Treatment of arthritis with tumour necrosis factor antagonists. Clinical, immunological and biochemical aspects

Abstract The treatment of arthritis has undergone a dramatic change since biological agents targeting specific mediators of the disease process have been introduced. Tumour necrosis factor (TNF) antagonists have been shown to reduce signs and symptoms of disease and to retard the development of tissue damage in the majority of patients. This thesis focuses on clinical, immunological and biochemical aspects of treatment with TNF antagonists in patients with arthritis. In particular, the studies examine: (i) the feasibility of a structured protocol with central data handling for the prospective monitoring treatment efficacy and tolerability of new treatments in clinical practice, (ii) whether serum levels of cartilage oligomeric matrix protein (COMP) change during treatment with TNF antagonists in a way that corroborates a tissue protective effects of these agents in rheumatoid arthritis (RA), (iii) how different anti-rheumatic treatments modulate the immune response induced by polysaccharide or polypeptide vaccines in patients with RA and (iv) potential predictors of infusion reactions during treatment with infliximab. All the patients who participated in the studies were monitored according to a standardised clinical protocol of the South Swedish Arthritis Treatment Group (SSATG) developed at the Department of Rheumatology in Lund. We found that such a protocol could be used for monitoring newly introduced anti-rheumatic treatments both at a university department and at other rheumatology units. The performance of TNF antagonists regarding efficacy and safety complied with results of previously published clinical trials. Serum levels of COMP were measured in RA patients treated with infliximab and etanercept during the initial 6 months of treatment. Serum COMP levels decreased in patients with and without a clinical response, suggesting a damage retarding effect of TNF antagonist treatment. Altogether, 149 patients with RA participated in studies of the immune response to pneumococcal or influenza vaccination. Patients treated with TNF antagonists and controls showed similar responses to pneumococcal vaccine, whereas methotrexate treated patients showed reduced response to this vaccine regardless of concomitant treatment with TNF antagonists. In contrast, RA patients treated with methotrexate without TNF antagonists had significantly better immune response to influenza vaccination than those receiving TNF antagonists alone or in combination with methotrexate and/or other disease modifying antirheumatic drugs. Possible predictors of infliximab related infusion reactions were studied in a cohort of 213 patients with RA and 76 patients with spondylarthropaties. Infliximab without methotrexate and positive baseline ANA (antinuclear antibodies) were independent risk factors for developing infusion reactions in RA but not in spondylarthropaties. In conclusion, a structured protocol with central data handling is feasible in clinical practice for documenting the efficacy of and adverse events associated with drugs used for the treatment of arthritis. Serum COMP has the potential to be a useful marker for evaluating tissue effects of novel treatment modalities in RA. Methotrexate treatment in RA reduces antibody response to pneumococcal vaccine, suggesting that RA patients should be vaccinated before the initiation of his treatment. The immune response to influenza vaccination is sufficiently good to warrant vaccination of all RA patients, regardless of treatment. Positive ANA at initiation of infliximab treatment and the use of infliximab as monotherapy is associated with increased risk of infusion reactions in RA

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

Introduction: The 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. Methods: Of 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. Results: Of 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; chi(2) 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. Conclusions: After 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

Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

Introduction: The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA). Methods: Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post-and pre-vaccination antibody levels and a positive antibody response (posAR) was AR >= 2. Results: In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%. Conclusion: In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment

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

Serum cartilage oligomeric matrix protein (COMP) decreases in rheumatoid arthritis patients treated with infliximab or etanercept.

Changes in serum cartilage oligomeric matrix protein (COMP) were studied during a 6-month period from initiation of treatment of rheumatoid arthritis patients with either infliximab or etanercept, to elucidate whether the favourable results of tissue protection reported in clinical trials are corroborated by changing levels of circulating COMP. Rheumatoid arthritis patients commencing treatment with infliximab (N = 32) or etanercept (N = 17) were monitored in accordance with a structured protocol. Only patients who were not receiving glucocorticoids or who were on a stable dose of oral prednisolone (<10 mg daily) were included. Serum COMP was measured by a sandwich immunoassay based on two monoclonal antibodies against human COMP in samples obtained at treatment initiation and at 3 and 6 months. Serum COMP decreased at 3 months in both infliximab- and etanercept-treated patients (P < 0.001 and <0.005, respectively) and remained low at 6 months. There was no significant correlation between changes in or concentrations of serum COMP and serum C-reactive protein at any time point. A decrease in serum COMP was seen both in ACR20 responders (patients meeting the American College of Rheumatology criteria for 20% improvement) and in nonresponders. The pattern of changes of serum COMP, a marker for cartilage turnover, in these patient groups supports the interpretation that infliximab and etanercept have a joint protective effect. Serum COMP has potential as a useful marker for evaluating tissue effects of novel treatment modalities in rheumatoid arthritis

Early changes in bone mineral density measured by digital X-ray radiogrammetry predict up to 20 years radiological outcome in rheumatoid arthritis

ABSTRACT: INTRODUCTION: Change in bone mineral density (BMD) in the hand, as evaluated by digital X-ray radiogrammetry (DXR) of the II-IV metacarpal bones, has been suggested to predict future joint damage in rheumatoid arthritis (RA). This study's objective was to investigate if DXR-BMD loss early in the disease predicts development of joint damage in RA patients followed for up to 20 years. METHODS: 183 patients (115 women and 68 men) with early RA (mean disease duration 11 months) included from 1985 to 1989 were followed prospectively (the Lund early RA cohort). Clinical and functional measures were assessed yearly. Joint damage was evaluated according to the Larsen score on radiographs of hands and feet taken in years 0 to 5, 10, 15 and 20. These radiographs were digitized and BMD of the II-IV metacarpal bones was evaluated by DXR (Sectra, Linkoping. Sweden). Early DXR-BMD change rate (bone loss) per year calculated from the first 2 radiographs taken on average 9 months apart (SD 4.8) were available for 135 patients. Mean values of right and left hand were used. RESULTS: Mean early DXR-BMD loss during the first year calculated was -0.023 g/cm2 (SD 0.025). Patients with marked bone loss, i.e. early DXR-BMD loss above the median for the group, had significantly worse progression of joint damage at all examinations during the 20-year period. CONCLUSIONS: Early DXR-BMD progression rate predicted development of joint damage evaluated according to Larsen at year one and further onwards up to 20 years in this cohort of early RA patients

Long-term mortality rate in rheumatoid arthritis patients with disease onset in the 1980s.

Objective: To investigate the mortality rate and possible early predictive factors of mortality after 19-23 years in a cohort of patients with rheumatoid arthritis (RA) followed prospectively from disease onset. Patients and methods: A community-based cohort of 183 patients (63% female) with RA and disease duration < 2 years was recruited 1985-1989. The patients were followed yearly from diagnosis until death or 31 December 2008. Mean age and mean duration of symptoms (range) at diagnosis were 52 (18-78) years and 11 (0-24) months, respectively. Death certificates were obtained from the Swedish Cause of Death Register and causes of death were coded by the International Classification of Diseases (ICD-10). Death rates of RA patients were compared to those of age- and sex-matched controls. Possible predictors of mortality were analysed using a Cox regression model. Results: By 31 December 2008, 69 patients (37 women and 32 men) had died. The standardized mortality ratio (SMR) was 1.23 [95% confidence interval (CI) 0.97-1.55] and p < 0.09. Older age, male sex, smoking, and the presence of cardiovascular disease (CVD) at RA diagnosis were identified as early predictors of mortality. CVD was the most common cause of death (46%), followed by malignancies (29%) and infections (13%). RA was not stated as the direct cause of death in any patient and was mentioned among underlying causes in only 16/69 (23%) patients. Conclusion: Mortality rate after 19-23 years of disease duration in this cohort of patients with disease onset in the 1980s was not significantly increased compared to age- and sex-matched controls. No RA disease-related factor predicted mortality