Evaluation of an individually tailored smoking-cessation intervention for patients with rheumatoid arthritis in an outpatient clinic.

OBJECTIVE: The aim of this study was to evaluate an individually tailored smoking-cessation intervention delivered in rheumatology care and compare the characteristics of patients who quit smoking with those who did not. METHOD: This was an open single-group prospective intervention study over 24 months, with assessments at baseline and at 6, 12, 18, and 24 months. Current smokers with rheumatoid arthritis (RA) were invited to a smoking-cessation programme including behavioural change support, with or without pharmacotherapy. Data on disease activity, medical treatment, and patient-reported outcomes were retrieved from the Swedish Rheumatology Quality Register. The primary outcome was the proportion of patients at month 24 who reported having quit smoking with self-reported 7 day smoking abstinence. RESULTS: In total, 99 patients participated in the study. Median age was 58 years (interquartile range 50-64); 69% were female and 88% rheumatoid factor and/or anti-cyclic citrullinated peptide positive. At 24 months, 21% of the patients had quit smoking. At 6, 12, and 18 months, 12%, 12%, and 14% of patients, respectively, had quit smoking. For patients still smoking at 24 months, the median number of cigarettes per day was significantly reduced from 12 to 6 (p ≤ 0.001). Among patients who had quit smoking at 24 months, a smaller proportion reported anxiety at baseline compared to those still smoking (28% vs 58%, p = 0.02). CONCLUSION: A smoking-cessation intervention including behavioural change support with or without pharmacotherapy can be helpful for a substantial number of RA patients. Anxiety is associated with lower smoking-cessation success rates.

Social stressors and risk of rheumatoid arthritis and their relationship to known modifiable risk factors: results from the Swedish EIRA study.

Objectives: To investigate whether low social support or low decision latitude at work correlate with risk of rheumatoid arthritis (RA), and whether and how those factors are associated with known modifiable risk factors for RA.Method: The Swedish population-based EIRA study included, from 1996 to 2015, 3724 incident RA cases and 5935 controls, matched for age, gender, and residential area. Participants filled in detailed questionnaires at diagnosis. Using logistic regression, we investigated whether low social support and low decision latitude at work were associated with RA risk, and whether and how these exposures are associated with known modifiable risk factors for RA.Results: Low decision latitude at work was associated with RA risk in unadjusted analyses [odd ratio (OR) = 1.52, 95% confidence interval (CI) = 1.20-1.94], but this association was weakened after adjustment for known RA risk factors (adjusted OR = 1.24, 95% CI = 0.93-1.63). Low social support was not associated with RA risk (unadjusted OR = 1.05, 95% CI = 0.95-1.15). Cases reporting low decision latitude were more often smokers (OR = 2.05, 95% CI = 1.33-3.16), without university degrees (OR = 8.23, 95% CI = 5.13-13.22), and more often female (OR = 2.52, 95% CI = 1.66-3.81), with a similar pattern among controls. Cases reporting low social support were more often men (OR = 1.60, 95% CI = 1.40-1.83), smokers (OR = 1.46, 95% CI = 1.26-1.70), obese (OR = 1.29, 95% CI = 1.09-1.54), physically inactive (OR = 2.78, 95% CI = 1.98-3.90), and without university degrees (OR = 2.04, 95% CI = 1.77-2.36), with a similar pattern among controls.Conclusion: Low decision latitude coexisted with several known environmental/social risk factors for RA, together defining groups of individuals at increased risk of RA. These risk factors should be viewed in context when testing actions to diminish RA risk in prospective studies.

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis.

The current review uses rheumatoid arthritis (RA) as a prominent example for how studies on the interplay between environmental and genetic factors in defined subsets of a disease can be used to formulate aetiological hypotheses that subsequently can be tested for causality using molecular and functional studies. Major discussed findings are that exposures to airways from many different noxious agents including cigarette smoke, silica dust and more interact with major susceptibility genes, mainly HLA-DR genetic variants in triggering antigen-specific immune reactions specific for RA. We also discuss how several other environmental and lifestyle factors, including microbial, neural and metabolic factors, can influence risk for RA in ways that are different in different subsets of RA.The description of these processes in RA provides the best example so far in any immune-mediated disease of how triggering of immunity at one anatomical site in the context of known environmental and genetic factors subsequently can lead to symptoms that precede the classical inflammatory disease symptoms and later contribute also to the classical RA joint inflammation. The findings referred to in the review have led to a change of paradigms for very early therapy and prevention of RA and to efforts towards what we have named 'personalized prevention'. We believe that the progress described here for RA will be of relevance for research and practice also in other immune-mediated diseases.

Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis: results from the SWEFOT trial population.

Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 µg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 µg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 < 2.6). Baseline characteristics were assessed as potential predictors of sIFX < 0.2 µg/mL or ADA positivity, using logistic regression. Results: Categorization of sIFX levels into < 0.2, 0.2-2.9, 3.0-7.0, and > 7.0 µg/mL showed a dose-response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX < 0.2 µg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX > 0.2 µg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up. Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX < 0.2 µg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders. Trial registration: SWEFOT NCT00764725 ( https://clinicaltrials.gov/ct2/show/NCT00764725 ).

Smoking and response to rituximab in rheumatoid arthritis: results from an international European collaboration.

OBJECTIVES: To investigate whether smoking habits predict response to rituximab (RTX) in rheumatoid arthritis (RA). METHOD: We included patients from the CERERRA international cohort receiving the first treatment cycle with available smoking status (n = 2481, smokers n = 528, non-current smokers n = 1953) and at least one follow-up visit. Outcome measures were change in Disease Activity Score based on 28-joint count (ΔDAS28) and European League Against Rheumatism (EULAR) good response at 6 months, with non-current smokers as the referent group. RESULTS: Compared with non-smokers at baseline, smokers were more often rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) positive and males, had shorter disease duration, lower DAS28 and Health Assessment Questionnaire (HAQ) score, a higher number of prior biological disease-modifying anti-rheumatic drugs, and were more likely to receive concomitant conventional synthetic disease-modifying anti-rheumatic drug (csDMARDs). Disease activity had decreased less in smokers at 6 months (ΔDAS28 = 1.5 vs 1.7, p = 0.006), although the difference was no longer significant after correction for baseline DAS28 (p = 0.41). EULAR good response rates did not differ between smokers and non-smokers overall or stratified by RF/ACPA status, although smokers had lower good response rates among seronegative patients (ACPA-negative: 6% vs 14%, RF-negative: 11% vs 18%). Smoking did not predict good response [odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.76-1.41], while ACPA, DAS28, HAQ, and concomitant csDMARDs were significant predictors for good response. However, when stratified by country, smokers were less likely to achieve good response in Sweden (unadjusted OR = 0.24, 95% CI = 0.07-0.89), and a trend was seen in the Czech Republic (OR = 0.45, 95% CI = 0.16-1.02). CONCLUSION: In this large, observational, multinational RA cohort, smokers starting RTX differed from non-smokers by having shorter disease duration and lower disease activity, but more previous treatments. The overall results do not support smoking as an important predictor for response to RTX in patients with RA.

Mannan-binding lectin may facilitate the clearance of circulating immune complexes--implications from a study on C2-deficient individuals.

Deficiency of both mannan-binding lectin (MBL) and complement components C4 and C2 has been associated with increased risk of systemic lupus erythematosus (SLE). MBL can activate the complement system either through C4 and C2 or directly through C3. Circulating immune complexes (CICs) are believed to play a pathogenic role in SLE and MBL has been shown to bind certain forms of immunoglobulins, including IgM, IgG and IgA. Thus, MBL might promote CIC clearance. In order to evaluate this, six individuals with non-functional classical pathway due to the rare homozygous C2 deficiency were chosen, as the classical pathway is known to have a fundamental role in CIC clearance. Four of the six C2-deficient individuals had SLE, two of whom also had MBL deficiency. MBL serum levels and genotypes were compared with the serum levels of CICs, as measured by their content of kappa, lambda, IgM, IgA, IgG and C3 opsonization. The C2-deficient individuals had higher serum levels of CICs than 16 healthy controls (P < 0.0001). Furthermore, an inverse association was observed between MBL and CIC levels in the C2-deficient individuals, which was strongest for IgM-CICs (r = - 0.84, P = 0.037). Moreover, C3 opsonization of the CICs correlated positively with MBL levels in the C2-deficient individuals (r = 0.89, P = 0.017). In conclusion, individuals with C2 deficiency have increased levels of CICs and MBL may facilitate their clearance. Defective CIC clearance might partly explain the increased risk of SLE associated with low MBL.

Mannan-binding lectin and complement C4A in Icelandic multicase families with systemic lupus erythematosus.

OBJECTIVE: To determine whether low mannan-binding lectin (MBL) and C4A null alleles (C4AQ0) are associated with systemic lupus erythematosus (SLE) in multicase families with SLE. METHODS: Low MBL level was determined by measuring serum levels and by genotyping for mutant structural (B/C/D, designated as 0) and promoter (LX) alleles (by real-time polymerase chain reaction). C4AQ0 was detected by protein electrophoresis and corroborated with haplotype and genotype analysis. In nine Icelandic families, 24 patients with SLE were compared with 83 first-degree and 23 second-degree relatives without SLE. Twenty four unrelated family members and a population group of 330 Icelanders served as controls. RESULTS: Overall, the frequency of low MBL genotypes (0/0, LX/0 and wild-type/0) tended to be higher in patients with SLE than in their first-degree and second-degree relatives (p = 0.06), but the frequency was similar in the families and in the controls (p = 0.6). The frequency of C4AQ0 was, however, increased in patients and their relatives compared with that in the controls (p = 0.04). The combination of low MBL genotypes and C4AQ0 was found more often in the patients than in their relatives (p = 0.03) and controls (p = 0.02). However, low MBL level was observed only in patients and first-degree relatives in five of the nine multicase families. In these five families, patients with SLE had low MBL genotypes more often (64%) than their first-degree (38%) and second-degree (0%) relatives (p = 0.001), and the patients with SLE also had, accordingly, lower MBL levels than their relatives (p = 0.001). CONCLUSIONS: These findings indicate that low MBL levels can predispose people to SLE and highlight the genetic heterogeneity of this disease.

The potential role of mannan-binding lectin in the clearance of self-components including immune complexes.

Mannan-binding lectin (MBL) is a pattern recognition receptor in the innate immune system. It recognizes certain sugar residues arranged in a pattern that enables MBL to bind with sufficient strength. Such sugar patterns are common on the surface of many microorganisms, and MBL has therefore been considered to be an agent that can discriminate between self and nonself. There is, however, increasing evidence supporting that MBL, like many membrane-bound C-type lectin-like receptors, also helps to dispose of various outworn or abnormal body components. Most self-components are protected with sialic acid or galactose that disrupt the pattern of the sugars that MBL can bind, but MBL may be significantly involved in the elimination of self-components that have lost these protective terminal residues. The role of MBL in the clearance of invading pathogens has previously been thoroughly reviewed. Here, we review some findings that support the notion that MBL may contribute to noninflammatory removal of immune complexes and abnormal cells by the reticuloendothelial system. Defects in this clearance mechanism may cause an accumulation of potentially dangerous self-components, thereby increasing the likelihood of chronic inflammation and autoimmunity.

Human plasma-derived mannose-binding lectin: a phase I safety and pharmacokinetic study.

Mannose-binding lectin (MBL) is an important component of innate immunity that can bind to certain sugar residues on the surface of many types of pathogenic micro-organisms. On binding, MBL generates opsonic activity mainly through activation of the complement system. Genetically determined MBL deficiency is very common and can be associated with increased susceptibility to a variety of infections, especially in children and immunosuppressed individuals. The potential benefits of MBL reconstitution therapy therefore need to be evaluated. We have carried out a phase I safety and pharmacokinetic study on 20 MBL-deficient healthy adult volunteers. The MBL was prepared from plasma of nonremunerated, voluntary Danish donors tested and found negative for hepatitis B surface antigen, antibodies to human immunodeficiency virus (HIV) and hepatitis C virus. Each volunteer received a total of 18 mg of MBL in three 6 mg doses given intravenously, once weekly over a period of 3 weeks. The volunteers were closely monitored at the University Hospital in Reykjavik for 8 h after each infusion and daily thereafter for 5 days after each infusion. No adverse clinical or laboratory changes were observed in any of the 20 participants, and frequent measurements did not reveal any signs of infusion-associated complement activation. No antibodies to MBL, HIV or hepatitis viruses were observed 24 weeks after the last infusion. Serum MBL levels increased up to normal levels (1200-4500 ng/ml) immediately after each infusion, but the half-life of the infused MBL was highly variable, ranging from 18 to 115 h (mean 69.6). It is concluded that infusion of purified MBL as prepared by Statens Serum Institut (SSI) is safe. However, adults have to be given at least 6 mg twice or thrice weekly for maintaining protective MBL levels assumed to be about 1000 ng/ml.

Low mannose binding lectin predicts poor prognosis in patients with early rheumatoid arthritis. A prospective study.

OBJECTIVE: To determine whether low mannose binding lectin (MBL) is associated with poor prognosis in rheumatoid arthritis (RA) and whether patients with RA have increased frequency of MBL deficiency. METHODS: Patients with recent onset symmetric polyarthritis (< 1 year, median 3 mo) were recruited if they had not been treated longer than 2 weeks with disease modifying drugs. They were reevaluated after 6 months and their disease activity and progression were correlated with their MBL concentration, rheumatoid factor (RF) isotypes, and C-reactive protein (CRP). Sixty-three female patients with advanced RA were also analyzed. RESULTS: Sixty-five patients with early arthritis fulfilled American College of Rheumatology criteria for RA and 52 were followed for 6 months or longer. Low MBL was associated with raised RF, IgA RF in particular (p = 0.02). and also with a combined elevation of IgM and IgA RF (p = 0.035). Patients with low MBL (lowest 25th percentile) showed less improvement after 6 months of treatment than patients in the highest MBL quartile. This applied to the Thompson joint score (p = 0.03) and grip strength (p = 0.004). Low MBL was also significantly associated with radiological joint erosions at recruitment and at 6 month followup (p = 0.039); and the group with advanced RA also showed a significant association between low MBL concentration and radiological damage (p = 0.036). However. neither patient group had increased frequency of MBL deficiency compared to healthy controls. CONCLUSION: Low MBL predicts poor prognosis in patients with early RA.