillectomy: A Randomized Controlled Trial.

Psoriasis is a chronic inflammatory skin disease with profound effects on patients' health-related quality of life (HRQoL). Twenty-nine patients with plaque psoriasis and a history of streptococcal-associated psoriasis exacerbations were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and followed for 24 months. Patients were evaluated with the Psoriasis Disability Index, Psoriasis Life Stress Inventory and Psoriasis Area and Severity Index. HRQoL and psoriasis-related stress improved significantly in the tonsillectomy group compared with the control group (p = 0.037 and p = 0.002, respectively), with a mean 50% improvement in HRQoL and a mean 59% improvement in psoriasis-induced stress. Clinical improvement correlated significantly with improved HRQoL (r = 0.297, p = 0.008) and psoriasis-related stress (r = 0.310, p = 0.005). Of the tonsillectomized patients, 87% concluded that the procedure was worthwhile. Tonsillectomy may improve quality of life for selected patients with plaque psoriasis.

HLA-Cw6 homozygosity in plaque psoriasis is associated with streptococcal throat infections and pronounced improvement after tonsillectomy: A prospective case series.

BACKGROUND: Carriage of the HLA-Cw*0602 allele is associated with a particular set of clinical features and treatment responses in psoriasis. Tonsillectomy can improve psoriasis. OBJECTIVES: We sought to evaluate whether HLA-Cw*0602 predicts a favorable outcome after tonsillectomy of patients with psoriasis. METHODS: This prospective case series followed up 28 tonsillectomized patients with plaque psoriasis for 24 months. The Psoriasis Area and Severity Index, Psoriasis Disability Index, and Psoriasis Life Stress Inventory were used for assessment. Tonsils were swabbed for bacteria and patients genotyped for HLA-Cw*0602. RESULTS: After tonsillectomy, HLA-Cw*0602 homozygotes showed significantly more improvement, compared with heterozygous and HLA-Cw*0602-negative patients. Thus, Psoriasis Area and Severity Index score was reduced by 82% in the homozygous patients compared with 42% and 31%, respectively (P < .001), Psoriasis Disability Index score improved by 87% compared with 38% and 41%, respectively (P < .001), and Psoriasis Life Stress Inventory score was 82% reduced compared with 60% and 54%, respectively (P < .001). The homozygotes more often had psoriasis onset associated with a throat infection (P = .007) and an increased frequency of streptococcal throat infections per lifetime (P = .038). LIMITATIONS: Few patients were included and some data were retrospective. CONCLUSIONS: Homozygous HLA-Cw*0602 carriage in plaque psoriasis may predict a favorable outcome after tonsillectomy.

Throat Infections are Associated with Exacerbation in a Substantial Proportion of Patients with Chronic Plaque Psoriasis.

Streptococcal throat infections are known to trigger or exacerbate psoriasis, and several studies support the benefit of tonsillectomy. To evaluate the potential of tonsillectomy as a treatment, we used a retrospective study-specific questionnaire to assess the proportion of psoriasis patients with sore throat-associated psoriasis exacerbations. Our survey sampled 275 psoriasis patients. Of patients with plaque psoriasis, 42% reported sore throat-associated psoriasis exacerbations, and of patients with confirmed streptococcal infections, 72% reported aggravation. Notably, women and patients with early onset psoriasis were more likely to report psoriasis exacerbation after a sore throat (p < 0.001, p = 0.046, respectively). Other psoriasis aggravation factors were more common in patients with sore throat-associated exacerbations (p < 0.01). Of tonsillectomized patients, 49% reported subsequent improvement and had more frequent sore throat-associated aggravation of psoriasis than patients who did not improve after tonsillectomy (p = 0.015). These findings suggest a closer association between sore throats, streptococcal throat infections and plaque psoriasis than reported previously.

Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants.

Exacerbation of chronic psoriasis can be associated with streptococcal throat infections, and T cells that respond to peptide sequences common to streptococcal M proteins and skin keratins have been detected in patients' blood. To our knowledge, we have conducted the first blinded, prospective study to assess the impact of tonsillectomy on psoriasis. Twenty-nine patients with chronic psoriasis and history of exacerbation after sore throat were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and monitored for 2 y clinically and by enumeration of circulating skin homing T cells that respond to short homologous M protein or keratin peptides. Thirteen patients (86%) showed sustained improvement after tonsillectomy ranging from 30 to 90% reduction in disease severity. Furthermore, there was a close correlation between the degree of clinical improvement in individual patients and reduction in the frequency of peptide-reactive skin-homing T cells in their circulation. No corresponding clinical or immunologic changes were observed among the controls. These findings indicate that tonsillectomy may have a beneficial effect on chronic psoriasis because the palatine tonsils generate effector T cells that recognize keratin determinants in the skin.

The anti-microbial peptide LL-37 modulates immune responses in the palatine tonsils where it is exclusively expressed by neutrophils and a subset of dendritic cells.

Antimicrobial peptides are essential elements of epithelial defense against invading micro-organisms. The palatine tonsils are positioned at the entry of the airway and the gut and as such are ideally situated to act as immune sentinels in the pharynx protecting against microbial invasion. Tonsils express a number of antimicrobial peptides including hCAP18/LL-37. Here we clearly define the expression of hCAP18/LL-37 in the tonsils showing unequivocally that hCAP18/LL-37 is mainly expressed by infiltrating neutrophils and follicular CD11c+CD13+HLA-DR+ dendritic cells, rarely by macrophages, and never by the epithelium itself. To explore possible functions for follicle-derived LL-37, we stimulated tonsil mononuclear cells with LL-37 in vitro and observed the secretion of the proinflammatory cytokines CCL5 and CXCL9, expression of IFN-γ and MX-1 and down-regulation of chemokine receptors CCR4 and CCR6 which are involved in tissue-selective T cell trafficking. Taken together, these data illustrate new potential immunoregulatory functions for hCAP18/LL-37 in the tonsils.

Psoriasis--as an autoimmune disease caused by molecular mimicry.

Psoriasis is strongly associated with streptococcal throat infection, and patients have increased occurrence of such infections. Psoriatic lesional T cells are oligoclonal, and T cells recognizing determinants common to streptococcal M-protein and keratin have been detected in patients' blood. We propose that CD8(+) T cells in psoriatic epidermis respond mainly to such determinants, whereas CD4(+) T cells in the dermis preferentially recognize determinants on the streptococcal peptidoglycan that might itself act as an adjuvant. The streptococcal association might reflect the concurrence of superantigen production promoting skin-homing of tonsil T cells, M-protein mimicking keratin determinants, and adjuvant effects of the peptidoglycan. Accordingly, improvement of psoriasis after tonsillectomy should be associated with fewer T cells that recognize keratin and streptococcal determinants.

A long-term follow-up of allergic diseases in Iceland.

INTRODUCTION: Allergic disorders are an increasing health problem in many countries, in particular among children. We have evaluated the prevalence and manifestations of allergy in a cohort of young Icelanders for more than two decades. Variations in the epidemiology and clinical expression of allergy in different communities may help to identify etiological factors contributing to these disorders. METHODS: A cohort of 179 children has been monitored for allergic manifestations for two decades, at the ages of two, four, eight, and 15 years, and most recently at the age of 21 years involving 120 of the participants. RESULTS: Cumulative prevalences of 40%, 45%, and 29% have been observed, respectively, for rhinoconjunctivitis, eczema, and asthma during the study period. None had developed rhinoconjunctivitis at the age of about 2 years, but the point prevalence gradually increased to 33% at the age of 21 years. Conversely, the prevalence of eczema was 31% at the age of 2 years, but gradually declined to 8% at the age of 21 years. The prevalence of asthma peaked at 28% at the age of 4 years, but declined thereafter and has remained stable at about 13% from the age of eight to 21 years. DISCUSSION: The prevalence of allergic diseases is high in Iceland among children and young individuals. Asthma and atopic eczema are very common in childhood, but decreases with age while the prevalence of rhinoconjunctivitis increases markedly. The very high and increasing prevalence of rhinoconjunctivitis among 15- to 21-year-old individuals is noteworthy.

Mannan binding lectin as an adjunct to risk assessment for myocardial infarction in individuals with enhanced risk.

Inflammation can predispose to myocardial infarction (MI), and mannan binding lectin (MBL) promotes phagocytic clearance of inflammatory agents, but the predictive value of MBL levels for MI is not known. MBL was analyzed in subgroups of the population-based Reykjavik study, a cohort of 19,381 participants recruited from 1967. MBL levels were very stable over time (self correlation: 0.86). In a cross-sectional group from the original cohort (n = 987), high MBL (>1,000 microg/L) was associated with a greatly lowered odds ratio for MI (0.64, P < 0.001). To verify this finding, a nested case control sample (n = 1,309) was randomly selected from the cohort. High MBL at recruitment was also associated with decreased MI risk in this follow-up group, but to a lesser extent and not significant for the whole group, smokers, or hypertensive individuals. However, high MBL was as in the cross-sectional group, associated with greatly decreased MI risk in diabetic (P = 0.02) or hypercholesterolemic individuals (P = 0.004). This also applied to raised erythrocyte sedimentation rate (P = 0.007). Diabetic patients with high MBL did not have a higher MI risk than nondiabetic individuals. Our findings indicate that high MBL may predict decreased likelihood of MI, particularly in diabetics, and are consistent with the possibility that MBL may promote clearance of atherogenic agents.

Effect of rheumatoid factor on mortality and coronary heart disease.

OBJECTIVE: An association between rheumatoid factor (RF) and increased mortality has been described in individuals with rheumatoid arthritis. The objective of this study was to determine the effect of RF on mortality and coronary heart disease (CHD) in the general population. SUBJECTS: were participants in a population-based study focused on cardiovascular disease who attended for a study visit during the years 1974-84. RF was measured and information obtained on cardiovascular risk factors, joint symptoms and erythrocyte sedimentation rate (ESR). The subjects were followed with respect to mortality and incident CHD through 2005. Adjusted comparison of overall survival and CHD event-free survival in RF-positive versus RF-negative subjects was performed using Cox proportional hazards regression models. RESULTS: Of 11 872 subjects, 140 had positive RF. At baseline RF was associated with diabetes mellitus and smoking and inversely associated with serum cholesterol. RF-positive subjects had increased all-cause mortality (HR 1.47, 95% CI 1.19 to 1.80) and cardiovascular mortality (HR 1.57, 95% CI 1.15 to 2.14) after adjusting for age and sex. Further adjustment for cardiovascular risk factors and ESR only modestly attenuated this effect. An increase in CHD among the RF-positive subjects did not reach statistical significance (HR 1.32, 95% CI 0.96 to 1.81, adjusted for age and sex). Subjects with RF but without joint symptoms also had increased overall mortality and cardiovascular mortality (HR for overall mortality 1.33, 95% CI 1.01 to 1.74, after adjustment). CONCLUSION: In a general population cohort, RF was associated with increased all-cause mortality and cardiovascular mortality after adjustment for cardiovascular risk factors, even in subjects without joint symptoms.

Low serum mannose-binding lectin level increases the risk of death due to pneumococcal infection.

BACKGROUND: Previous studies have shown associations between low mannose-binding lectin (MBL) level or variant MBL2 genotype and sepsis susceptibility. However, MBL deficiency has not been rigorously defined, and associations with sepsis outcomes have not been subjected to multivariable analysis. METHODS: We reanalyzed MBL results in a large cohort with use of individual data from 4 studies involving a total of 1642 healthy control subjects and systematically defined a reliable deficiency cutoff. Subsequently, data were reassessed to extend previous MBL and sepsis associations, with adjustment for known outcome predictors. We reanalyzed individual data from 675 patients from 5 adult studies and 1 pediatric study of MBL and severe bacterial infection. RESULTS: XA/O and O/O MBL2 genotypes had the lowest median MBL concentrations. Receiver operating characteristic analysis revealed that an MBL cutoff value of 0.5 microg/mL was a reliable predictor of low-producing MBL2 genotypes (sensitivity, 82%; specificity, 82%; negative predictive value, 98%). MBL deficiency was associated with increased likelihood of death among patients with severe bacterial infection (odds ratio, 2.11; 95% confidence interval, 1.30-3.43). In intensive care unit-based studies, there was a trend toward increased risk of death among MBL-deficient patients (odds ratio, 1.58; 95% confidence interval, 0.90-2.77) after adjustment for Acute Physiology and Chronic Health Enquiry II score. The risk of death was increased among MBL-deficient patients with Streptococcus pneumoniae infection (odds ratio, 5.62; 95% confidence interval, 1.27-24.92) after adjustment for bacteremia, comorbidities, and age. CONCLUSIONS: We defined a serum level for MBL deficiency that can be used with confidence in future studies of MBL disease associations. The risk of death was increased among MBL-deficient patients with severe pneumococcal infection, highlighting the pathogenic significance of this innate immune defence protein.

The genetic basis of psoriasis.

For a complex genetic disease, psoriasis has a high penetration within families and a concordance rate of up to 70% in identical twins. Despite this and the endeavors of many research groups for more than a decade, no susceptibility allele has so far been unequivocally identified, although about 20 genetic loci associated with psoriasis have been reported from linkage-based studies. Moreover, only 1 of these linkage-based loci, PSORS1, that includes the HLA-C gene on chromosome 6p21, has been universally confirmed. Very recent data strongly indicate that HLA-Cw*0602 is the susceptibility allele in this locus, a finding that is consistent with the notion that the pathogenesis of psoriasis involves autoantigen recognition by epidermal CD8+ T lymphocytes. Several candidate genes in some of the other 7 PSORS designated loci are currently being evaluated. The relative lack of success in elucidating the genetic basis of psoriasis highlights the formidable challenge of dissecting the genetic basis of diseases with a complex mode of inheritance.

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations.

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.

Distinct clinical differences between HLA-Cw*0602 positive and negative psoriasis patients--an analysis of 1019 HLA-C- and HLA-B-typed patients.

A major susceptibility gene for psoriasis is located in the major histocompatibility complex class I region on chromosome 6 very close to the HLA-Cw6 gene. We collected a cohort of 1,019 patients with chronic plaque psoriasis. The patients were typed for HLA-C and HLA-B. A total of 654 (64.2%) were HLA-Cw*0602 positive but 365 (35.8%) carried other HLA-C alleles. We confirmed that HLA-Cw*0602 positive patients have younger age of onset (17.5 vs 24.3 years, P<10(-10)), higher incidence of guttate and the eruptive type of psoriasis (P<0.0001), more frequent exacerbations with throat infections (P=0.01), higher incidence of the Koebner's phenomenon (P=0.01), and more extensive disease (P=0.03). A striking new finding was a diverging pattern of disease severity in HLA-Cw*0602 positive and negative patients depending on the age of onset of the disease (P=0.0006). HLA-Cw*0602 positive women also had more frequent remissions during pregnancy (P<0.0001). All types of nail changes were, however, more common in the Cw*0602 negative patients (P=0.003) and they more often had multiple types of nail lesions (P<0.0001). The three ancestral haplotypes of Cw*0602 all conferred an increase in odds ratio but showed no difference in any of the clinical features studied. Our findings indicate that the genetic factor on chromosome 6 has a strong influence on the phenotype of the disease, and underline that differences in clinical features of psoriasis may be to a large extent genetically determined.

Genetics of psoriasis in Iceland: evidence for linkage of subphenotypes to distinct Loci.

Psoriasis is a chronic inflammatory skin disease with overlapping subphenotypes. It has a strong complex genetic component, but has been problematic to identifying significant loci. We evaluated 1000 patients with chronic plaque psoriasis and documented several subphenotypes. Here we report results of genome-wide linkage scans for psoriasis genes in 238 Icelandic families with 874 patients. MHC linkage was confirmed with LOD score of 10.9. When the entire cohort was analyzed, two other loci with LOD scores of 2.5 and 1.5 were observed on 16q and 4q, respectively. Stratification into subphenotypes revealed additional loci with LOD scores exceeding or approaching significance. A LOD score of 5.7 appeared on 16q in PsA patients with analysis conditioned on parental inheritance. A LOD score of 3.6 on 4q was detected when disease occurred at or older than 17 y, our median cohort age. This locus was defined by a marker near one reportedly displaying significant linkage in a Chinese psoriasis population and near suggestive linkage in a Caucasian population. A LOD of 3.0 was observed on 10q when disease onset occurred in the scalp. Furthermore, clinical stratification either revealed or increased LOD scores when compared to unstratified analysis and some coincided with previous reports.

Narrowband-UVB irradiation decreases the production of pro-inflammatory cytokines by stimulated T cells.

Narrow-band ultraviolet B (UVB) phototherapy is an effective treatment for psoriasis. Owing to its limited penetration, the direct effects of UVB are mostly restricted to cells residing in the epidermis and papillary dermis, and are associated with epidermal depletion of Langerhans' cells (LC) and T cells. It has been argued that the depletion of the skin-resident T-cell population may be due to a combination of UVB-induced apoptosis and decreased recruitment from the blood due to lower expression of the required adhesion and homing molecules. We have previously demonstrated that UVB treatment can alter the expression of adhesion molecules by blood lymphocytes, and as these can be influenced by cytokines, the aim of this study was to investigate whether UVB irradiation can also influence the cytokine production of circulating T cells. Four patients with active chronic plaque psoriasis were treated daily with narrow-band 312 nm UVB irradiation and blood samples obtained before treatment and weekly thereafter for 2 weeks. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with a streptococcal superantigen or a conventional streptococcal antigen preparation, and cell culture supernatants were assayed for various cytokines. When stimulated with the superantigen, PBMCs from UVB-treated psoriasis patients secreted greater amounts of the anti-inflammatory cytokine IL-10, and showed markedly decreased production of IL-1beta, IL-2, IL-5 and IL-6 compared to the pre-treatment values; the production of IFN-gamma, IL-8 and IL-12p70 were also decreased but did not reach statistical significance. Thus, the combination of UVB-induced apoptosis, increased secretion of anti-inflammatory cytokines and decreased trafficking to the skin may help to explain the beneficial effects of UVB treatment on psoriasis and why disease remission can sometimes be sustained for a prolonged period.

HLA-Cw6-positive and HLA-Cw6-negative patients with Psoriasis vulgaris have distinct clinical features.

Psoriasis is associated with HLA-Cw6, and Caucasians who carry this allele have about a 10-fold increased risk of developing psoriasis. We have HLA-C typed 369 patients with familial psoriasis and compared the clinical features of the patients carrying HLA-Cw6 against those carrying other HLA-C types. Some striking clinical differences were observed between the two groups. Patients who are Cw6 positive had a lower age at onset (p=3x10(-7)). Cw6-positive women had an earlier disease onset than Cw6-positive men (p =0.02), but such a difference was not observed for the Cw6-negative patients. The guttate-type onset of psoriasis was mostly confined to this group (p=2x10(-4)) and persistent disseminated guttate-like papules were also predominantly observed in the Cw6-positive patients (p <10(-)4). The Cw6-positive patients also had more extensive plaques on their arms, legs, and trunk (p =0.001), more severe disease (p =0.003), higher incidence of the Koebner's phenomenon (p =0.005), reported more often that their psoriasis got worse during or after throat infections (p =0.02), and more often a favorable response to sunlight (p =0.008) In contrast, dystrophic nail changes were more common in the Cw6-negative patients (p =0.002) and also psoriatic arthritis, although this was not significant (p =0.135). It is concluded that patients with psoriasis have different clinical features depending on whether they are HLA-Cw6 positive or negative.

Generation of heterohybridomas secreting human immunoglobulins; pokeweed mitogen prestimulation is highly effective but phytohemagglutinin drives most B cells into apoptosis.

Human monoclonal antibodies have commonly been generated by forming hybridomas of stable lymphoblastoid cell lines and Epstein-Barr virus (EBV)-transformed human B cells that have been exposed to phytohaemagglutin (PHA)-stimulated T cells. However, this technique has predominantly given rise to IgM- but very rarely IgG- or IgA-producing clones. We now report that, regardless of prior EBV infection, pokeweed mitogen (PWM) stimulation of human peripheral blood mononuclear cells (PBMCs) generated much higher numbers of IgM-, IgA- and IgG-producing B cells than did stimulation with PHA. Fusion of PWM-stimulated PBMCs with a mouse myeloma cell line also gave rise to 7- to 12-fold higher numbers of IgG- and IgA-producing heterohybridomas than PBMCs that were prestimulated with PHA. Judged by Annexin V staining, stimulation with PHA induced a very high rate of B cell apoptosis within 24 h, whereas, even after 7 days, PWM stimulation only induced marginal B cell apoptosis. This should explain why PHA is much inferior to PWM in stimulating immunoglobulin (Ig) production in vitro and in generating immunoglobulin-producing human B cell hybridomas. It is concluded that PWM stimulation may greatly facilitate the generation of human monoclonal antibodies of all isotypes.

Defective immunoglobulin A (IgA) glycosylation and IgA deposits in patients with IgA nephropathy.

Defective glycosylation and immune complex (IC) formation may be of primary importance in immunoglobulin A nephropathy (IgAN) pathogenesis. The aim of this study was to determine whether defective IgA1 glycosylation might support renal deposition of IgA and disease activity. IgA was isolated from the serum of 44 IgAN patients and 46 controls and glycosylation analysed by ELISA using glycan-specific lectins. IgA was measured by immunodiffusion and immune complexes by ELISA. IgA subclasses in IC deposits in kidney glomeruli were identified by immunohistochemical methods. A significant increase in N-acetylgalactosamine (GalNAc) in terminal position (p = 0.02) observed in some of the IgAN patients, became more pronounced when sialic acid was removed from IgA1, indicating enhanced expression of α-2,6-sialyltransferase in patients compared with controls (p < 0.0001). Patients with defective galactosylation had lower serum IgA than other IgAN patients (p = 0.003). IgAN patients with both IgA1 and IgA2 glomerular deposits (21.7%) had increased GalNAc in terminal position (p = 0.003). Taken together, our results show that increased IgA glycosylation in IgAN associates with low levels of IgA, concomitant IgA1 and IgA2 glomerular deposits and poor clinical outcome.

Psoriatic arthritis and onycholysis -- results from the cross-sectional Reykjavik psoriatic arthritis study.

OBJECTIVE: To measure the associations between subtypes of nail changes and psoriatic arthritis (PsA) among patients with psoriasis. METHODS: Patients age 18 years and older with active psoriasis were examined for skin and nail changes and asked if they had been diagnosed with PsA. Patients with arthritis were invited for a separate study 1-6 years after their initial visit. Univariate and multivariate analyses were used to test the strength of associations between subtypes of nail changes and arthritis. RESULTS: Of 1116 patients with psoriasis, 37% (95% CI 34%-40%) had nail changes. Age, any nail change, onycholysis, and pitting were each associated with PsA on univariate analysis. Multivariate analysis showed that onycholysis was the only type of nail change independently associated with PsA (OR 2.05, p < 0.001). Nail changes persisted and had increased in prevalence at the followup examination at a mean of 3.8 (median 4 yrs, interquartile range 3-4) years later. Previously reported associations between psoriasis location and arthritis were not seen in this dataset. CONCLUSION: PsA is associated with onycholysis. Associations with pitting and subungual hyperkeratosis were not statistically significant. Subtypes of nail changes should be analyzed separately in future studies of PsA.

Mannan Binding Lectin (MBL) genotypes coding for high MBL serum levels are associated with rheumatoid factor negative rheumatoid arthritis in never smokers.

INTRODUCTION: Previous studies have provided inconsistent results on whether variants in the MBL2 gene, coding for the complement-activating mannan-binding lectin (MBL) protein, associate with rheumatoid arthritis (RA). We re-evaluated this in context of the main environmental and genetic risk factors (smoking, HLA-DRB1 'shared epitope' (SE), PTPN22*620W), which predispose to rheumatoid factor (RF) and/or anti-citrullinated-protein antibody (ACPA)-positive RA. METHODS: In this population-based EIRA study, rheumatoid factor (RF), ACPA, smoking, SE and PTPN22*620W status was determined in incident RA cases and matched controls. MBL-high (n = 1330) and MBL-low (n = 1257) genotypes predicting MBL levels were constructed from four promoter and exon-1 polymorphisms in the MBL2 gene. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated by logistic regression. In extended families (n = 316), previously reported data were re-analyzed, considering RF and smoking. RESULTS: MBL-high genotypes tended to be associated with RF-negative (OR = 1.20, 95% CI 0.96-1.51) but not RF-positive (OR = 1.00, 95% CI 0.83-1.20) RA. Results divided by ACPA status did not differ. When stratified for smoking, MBL-high genotype was strongly associated with RF-negative RA in never smokers (OR = 1.82, 95% CI 1.24-2.69) but not in ever smokers (OR = 0.96, 95% CI 0.73-1.30). In never smokers, the association was observed in both the RF-negative/ACPA-negative (OR = 1.67, 95% CI 1.10-2.55) and RF-negative/ACPA-positive subgroups (OR = 3.07, 95% CI 1.37-6.89), and remained on an SE/PTPN22*620W negative background. In the extended families, the reported association between high MBL and RA was in fact confined to never smokers. CONCLUSIONS: High MBL may predispose to RF-negative RA but only in individuals who have never smoked. This illustrates the importance of phenotypic subgrouping in genetic studies.