Maintenance of improvement in spinal mobility, physical function and quality of life in patients with ankylosing spondylitis after 5 years in a clinical trial of adalimumab.

OBJECTIVE: Chronic pain and progressive loss of physical function with AS may adversely affect health-related quality of life (HRQoL). The objective of this study was to assess the 5-year data regarding spinal mobility, physical function and HRQoL in patients with AS who participated in the Adalimumab Trial Evaluating Long-term Efficacy and Safety for AS (ATLAS) study. METHODS: Patients received blinded adalimumab 40 mg or placebo every other week for 24 weeks, then open-label adalimumab for up to 5 years. Spinal mobility was evaluated using linear BASMI (BASMIlin). BASDAI, total back pain, CRP, BASFI, Short Form-36 and AS quality of life (ASQoL) were also assessed. Correlations between BASMIlin and clinical, functional and ASQoL outcomes after 12 weeks and after 5years of adalimumab exposure were evaluated using Spearman's rank correlation. Associations were further analysed using multivariate regression. RESULTS: Three hundred and eleven patients received ≥1 dose of adalimumab; 125 of the 208 patients originally randomized to adalimumab received treatment for 5 years. Improvements in BASMIlin were sustained through 5 years, with a mean change of -0.6 from baseline in the population who completed 5 years of treatment with adalimumab. Improvements in disease activity, physical function and ASQoL were also sustained through 5 years. BASMIlin was significantly correlated with all evaluated clinical outcomes (P < 0.001). The highest correlation was with BASFI at 12 weeks (r = 0.52) and at 5 years (r = 0.65). Multivariate regression analysis confirmed this association (P < 0.001). CONCLUSION: Treatment with adalimumab for up to 5 years demonstrated sustained benefits in spinal mobility, disease activity, physical function and HRQoL in patients with active AS. Spinal mobility was significantly associated with short- and long-term physical function in these patients. TRIAL REGISTRATION: Clinicaltrials.gov; https://clinicaltrials.gov/NCT00085644.

Biological vs. conventional combination treatment and work loss in early rheumatoid arthritis: a randomized trial.

IMPORTANCE: The introduction of biological tumor necrosis factor inhibitors has improved the treatment of rheumatoid arthritis (RA) but at a substantial cost. These drugs have been shown to lead to superior radiological outcomes compared with a combination of conventional disease-modifying antirheumatic drugs over 2 years. OBJECTIVE: To investigate whether radiological superiority translates into better work loss outcomes. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, 2-arm, parallel, randomized, active-controlled, open-label trial. Patients with early RA (symptom duration <1 year) were recruited from 15 rheumatology clinics in Sweden from October 1, 2002, through December 31, 2005. The study population was restricted to working-age patients (aged <63 years). INTERVENTIONS: Patients who did not achieve low disease activity after 3 to 4 months of methotrexate therapy were randomized to receive additional biological treatment with infliximab or conventional combination treatment with sulfasalazine plus hydroxychloroquine. MAIN OUTCOMES AND MEASURES: Monthly sick leave and disability pension days 21 months after randomization retrieved from the nationwide Swedish Social Insurance Office register. Main analyses were by intention to treat, including all patients, and adjusted for baseline sick leave and disability pension. RESULTS: Of 204 eligible patients, 105 were randomized to biological and 99 to conventional treatment. Seven patients in the biological and 4 in the conventional treatment group never received the study drug, and 72 and 52 patients, respectively, followed the study per protocol for 21 months. The baseline mean (SD) work loss was 17 (13) d/mo (median, 16 d/mo) in both groups (mean difference, 0.6 d/mo; 95% CI, -3.0 to 3.9). The mean changes in work loss at 21 months were -4.9 d/mo in the biological and -6.2 d/mo in the conventional treatment group (adjusted mean difference, 1.6 d/mo; 95% CI, -1.2 to 4.4). Including only patients receiving at least 1 dose of assigned treatment, the adjusted mean difference was 1.5 d/mo (95% CI, -1.5 to 4.4), and in per-protocol analysis the adjusted mean difference was 0.3 d/mo (95% CI, -2.8 to 3.8). CONCLUSIONS AND RELEVANCE: The radiological superiority of biological compared with conventional combination therapy did not translate into better work loss outcomes in patients with early RA who had experienced an insufficient response to methotrexate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00764725.

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled, SWEFOT trial.

OBJECTIVE: To compare EuroQol 5-Dimensions (EQ-5D) utility and quality-adjusted life-years (QALYs) in patients with early, methotrexate (MTX) refractory rheumatoid arthritis (RA), randomised to addition of infliximab (IFX) or sulfasalazine and hydroxychloroquine (SSZ+HCQ). METHODS: RA-patients with symptoms <1 year were enrolled between 2002 and 2005 at 15 Swedish centres. After 3-4 months of MTX monotherapy, patients with a remaining DAS28>3.2 were randomised to addition of IFX or SSZ+HCQ and followed for 21 months. EQ-5D profiles were collected every 3 months. Between-group comparisons of utility change and accumulated QALYs were performed, using last observation carried forward (LOCF) following protocol breach. Missing data were imputed by linear interpolation or LOCF. Sensitivity analyses applying baseline observation carried forward (BOCF) or restricted to completers were conducted. RESULTS: Of 487 patients initially enrolled, 128 and 130 were randomised to IFX or SSZ+HCQ, respectively. Mean utility in the IFX and SSZ+HCQ groups increased from 0.52 (SD 0.27) and 0.55 (SD 0.27) at randomisation to 0.66 (SD 0.25) and 0.63 (SD 0.27) at 21 months (adjusted mean difference favouring IFX 0.04; 95% CI -0.01, 0.09; p=0.15). Average accumulated QALYs were 1.10 (SD 0.37) and 1.07 (SD 0.42) in the IFX and SSZ+HCQ groups, respectively (adjusted mean difference favouring IFX 0.07; 95%CI -0.01, 0.14; p=0.07). BOCF analysis showed similar results, while differences were reversed, though remained statistically non-significant among completers. Dropout rates in the IFX/SSZ+HCQ groups were 30%/43% (p=0.01). CONCLUSIONS: Comparing addition of IFX or SSZ+HCQ to MTX in active early RA, no statistically significant differences in utility or QALY gain could be detected over 21 months. TRIAL REGISTRATION: Registered in WHO database at the Karolinska University Hospital, number CT20080004.

Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial.

BACKGROUND: Analysis of the Swedish Farmacotherapy (Swefot) trial at 12 months showed that the addition of an anti-tumour-necrosis-factor agent gave an improved clinical outcome compared with the addition of conventional disease-modifying antirheumatic drugs in patients with methotrexate-refractory early rheumatoid arthritis. Here we report the 2 year follow-up assessment. METHODS: In this randomised, non-blinded, parallel-group trial, we enrolled adult patients older than 18 years with rheumatoid arthritis and a symptom duration of less than 1 year from 15 rheumatology units in Sweden between December, 2002 and December, 2006. All patients were started on methotrexate. After 3-4 months, those who failed treatment were randomly assigned (1:1) to group A (conventional treatment; additional sulfasalazine and hydroxychloroquine) or group B (biological treatment; additional infliximab). Randomisation was done with a computer-generated sequence. We analysed clinical outcomes at months 18 and 24 by the response criteria of the American College of Rheumatology and the European League Against Rheumatism, and radiographs of patients' hands and feet at months 12 and 24 using the Van der Heijde modification of the Sharp score. Analysis was by intention to treat. This trial is registered with www.ClinicalTrials.gov, number NCT00764725. FINDINGS: Of 493 screened individuals, we enrolled 487, of whom 258 were randomly allocated to treatment. The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months (49 of 128 [38%] vs 38 of 130 [29%]) and at 24 months (49 of 128 [38%] vs 40 of 130 [31%]; p=0·204). After 24 months, radiological disease progression was greater in patients in group A than it was in those in group B (mean 7·23 [SD 12·72] vs 4·00 [10·0]; p=0·009). We recorded three serious adverse events: an extended generalised illness in group A, an extended febrile episode in group B, and a generalised illness in group B. INTERPRETATION: Additional biological treatment is a valid option for patients who fail initial methotrexate treatment. However, improved clinical outcomes after 12 months and better radiographical results after 24 months should be weighed against the absence of a convincing clinical difference at 24 months and substantially higher costs. Therefore, for many patients who fail initial methotrexate treatment, add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option. FUNDING: Swedish Rheumatism Association, Stockholm County, and Schering-Plough/Merck Sharp and Dohme.

High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations.

High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is increasingly recognized as an important proinflammatory mediator actively secreted from monocytes and macrophages and passively released from necrotic cells. In antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), the kidneys are commonly affected vital organs, characterized by focal necrotizing and/or crescentic pauci-immune glomerulonephritis. The aim of the study was to determine whether HMGB1 serum levels are elevated in AAV with renal manifestations. A total of 30 AAV patients (16 female and 14 male; median age 59 years, range 17-82) with Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome with available renal biopsies and serum samples were included. In seven cases, serum was also obtained at rebiopsy in remission. HMGB1 was analyzed with Western blot. Birmingham Vasculitis Activity Score (BVAS, version 2003), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), urinanalysis, creatinine, estimated glomerular filtration rate, sex and age were included in the analysis. Twenty-five episodes of biopsy-proven active disease with BVAS 17.9 ± 4.6 and 13 cases with inactive biopsies and BVAS 2.3 ± 3.7 (P = 0.0001) were identified. CRP, ESR, hematuria and proteinuria were significantly higher in active cases. HMGB1 was significantly elevated (P = 0.01) comparing active with inactive cases (120 ± 48 versus 78 ± 46 ng/mL) and significantly lower in the seven control patients (P = 0.03) at rebiopsy in remission. HMGB1 remained higher in inactive cases compared with historic healthy controls (10.9 ± 10.5 ng/mL). HMGB1 levels did not differ significantly between AAV subgroups. CRP and ESR did not correlate with HMGB1. HMGB1 is significantly increased in AAV with renal involvement. Residual HMGB1 elevation in remission could possibly reflect low-grade inflammatory activity or tissue damage. Future studies may further reveal whether HMGB1 is useful as a marker of disease activity and a predictor of outcome in AAV.

Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial.

OBJECTIVE: To identify predictors of response to methotrexate (MTX) in early rheumatoid arthritis (RA). METHODS: In the SWEFOT trial, patients with RA with symptom duration <1 year started MTX monotherapy (20 mg/weekly) and 405/487 continued until the 3-4- month visit. The primary outcome measure was the DAS28-based European League against Rheumatism (EULAR) response criteria. Multivariate logistic regression was used to study the association between response and the following baseline characteristics: gender, age, symptom duration, cigarette smoking habits, autoantibody status, Health Assessment Questionnaire (HAQ) score, concurrent prednisolone and treatment with non-steroidal anti-inflammatory drugs. Secondary response and remission measures were the American College of Rheumatology and the Simple Disease Activity Index and Clinical Disease Activity Index (SDAI/CDAI)-derived criteria. RESULTS: After 3-4 months of MTX treatment, the frequency of EULAR good/moderate/no response was 34%/41%/25%, respectively. Parameters associated with a decreased likelihood of EULAR response were female gender (adjusted OR (adj OR) 0.50, 95% CI 0.31 to 0.81), symptom duration (adj OR per month increase 0.93, 95% CI 0.88 to 0.99), current smoking (adj OR 0.35, 95% CI 0.20 to 0.63) and higher HAQ (adj OR 0.56, 95% CI 0.40 to 0.80). Parameters associated with an increased likelihood of EULAR response were higher age (adj OR per 10-year increase 1.30, 95% CI 1.11 to 1.51) and prednisolone treatment (adj OR 2.84, 95% CI 1.43 to 5.63). The findings were similar when patients on prednisolone were excluded and other response criteria tested, although current smoking was the only significant predictor using all response criteria, while HAQ was the only significant predictor of all the remission criteria used. A matrix showed up to ninefold differences between subgroups stratified by the main predictors. CONCLUSION: Current smoking, female sex, longer symptom duration and younger age predict a worse response to MTX in patients with new-onset RA. TrialRegNo NCT00764725.

Endogenous glutamate in association with inflammatory and hormonal factors modulates bone tissue resorption of the temporomandibular joint in patients with early rheumatoid arthritis.

PURPOSE: The aim of this study was to investigate the relation between plasma level of glutamate and extent of radiographic bone erosion of the temporomandibular joint (TMJ) in patients with early rheumatoid arthritis (RA) in relation to inflammatory disease activity as well as estradiol and testosterone. MATERIALS AND METHODS: A total of 47 patients (29 women and 18 men) of whom 24 were seropositive were included shortly after being diagnosed with RA. Radiographic signs of bone tissue resorption (erosions) in the TMJ were recorded by cone-beam CT images, and an erosion score (0 to 24) was calculated for each patient. Venous blood was analyzed for rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate, leukocyte particle count, glutamate, estradiol, and testosterone. Nonparametric statistical methods were used in the analysis. RESULTS: Resorptive changes of the TMJ were found in a major part of the patients. There was a significant positive correlation between plasma level of glutamate and extension of radiographic erosions that was strongest in the patients with low levels of C-reactive protein, estradiol, or testosterone. By contrast, erosions were correlated with C-reactive protein in patients with high levels of estradiol. The highest levels of glutamate were found in patients with low levels of C-reactive protein and estradiol. CONCLUSIONS: This study shows that a majority of patients with early RA presents radiographic signs of bone tissue resorption of the TMJ and that circulating glutamate is associated with the extent of these changes. The relationship between glutamate and bone resorption seems to be influenced by systemic inflammatory activity as well as estradiol and testosterone levels.

Fcgamma receptor type IIIA genotype and response to tumor necrosis factor alpha-blocking agents in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether a functional single-nucleotide polymorphism in the gene encoding Fcgamma receptor type IIIA (FcgammaRIIIA) correlates with the response to treatment with tumor necrosis factor alpha inhibitors in rheumatoid arthritis (RA). METHODS: The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease-modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi-square test was used to compare response rates across FcgammaRIIIA genotypes. RESULTS: No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria. CONCLUSION: Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcgammaRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.

Reduction of temporomandibular joint pain after treatment with a combination of methotrexate and infliximab is associated with changes in synovial fluid and plasma cytokines in rheumatoid arthritis.

The aims were to investigate the effect of intravenous infusions of the tumor necrosis factor-alpha (TNF-alpha) antibody infliximab on symptoms and signs of temporomandibular joint (TMJ) involvement in relation to effects on synovial fluid and plasma proinflammatory TNF-alpha, interleukin-1beta (IL-1beta) and interleukin-6 as well as antiinflam matory soluble TNF receptor II (TNF-sRII), interleukin-1 receptor antagonist (IL-1ra), soluble IL-1 receptor II (IL-1sRII) and interleukin-10 (IL-10) in patients with active rheumatoid arthritis (RA). Nineteen patients with TMJ involvement taking methotrexate were included in the study. TMJ and general joint pain intensity as well as pain on mandibular movements, tenderness to digital palpation, pressure pain threshold and maximum mouth-opening capacity were assessed in a clinical examination. The effect of infliximab was assessed after 2 and 14 or 22 weeks. TMJ synovial fluid and venous blood were collected for cytokine analysis at all occasions while determination of erythrocyte sedimentation rate and C-reactive protein were performed at baseline and at long-term follow-up only. Reduction of TMJ pain was associated with raised levels of synovial fluid TNF-sRII and IL-1sRII as well as raised plasma levels of IL-1ra and IL-10. Decreased erythrocyte sedimentation rate was associated with decreased tenderness to digital palpation. Reduced general joint pain intensity was associated with reduced plasma levels of IL-6 and C-reactive protein. In conclusion, systemic treatment with a combination of infliximab and methotrexate reduces TMJ pain in RA in association with an increase in anti-inflammatory cytokines and receptors in synovial fluid and plasma.

[Chronic granulomatous disease--not only the lack of oxygen radicals]. / Kronisk granulomatös sjukdom--inte bara brist på syreradikaler.

Chronic granulomatous disease (CGD) is caused by mutations in the phox-family of superoxide ion generating enzymes. The clinical manifestations of CGD include increased infection susceptibility, a lupus like dermatitis and inflammatory bowel disease. The severe consequences of this rare disorder need to be handled by specialists, experienced in the care of CGD patients. Many CGD manifestations are due to the lack of superoxide ions, but some also to deficient pumping of protons to the extracellular space. An excessive inflammatory component, e.g. the granuloma formation in various organs, might be secondary to impaired superoxide ion dependent inactivation of inflammatory mediators. CGD can be successfully treated by hematopoietic stem cell transplantation, and gene therapy might become an alternative in the future.

Wegener's granulomatosis is associated with organ-specific antiendothelial cell antibodies.

BACKGROUND: Antiendothelial cell antibodies (AECA), usually detected using human umbilical vein endothelial cells (HUVEC), are frequently observed in systemic vasculitis, but their pathogenic role is unclear. Heterogeneity of endothelial cells necessitates use of clinically relevant endothelial cells for elucidation of the role of AECA in systemic vasculitis involving small blood vessels of specific organs. METHODS: Human endothelial cells were isolated from normal tissue specimens from the nose, kidney, lung, liver, and umbilical vein. Using flow cytometry, AECA were detected against both unstimulated and cytokine-stimulated [tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] endothelial cells. Functional capacity of AECA was determined by complement fixation assay. Sera from patients with Wegener's granulomatosis (16), limited Wegener's granulomatosis (8), renal limited disease (4), microscopic polyangiitis (MPA) (5), rheumatoid arthritis (10), and systemic lupus erythematosus (SLE) (9), and from healthy controls (20) were analyzed. RESULTS: Compared with controls (1) Wegener's granulomatosis is significantly associated with noncytotoxic AECA that selectively bind surface antigens on unstimulated nasal, kidney, and lung endothelial cells; (2) binding of Wegener's granulomatosis AECA to kidney and nasal endothelial cells in particular was lost upon treatment with IFN-gamma and TNF-alpha; (3) the two cytokines per se were cytotoxic (30%) to nasal and lung endothelial cells and lysis was further increased (60%) by addition of systemic vasculitis serum; and (4) Wegener's granulomatosis serum caused agglutination of cytokine-stimulated nasal endothelial cells. CONCLUSION: Based on these findings we suggest that AECA may be one factor involved in the initiation of Wegener's granulomatosis. Antigen identification and elucidation of the pathogenic roles of AECA and inflammatory cytokines in systemic vasculitis using these cells will be particularly important.

Etanercept versus etanercept plus methotrexate: a registry-based study suggesting that the combination is clinically more efficacious.

Etanercept can be used both as monotherapy and in combination with methotrexate (MTX), but direct comparisons of these two options have not yet been reported. In order to compare the results seen in actual practice between these two options, clinical data on 97 patients followed in the Stockholm TNFalpha Follow-Up Registry were analysed. In 57 of these patients etanercept was added to previously started MTX while the others were treated with etanercept alone. The two groups had similar levels of disease activity at baseline. After 3 months, a significantly lower mean disease activity score (28-joint count-based disease activity score) was attained by the patients on etanercept plus MTX. In this group, the number of patients achieving European League Against Rheumatism-defined remission was also significantly greater. Other disease outcomes showed non-significant trends in the same direction. These data suggest that the combination of etanercept plus MTX is clinically more efficacious than etanercept alone.

Serum sFAS levels are elevated in ANCA-positive vasculitis compared with other autoimmune diseases.

The role of the Fas/FasL system in ANCA-associated vasculitis is unclear. We therefore assessed levels of soluble Fas (sFas) in sera and Fas expression on mononuclear cells from patients with ANCA-positive vasculitis and compared the results with those found in other rheumatic diseases. Serum levels of sFas were determined by ELISA. The ANCA-positive vasculitis patients studied included 29 at onset, 17 in first remission while on therapy, and 12 in quiescence. For comparison, 10 patients with Sjogren's syndrome (SS), 14 patients with systemic lupus erythematosus (SLE), 29 patients with rheumatoid arthritis (RA), 7 patients on dialysis (DP), and 26 healthy controls (HC) were studied. In addition, Fas expression in mononuclear cells was examined at the mRNA level using reverse transcriptase (RT)-PCR in 6 vasculitis patients at onset and in first remission. The expression of CD95 on the surface of leukocytes was determined by flow cytometry in 6 vasculitis patients at onset of the disease, in 6 patients in clinical remission, and in 6 HC. Expression of Fas and FasL in renal biopsy specimens was studied using immunohistochemistry. Patients with vasculitis had high sFas levels irrespective of disease phase. Both vasculitis patients and patients with RA and SLE had significantly increased sFas levels compared with healthy controls. All patient groups had sFas levels, which correlated with raised serum creatinine values. However, the sFas levels in vasculitis patients in first remission and in quiescence were increased despite a lower serum creatinine compared with onset. Some of the vasculitis patients showed an increased mRNA expression of Fas in mononuclear cells after treatment, suggesting that Fas production fluctuates with the intensity of the disease. The expression of CD95 on leukocytes was slightly decreased in vasculitis patients compared to healthy controls. No alterations of Fas and FasL expression were seen in renal biopsy specimens. These results show that ANCA-positive vasculitis patients have high sFas levels and that the levels remain elevated even in clinical remission. The findings indicate that perturbations in the Fas/Fas ligand system may play a role in the disease process in ANCA vasculitis.