Enthesitis in a European registry-based cohort of patients with psoriatic arthritis treated with tumour necrosis factor inhibitors: clinical burden, patient-reported outcomes, and treatment response.

OBJECTIVE: To explore the registration of enthesitis among biologic-naïve patients with psoriatic arthritis (PsA) initiating tumour necrosis factor inhibitor (TNFi) treatment across 12 European registries, compare the disease burden and patient-reported outcomes (PROs) between patients with and without enthesitis, and assess the enthesitis treatment response. METHOD: Demographics, clinical characteristics, and PROs at first TNFi (TNFi-1) initiation (baseline) were assessed in patients with PsA, diagnosed by a rheumatologist, with versus without assessment of entheses and between those with versus without enthesitis. Enthesitis scores and resolution frequency were identified at follow-up. RESULTS: Of 10 547 patients in the European Spondyloarthritis (EuroSpA) Research Collaboration Network initiating TNFi, 1357 underwent evaluation for enthesitis. Eight registries included a validated scoring system for enthesitis. At baseline, 874 patients underwent entheses assessment [Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) 485 patients, Spondyloarthritis Research Consortium of Canada (SPARCC) 389 patients]. Enthesitis was detected by MASES in 170/485 (35%, mean score ± sd 3.1 ± 2.4) and by SPARCC in 236/389 (61%, 4 ± 3.4). Achilles enthesitis was most frequent, by both MASES (unilateral/bilateral 28%/9%) and SPARCC (48%/18%). MASES/SPARCC baseline and follow-up scores for TNFi-1 were available for 100/105 patients. Of these, 63 patients (63%) (MASES) and 46 (43.8%) (SPARCC) achieved resolution of enthesitis. The site-specific enthesitis resolution was overall lower at SPARCC sites (peripheral; 63-80%) than at MASES sites (mainly axial; 82-100%) following TNFi-1. Disease activity and PROs were worse in patients with versus without enthesitis. CONCLUSION: Entheseal assessments are only registered in a minority of patients with PsA in routine care. When assessed, enthesitis was common, and a substantial proportion demonstrated resolution following treatment with TNFi-1.

Immunogenicity of subcutaneous TNF inhibitors and its clinical significance in real-life setting in patients with spondyloarthritis.

KEY MESSAGES: Considerable proportion of patients with SpA have been immunized to the subcutaneous anti-TNF drug they are using. Concomitant use of MTX protects from immunization, whereas SASP does not. Patients with SpA using subcutaneous anti-TNF drugs can benefit from monitoring of the drug trough levels. Immunization to biological drugs can lead to decreased efficacy and increased risk of adverse effects. The objective of this cross-sectional study was to assess the extent and significance of immunization to subcutaneous tumor necrosis factor (TNF) inhibitors in axial spondyloarthritis (axSpA) patients in real-life setting. A serum sample was taken 1-2 days before the next drug injection. Drug trough concentrations, anti-drug antibodies (ADAb) and TNF-blocking capacity were measured in 273 patients with axSpA using subcutaneous anti-TNF drugs. The clinical activity of SpA was assessed using the Bath AS Disease Activity Index (BASDAI) and the Maastricht AS Entheses Score (MASES). ADAb were found in 11% of the 273 patients: in 21/99 (21%) of patients who used adalimumab, in 0/83 (0%) of those who used etanercept, in 2/79 (3%) of those who used golimumab and in 6/12 (50%) of those who used certolizumab pegol. Use of methotrexate reduced the risk of formation of ADAb, whereas sulfasalazine did not. Presence of ADAb resulted in decreased drug concentration and reduced TNF-blocking capacity. However, low levels of ADAb had no effect on TNF-blocking capacity and did not correlate with disease activity. The drug trough levels were below the consensus target level in 36% of the patients. High BMI correlated with low drug trough concentration. Patients with low drug trough levels had higher disease activity. The presence of anti-drug antibodies was associated with reduced drug trough levels, and the patients with low drug trough levels had higher disease activity. The drug trough levels were below target level in significant proportion of patients and, thus, measuring the drug concentration and ADAb could help to optimize the treatment in SpA patients.

Cost-effectiveness modelling of sequential biologic strategies for the treatment of moderate to severe rheumatoid arthritis in Finland.

OBJECTIVE: The main objective was to compare the cost-effectiveness of therapeutic options in moderate or severe rheumatoid arthritis (RA) when a clinical response to a first TNF-blocker, either etanercept (ETA), adalimumab (ADA), or infliximab (INF), is insufficient. METHODS: Effectiveness criteria were defined as remission (RS), low disease activity (LDAS), and moderate to high disease activity (MHDAS). Cost-effectiveness was derived as cost per day in RS and in LDAS using simulation modelling to assess six sequential biologic strategies over 2 years. Each sequential treatment strategy was composed of three biologic agents and included a first anti-TNF agent, ETA, ADA or INF, followed by either abatacept (ABA) or rituximab (RTX) as a second therapeutic option in case of an insufficient response, followed by another anti-TNF agent in case of further insufficient response. RESULTS: Over two years and taking into account biologic costs, the following estimated mean costs per day in RS and LDAS were respectively of €829 and €428 for the biologic sequence composed of ADA-ABA-ETA, €1292 and €516 for the sequence ADA-RTX-ETA, €829 and €429 for the sequence ETA-ABA-ADA, €1292 and €517 for the sequence ETARTX- ADA, €840 and €434 for the sequence INF-ABA-ETA, and €1309 and €523 for the sequence INF-RTX-ETA. CONCLUSION: The treatment sequences including ABA as the second biologic option appear more cost-effective than those including RTX in a patients with moderate to severe RA and an insufficient response to a first anti-TNF agent.

Early improvement of health-related quality of life during treatment with etanercept and adalimumab in patients with rheumatoid arthritis in routine practice.

OBJECTIVES: To assess health-related quality of life (HRQoL) in patients with rheumatoid arthritis (RA) treated with etanercept or adalimumab in routine clinical practice. METHODS: Patients with RA who started etanercept or adalimumab at Helsinki University Central Hospital or Lappeenranta Central Hospital during 2003-2006 were asked to participate in the study. In 97 patients, HRQoL was measured by the RAND 36-Item Health Survey 1.0 (RAND-36) at baseline and after three months of the treatment. HRQoL of the RA patients was compared to the Finnish age- and sex-matched general population values. In addition, changes in clinical parameters and disability index measured by the health assessment questionnaire (HAQ) were recorded. RESULTS: Treatment with etanercept and adalimumab increased the values in all domains of the RAND-36 during the first three months in routine practice. The improvement in both groups was statistically significant: with etanercept p=0.041 and with adalimumab p=0.019. The efficacy of etanercept and adalimumab in improving HRQoL during the first three months was comparable. The patients reported their best improvement in the subscales of bodily pain, role functioning/physical, energy, social functioning, and role functioning/emotional. Compared to the Finnish age- and sex-matched general population values, the HRQoL of the patients with RA was significantly lower at baseline and remained low at follow-up. The change in clinical parameters and the HAQ paralleled the improvement in HRQoL. CONCLUSION: Treatment of patients with RA with etanercept and adalimumab in routine clinical practice provides clinically important and statistically significant improvement in HRQoL already in the first three months.

Cost-effectiveness of infliximab in the treatment of rheumatoid arthritis in clinical practice.

OBJECTIVE: We evaluated the cost-effectiveness of infliximab therapy in Finnish RA patients in a real-life clinical setting and identified factors influencing it, using the national register of biological treatment (ROB-FIN). METHODS: A cost-utility analysis was performed, derived from EQ-5D, and related to HAQ score and disease activity using multiple regression. QALYs were calculated based on these utilities, using patient-level data up to the last control registered. Cost-effectiveness analyses included costs per ACR50 responder, and costs per low DAS28 score (<3.2) achieved, in combination with a clinically significant improvement (>1.2). The costs considered were direct medical costs of infliximab and cost of intravenous infusion. Patient-level costs were calculated based on dose and dosage frequency, and were related to the difference in QALYs resulting from infliximab therapy. RESULTS: The 297 patients had been treated with infliximab for an average of 21 months. The HAQ score and patient's global assessment improved significantly on infliximab therapy. More than two-thirds of the patients achieved a clinically important improvement in HAQ. A QALY gain occurred in 76%. 35% of these had an incremental cost-effectiveness ratio of < or =40,000 Euro/QALY gained, the median cost being 51,884 Euro. The cost per QALY gained was significantly lower for patients achieving an ACR50 response at 3, 12 and 24 months. CONCLUSION: Treatment with infliximab and aiming at ACR50 response appears cost-effective, remembering the restrictions of an observational study set up. Current Care guidelines, which require sufficient disease control when deciding on continuing biological therapy, get support from these findings.

Pharmacoeconomic study of patients with chronic inflammatory joint disease before and during infliximab treatment.

OBJECTIVE: To evaluate medical and work disability costs for patients with chronic inflammatory joint disease during one year before and one year after institution of infliximab treatment in routine clinical practice. METHODS: Starting from 1999, clinical and laboratory variables for patients treated with biological agents for inflammatory rheumatic diseases were systematically recorded at Helsinki University Central Hospital. From this database clinical information was collected on 96 patients in whom infliximab was started during the period 1999 to 2001. Economic analyses were based on costs incurred because of outpatient and inpatient visits, orthopaedic operations, drugs used, and days on sickness or rehabilitation allowance. Medical and work disability costs were calculated separately for the one year period before (period I) and the one year period after institution of infliximab (period II). RESULTS: Of the study group of 96 patients (arthritis duration 16 years (range 3 to 43)), 74 completed one year of infliximab treatment. Their clinical and laboratory variables improved significantly. The mean increase in medical costs during period II was euro12 015 (95% confidence interval, 6496 to 18,076). A minimal decrease in work disability costs occurred-mean decrease euro130 (-1268 to 1072). CONCLUSIONS: One year treatment with infliximab in patients with longstanding aggressive arthritis showed a good clinical effect but raised medical costs significantly. Work disability costs failed to show a substantial decrease. Starting infliximab in the earlier stages of chronic arthritis could in the long term prevent work disability and thus decrease the total cost to society.

Cytokine and chemokine receptor profile of peripheral blood mononuclear cells during treatment with infliximab in patients with active rheumatoid arthritis.

OBJECTIVES: To analyse immunological changes during treatment with a monoclonal anti-tumour necrosis factor alpha (TNFalpha) antibody, infliximab, in patients with rheumatoid arthritis (RA). METHODS: 25 patients with RA and 5 patients with other arthritides were studied during the first 6 weeks of treatment with infliximab. At the start of treatment and after 2 and 6 weeks, spontaneous expression of CCR3 and CCR5 on peripheral blood T cells and monocytes was studied by flow cytometry. The secretion and mRNA expression of interferon gamma (IFNgamma), interleukin (IL)4, IL5, and TNFalpha from phytohaemagglutinin (PHA) stimulated peripheral blood mononuclear cells was measured with an ELISA and RT-PCR. Plasma levels of C reactive protein, serum amyloid protein A, rheumatoid factor, and antibodies to filaggrin and citrullinated cyclic peptide were measured with an ELISA. RESULTS: The number of CD4 T cells and CD14 monocytes expressing CCR3 (p = 0.013, p = 0.009, respectively) and CD8 T cells expressing CCR5 (p = 0.040) as well as PHA stimulated secretion of IL4 and IFNgamma (p<0.05) increased during treatment in patients with RA. 15 (60%) patients with RA achieved clinical response (at least ACR20) during the first 2 weeks. The number of T cells expressing CCR3 and CCR5 was higher before treatment in non-responders than in responders (p<0.05). The number of T cells increased in responders. CONCLUSION: Increase in secretion of Th1 and Th2 cytokines together with induced expression of chemokine receptors on T cells and monocytes suggest restoration of peripheral cell mediated immunity and blockade of the accumulation of inflammatory cells in joints as response to treatment.

Mortality in patients with rheumatoid arthritis treated actively from the time of diagnosis.

OBJECTIVES: To evaluate the mortality rates among patients with early rheumatoid arthritis (RA) treated actively according to the "sawtooth" strategy. METHODS: The study included 150 early, disease modifying antirheumatic drug (DMARD) naive patients with RA from two patient cohorts. The first cohort was assembled between 1986 and 1989 (87 patients, aged 19-65 years at onset) and the second between 1991 and 1993 (63 patients, aged 27-83 years at onset). The mean duration of symptoms at the time of diagnosis was 7.1 months (range 2-24). The clinical data and the use of DMARDs were systematically recorded. The causes of death were obtained from death certificates and medical records, if available. The data were collected up to 1 November 2000. RESULTS: During a follow up time of 7-14 years, 24 patients died. The standardised mortality ratio was not increased (0.93 in the first cohort and 1.62 in the second cohort). Age adjusted mortality rates did not differ statistically significantly between the two patient cohorts. The causes of death included malignancy (8 patients); cardiovascular diseases (10); respiratory disease (4), including two patients with pneumonia; sepsis (one); and RA (one). High inflammatory activity, disease activity, and poor functional ability at study entry, and the presence of extra-articular features during the follow up were more common among the patients who had died. CONCLUSIONS: No statistically significant increase in mortality rates was seen in these actively treated early RA cohorts during the follow up. High disease activity at the onset and the development of extra-articular features seem to be associated with mortality.

Increased level of YKL-40 in sera from patients with early rheumatoid arthritis: a new marker for disease activity.

YKL-40 is a newly discovered major secretory protein of human chondrocytes and synoviocytes. We measured serum levels of YKL-40 in 52 patients with early onset rheumatoid arthritis (RA) by enzyme-linked immunosorbent assay (ELISA) during a 2-year prospective follow-up, correlating values with laboratory and clinical variables and radiographic progression. Levels at baseline before antirheumatic therapy were significantly higher in patients than in healthy controls. The levels of YKL-40 correlated with laboratory and clinical markers of disease activity both at baseline and during follow-up. Baseline YKL-40 values correlated with baseline Larsen scores but did not predict radiographic progression. Baseline and mean YKL-40 values did not differ between fast and slow radiological progressions. Mean YKL-40 levels correlated with the number of swollen joints but were not predictors of radiographic progression. These results suggest that in early RA, serum YKL-40 is an inflammatory marker correlating with disease activity. However, its levels do not predict clinical course or radiographic progression.

Effect of treatment on the outcome of very early rheumatoid arthritis.

OBJECTIVE: To evaluate the effect of treatment on the outcome of very early RA. METHODS: In a 3-year prospective study of 27 patients with very early RA (VERA) (symptoms <4 months before diagnosis) and 122 patients with early RA (symptoms between 4-24 months) the effect of active treatment on the clinical picture, functional capacity, and radiological progression was evaluated. RESULTS: Initially VERA patients had a more active clinical picture and worse functional capacity. Despite a higher number of DMARDs used in VERA patients, C-reactive protein and Ritchie index remained significantly higher in these patients (although significant improvement occurred). They also had a more rapidly progressive disease (higher Larsen score/month of symptoms) during pre-treatment period, the progression of which was retarded with early, active DMARD therapy. By the end of 3 years, the rate of progression ran parallel in both groups. CONCLUSION: Active treatment had an impact on the rate of radiological progression and clinical activity but not on the functional outcome in patients with initially active RA of short duration.

Effect of age on 3 year outcome in early rheumatoid arthritis.

OBJECTIVE: To investigate the effect of age on clinical and radiological outcome and on efficacy and tolerance of antirheumatic therapy in early rheumatoid arthritis (RA). METHODS: In a prospective 3 year study 113 patients (83 women, 30 men) were divided into 2 groups according to age at onset of disease: before (n = 55) and after 55 years of age (n = 58). For clinical outcome, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor, Ritchie index, and number of swollen joints were measured. Radiological progression was analyzed by Larsen score. The principles of the "sawtooth" strategy were applied in the treatment of all patients. RESULTS: At baseline, inflammatory activity (ESR, CRP) and the Larsen score for hands were significantly higher in patients with late onset RA (LORA) and they also developed more extraarticular symptoms compared to patients with early onset RA (EORA). However, no differences were found in Ritchie index, number of swollen joints, or CRP values between the groups. Also during the followup there was a trend toward increased inflammatory activity (ESR) among LORA patients. After the initiation of antirheumatic therapy a parallel improvement in clinical activity was observed in the 2 groups. The frequencies of remissions, side effects, and withdrawals due to drug inefficacy did not differ significantly between the 2 groups. The radiological progression was also comparable. CONCLUSION: The onset of RA was more active in patients with LORA. However, the clinical course and the radiological progression were parallel in LORA and EORA patients. The "sawtooth" therapy was equally tolerated in both patient groups.

Iloprost in the management of leg ulcer in polyarteritis nodosa. A case report.

The authors report the case of a patient with a large leg ulcer secondary to polyarteritis nodosa unresponsive to corticosteroid, cytotoxic, and anticoagulant therapy who was successfully treated with iloprost.

Comparison of intramuscular gold and sulphasalazine in the treatment of early rheumatoid arthritis. A one year prospective study.

We compared the effects of intramuscular gold and sulphasalazine on early, active rheumatoid arthritis in 128 consecutive patients. Intramuscular gold was started in the first 70 consecutive patients and sulphasalazine in the subsequent 58 patients. The patient groups were comparable with regard to clinical characteristics. In both groups clinical and laboratory parameters improved, but there was no significant difference between the two groups. The clinical improvement was most pronounced during the first three months. However, despite the clinical improvement a clear progression in radiological changes was observed in both groups, 40% of the patients taking gold and 48% of patients taking sulphasalazine discontinued the treatment because of adverse drug reactions or inefficacy during the one year follow-up. Adverse drug reactions were the main reason in both groups. These findings suggest that intramuscular gold and sulphasalazine seem to have an equal, positive effect on symptoms and clinical variables, but that radiological progression does occur in most patients none the less.