Meliha C Kapetanovic

Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register

OBJECTIVES To study treatment response rates of RA patients undergoing second- and third-line anti-TNF therapy and to identify baseline predictors of response to second-line treatment. METHODS RA patients monitored in a prospective, observational study, having switched anti-TNF therapy once (first-time switchers, n = 337) or twice (second-time switchers, n = 36)--i.e. following failures with one antibody- and one receptor-type agent--between March 1999 and December 2006, were studied. Treatment responses at 3 months were assessed by the ACR and European League Against Rheumatism (EULAR) response criteria. Predictive potentials for response to second-line treatment of demographics, baseline disease activity measures, disease and treatment characteristics were analysed using logistic regression. RESULTS ACR20 response was met by 51% of first-time and 35% of second-time switchers. Corresponding ACR50 rates were 27 and 18%; EULAR overall rates (EULAR good or moderate response) 71 and 58%; EULAR good rates 25 and 9% and 28-joint disease activity score (DAS28) remission rates 16 and 6%. Identified baseline predictors of response to second-line treatment were lower age and HAQ scores, elevated DAS28 values and having ceased the former anti-TNF treatment due to adverse events rather than inefficacy. No variable was predictive for all examined response criteria. CONCLUSIONS Response rates of first-time anti-TNF switchers are somewhat below those of anti-TNF naïve RA patients, while the markedly inferior response rates of second-time switchers suggest other therapeutic options to be considered in this situation. Identified baseline predictors of response may be useful indicators to second-line anti-TNF therapy, but vary depending on the response criteria set studied.

Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register

OBJECTIVE To identify factors predicting response to first TNF blocking treatment course in patients with established RA with a special focus on gender differences. METHODS Patients with active RA initiating their first treatment course of TNF-blocking therapy were enrolled. The study period was March 1999 through September 2006. The prospective protocol included information on demographics, clinical characteristics of patients and response measures. Fulfilment of ACR 50-70% improvement and European League Against Rheumatism (EULAR) good response or remission [28-joint disease activity score (DAS28) <2.6] at 3 months were chosen as primary outcome measures. Potential predictors of responses were identified using multivariate binary logistic regression models. RESULTS In total, 1565 patients were included in the study. Gender did not influence treatment response. Consistently, concomitant methotrexate (MTX) was significantly associated with EULAR remission, EULAR good response, ACR50 response and ACR70 response with odds ratios (ORs) 1.97, 2.13, 2.10 and 1.75, respectively. Concurrent treatment with other DMARDs was also significantly associated with EULAR remission, EULAR good response and ACR50 response (OR: 1.96, 2.24 and 1.94, respectively). Likewise, low HAQ at baseline consistently predicted good clinical outcome. Disease activity at baseline was directly associated with favourable response when measured by ACR50 and ACR70 (OR: 1.59 and 1.60, respectively), whereas DAS28 score at baseline was inversely associated with EULAR remission (OR: 0.78). CONCLUSIONS In this observational study of patients with established RA, gender did not predict response to anti-TNF therapy, whereas treatment with concomitant DMARDs, especially MTX and low disability were associated with good response. Choice of outcome measures may influence the predictive value of baseline features.

Antibody Response Is Reduced Following Vaccination With 7-Valent Conjugate Pneumococcal Vaccine in Adult Methotrexate-Treated Patients With Established Arthritis, but Not Those Treated With Tumor Necrosis Factor Inhibitors

OBJECTIVE To study the influence of antiinflammatory treatments, including methotrexate (MTX) and tumor necrosis factor (TNF) inhibitors, on antibody response following vaccination using a 7-valent conjugate pneumococcal vaccine in adult patients with established arthritis. METHODS Patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA) (including psoriatic arthritis) were vaccinated (n = 505). All patients were stratified into 6 prespecified groups based on diagnosis and treatment (RA patients receiving MTX, RA patients receiving anti-TNF agents and MTX, RA patients receiving TNF inhibitors as monotherapy, SpA patients receiving anti-TNF agents and MTX, SpA patients receiving TNF inhibitors as monotherapy, and SpA patients receiving nonsteroidal antiinflammatory drugs [NSAIDs] and/or analgesics). SpA patients receiving only NSAIDs/analgesics served as a control group. All patients received 1 dose (0.5 ml) of vaccine intramuscularly. Levels of IgG antibodies against 23F and 6B serotypes were measured at vaccination and at 4-6 weeks following vaccination, using standardized enzyme-linked immunosorbent assays. RESULTS Positive antibody response was defined as an antibody response ratio (ARR) (i.e., ratio of post- to prevaccination antibody levels) of ≥2. The ARR differed significantly between the groups. A better ARR was seen among patients in the control group compared to those in groups treated with MTX or MTX in combination with TNF inhibitors. Among patients treated with TNF inhibitors as monotherapy, ARRs for both serotypes were lower numerically, but were not significantly different, compared to those in controls. Ongoing MTX treatment was predictive of reduced response (odds ratio 0.41 [95% confidence interval 0.24-0.68], P = 0.001). Higher age was associated with impaired positive antibody response. Concomitant prednisolone treatment elicited better positive antibody response in patients with RA. CONCLUSION Treatment with MTX and higher age were predictive of an impaired antibody response to the 7-valent conjugate pneumococcal vaccine in this cohort of patients with chronic arthritis. TNF inhibitors did not significantly affect antibody responses.

Orthopaedic surgery in patients with rheumatoid arthritis over 20 years: prevalence and predictive factors of large joint replacement

Objective: To study the prevalence of orthopaedic surgery and to evaluate possible predictive factors for large joint replacements in patients with early rheumatoid arthritis (RA). Patients and methods: A cohort of 183 patients (116 (63.4%) female) with early RA was monitored for 16–20 years after recruitment during 1985–9. Mean (SD) age of patients 51.4 (12.4) years; mean (SD) duration of symptoms before inclusion 12 (7) months and mean (SD) duration of follow-up 16 (4) years. Occurrence of orthopaedic surgery was recorded continuously. A first prosthesis of a large joint (shoulder, elbow, wrist, hip, knee or ankle) was used as outcome variable in the predictive analyses. Results: In total, 386 orthopaedic interventions were performed in 106/183 (58%) patients during follow-up and a large joint replacement was performed in 44/183 (24%) patients. Using a Cox regression model, it was shown that Health Assessment Questionnaire, C-reactive protein and erythrocyte sedimentation rate at inclusion, and radiographic changes in small joints after 1 year, were associated with an increased risk of receiving prosthesis of large joints. Conclusion: In this cohort of patients with RA monitored from early disease stage, orthopaedic surgical procedures were performed in more than half of the patients. This included first large joint replacements in 24% of the cases. Easily available measures were identified as predictors of such joint replacements. This study could serve as a reference for comparison with cohorts of patients with RA recruited today, in which new more efficacious treatments are used.

Predictors of infusion reactions during infliximab treatment in patients with arthritis

In the present study we evaluated the impact of baseline antinuclear antibody (ANA) status and use of methotrexate on development of infliximab-related infusion reactions in patients with rheumatoid arthritis (RA) or spondylarthropathies (SpAs), including psoriatic arthritis. All patients with RA (n = 213) or SpA (n = 76) treated with infliximab during the period 1999–2005 at the Department of Rheumatology in Lund, Sweden were included. ANAs were present in 28% and 25% of RA and SpA patients, respectively. Because of differences in baseline characteristics, we used a binary logistic regression model to calculate odds ratios (ORs), adjusting for age, sex and prednisolone dosage. Altogether 21% of patients with RA and 13% of patients with SpA developed infusion reactions (P = 0.126). The OR for development of infusion reactions in RA patients with baseline ANA positivity alone was 2.1. Infliximab without methotrexate and infliximab as monotherapy were associated with ORs of 3.1 and 3.6, respectively. Combining infliximab without methotrexate and ANA positivity yielded an OR for infusion reaction of 4.6. Lower age at disease onset and longer disease duration were associated with infusion reactions (P = 0.012 and P = 0.036, respectively), but age, sex, C-reactive protein, erythrocyte sedimentation rate, Health Assessment Questionnaire and Disease Activity Score-28 at baseline were not. No predictors of infusions reactions were identified in SpA patients. RA patients treated with infliximab without methotrexate, and who are positive at baseline for ANAs are at increased risk for developing infliximab-related infusion reactions.

Common vaccinations among adults do not increase the risk of developing rheumatoid arthritis: results from the Swedish EIRA study

Objective To investigate the association between vaccinations in adults and the risk of developing rheumatoid arthritis (RA). Methods Data from the Swedish population-based Epidemiological Investigation of RA case-control study encompassing 1998 incident cases of RA aged 18–70 years and 2252 randomly selected controls matched for age, sex and residency were analysed. Those vaccinated within 5 years before disease onset were compared with those not vaccinated by calculating OR with 95% CI. Results Vaccinations neither increased the risk of RA overall (OR 1.0, 95% CI 0.9 to 1.1) nor the risk of two major subgroups of RA (antibodies to citrullinated peptide-positive (ACPA-positive) and ACPA-negative disease). Furthermore, vaccinations did not increase the risk of RA in smokers or carriers of HLA-DRB1 shared epitope alleles, two groups with established risk factors for RA. Conclusions In this case-control study of incident cases of newly diagnosed RA, no increased risk of RA following immunisation was observed for vaccinations overall or for any specific vaccination. This indicates that immunological provocation of adults with commonly used vaccines in their present form carries no risk of RA. These findings should be implemented among public healthcare providers in order to encourage vaccinations according to recommended national vaccination schedules.

Prevalence and predictive factors of comorbidity in rheumatoid arthritis patients monitored prospectively from disease onset up to 20 years: lack of association between inflammation and cardiovascular disease

Objectives: To study the prevalence of comorbid conditions at diagnosis and during follow-up in a cohort of patients with early rheumatoid arthritis (RA) followed prospectively over 20 years, and to identify possible early predictive factors for future comorbidities. Methods: A community-based cohort of 183 patients (mean age 52 years, 63% female) with early RA was recruited between 1985 and 1989. The presence of comorbidity at RA diagnosis and the occurrence of additional comorbidities were recorded continuously. Possible predictors of future comorbidities were analysed using the Cox proportional hazards model. Results: At RA diagnosis, at least one comorbid condition was present in 43% of the patients. Cardiovascular diseases (CVDs), including hypertension (16% of patients) and malignancy (6% of patients), were most common. In total, 82% of patients developed additional comorbidities during follow-up. CVD and malignancies remained the most frequent comorbidities. Higher age [p < 0.001, odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01–1.15] and the presence of any comorbidity at diagnosis (p = 0.02; OR 1.64, 95% CI 1.08–2.52) predicted future comorbidity. Measures of inflammation at diagnosis or during follow-up were not predictive for development of CVD. Conclusion: Comorbidity was present in a considerable proportion of patients in this cohort. More than 40% of patients had another disease at inclusion and during follow-up and > 80% developed additional conditions. The pattern of comorbidity remained unchanged, with CVD and malignancy being most common. Older age and the presence of comorbidity at RA diagnosis predicted the development of comorbidities. The degree of inflammation at any time point was not predictive of future CVD.

Persistence of antibody response 1.5 years after vaccination using 7-valent pneumococcal conjugate vaccine in patients with arthritis treated with different antirheumatic drugs

IntroductionThe aim of this study was to explore the persistence of an antibody response 1.5 years after vaccination with 7-valent pneumococcal conjugate vaccine in patients with rheumatoid arthritis (RA) or spondyloarthropathy (SpA) treated with different antirheumatic drugs.MethodsOf 505 patients initially recruited, data on current antirheumatic treatment and blood samples were obtained from 398 (79%) subjects after mean (SD, range) 1.4 (0.5; 1 to 2) years. Antibody levels against pneumococcal serotypes 23F and 6B were analyzed by using enzyme-linked immunosorbent assay (ELISA). Original treatment groups were as follows: (a) RA receiving methotrexate (MTX); (b) RA taking anti-TNF monotherapy; (c) RA taking anti-TNF+MTX; (d) SpA with anti-TNF monotherapy; (e) SpA taking anti-TNF+MTX; and (f) SpA taking NSAID/analgesics. Geometric mean levels (GMLs; 95% CI) and proportion (percentage) of patients with putative protective antibody levels ≥1 mg/L for both serotypes, calculated in different treatment groups, were compared with results 4 to 6 weeks after vaccination. Patients remaining on initial treatment were included in the analysis. Possible predictors of persistence of protective antibody response were analysed by using logistic regression analysis.ResultsOf 398 patients participating in the 1.5-year follow up, 302 patients (RA, 163, and SpA, 139) had unchanged medication. Compared with postvaccination levels at 1.5 years, GMLs for each serotype were significantly lower in all groups (P between 0.035 and <0.001; paired-sample t test), as were the proportions of patients with protective antibody levels for both serotypes (P < 0.001; χ2 test). Higher prevaccination antibody levels for both serotypes 23F and 6B were associated with better persistence of protective antibodies (P < 0.001). Compared with patients with protective antibody levels at 1.5 years, those not having protective antibody levels were older, more often women, had longer disease duration and higher HAQ and DAS, and had a lower proportion of initial responders to both serotypes.Concomitant anti-TNF treatment and MTX were identified as negative predictors of the persistence of protective antibodies among RA patients (P = 0.024 and P = 0.065, respectively). Only age 65 years or older (P = 0.017) and not antirheumatic treatment was found to be a negative predictor of protective antibodies in patients with SpA.ConclusionsAfter initial increase, 1.5 years after pneumococcal vaccination with 7-valent conjugate vaccine, postvaccination antibody levels decreased significantly, reaching levels before vaccination in this cohort of patients with established arthritis treated with different antirheumatic drugs. MTX and anti-TNF treatment predicted low persistence of protective immunity among patients with RA. To boost antibody response, early revaccination with conjugate vaccine might be needed in patients receiving potent immunosuppressive remedies.Trial registration numberEudraCT EU 2007-006539-29 and NCT00828997.

Smoking as a risk factor for the radiological severity of rheumatoid arthritis: a study on six cohorts

Background Smoking is a risk factor for the development of anti -citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA). Whether smoking predisposes to severe joint damage progression is not known, since deleterious, protective and neutral observations have been made. Objective To determine the effect of smoking on joint damage progression. Methods Smoking status was assessed in 3158 RA patients included in six cohorts (Leiden Early Arthritis Clinic (Leiden-EAC), BARFOT, Lund, Iceland, NDB and Wichita). In total 9412 radiographs were assessed. Multivariate normal regression and linear regression analyses were performed. Data were summarised in a random effects inverse variance meta-analysis. Results When comparing radiological progression for RA patients that were never, past and current smokers, smoking was significantly associated with more severe joint damage in Leiden-EAC (p=0.042) and BARFOT (p=0.015) RA patients. No significant associations were found in the other cohorts, though a meta-analysis on the six cohorts showed significantly more severe joint damage progression in smokers (p=0.01). Since smoking predisposes to ACPA, analyses were repeated with ACPA as additional adjustment factor. Then the association was lost (meta-analysis p=0.29). Conclusions This multi-cohort study indicated that the effect of smoking on joint damage is mediated via ACPA and that smoking is not an independent risk factor for radiological progression in RA.

Impact of anti-rheumatic treatment on immunogenicity of pandemic H1N1 influenza vaccine in patients with arthritis

IntroductionAn adjuvanted pandemic H1N1 influenza (pH1N1) vaccine (Pandemrix®) was reported as highly immunogenic resulting in seroconversion in 77 to 94% of adults after administration of a single dose. The aim of the study was to investigate the impact of different anti-rheumatic treatments on antibody response to pH1N1 vaccination in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA).MethodsPatients with arthritis (n = 291; mean age 57 years, 64% women) participated. Hemagglutination inhibition (HI) assay was performed on blood samples drawn before and after a mean (SD) of 8.3 (4) months following vaccination. A positive immune response i.e. seroconversion was defined as negative prevaccination serum and postvaccination HI titer ≥40 or a ≥4-fold increase in HI titer. All patients were divided into predefined groups based on diagnosis (RA or SpA) and ongoing treatment: methotrexate (MTX), anti-tumor necrosis factor (anti-TNF) as monotherapy, MTX combined with anti-TNF, other biologics (abatacept, rituximab, tocilizumab) and non-steroidal anti-inflammatory drugs (NSAIDs)/analgesics. Predictors of positive immune response were studied using logistic regression analysis.ResultsThe percentage of patients with positive immune response in the different treatment groups was: 1. RA on MTX 42%; 2. RA on anti-TNF monotherapy 53%; 3. RA on anti-TNF + MTX 43%; 4. RA on other biologics (abatacept 20%, rituximab 10% and tocilizumab 50%); 5. SpA on anti-TNF monotherapy 76%; 6. SpA on anti-TNF + MTX 47%; and 7. SpA on NSAIDs/analgesics 59%. RA patients on rituximab had significantly lower (P < 0.001) and SpA on anti-TNF monotherapy significantly better response rates compared to other treatment groups (P 0.001 to 0.033). Higher age (P < 0.001) predicted impaired immune response. Antibody titers 3 to 6 months after vaccination was generally lower compared to those within the first 3 months but no further decrease in titers were observed 6 to 22 months after vaccination.ConclusionsRituximab treatment severely reduced antibody response to pH1N1 influenza vaccine. The other treatment groups showed acceptable antibody responses. Protective antibody titers could be detected up to 22 months after vaccination in the current patient population, with the exception of rituximab treated patients.