Tumor necrosis factor (TNF) antagonists reduce the signs and symptoms of spondyloarthritides, including ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Our objective was to evaluate the effectiveness and safety of adalimumab, 40 mg every other week, for patients with AS or PsA and prior treatment with infliximab (IFX) and/or etanercept (ETN).
Both trials were 12-week, open-label studies with an optional extension period up to week 20. Patients were stratified by history of anti-TNF treatment, prior anti-TNF therapy received (IFX, ETN, or both), and reason for discontinuation of prior TNF antagonist. ETN was discontinued ≥ 3 weeks, and IFX was discontinued ≥ 2 months before the first adalimumab administration. Effectiveness at week 12 was evaluated by using observed standard-outcome measurements for AS and PsA.
At week 12 of adalimumab treatment, Bath Ankylosing Spondylitis Disease Activity Index 50 responses were achieved by 40.8% of 326 patients with AS who had received prior anti-TNF therapy and by 63.0% of 924 patients with AS who were naive to TNF antagonist. Observed response rates were generally greater for patients who discontinued the prior anti-TNF therapy because of loss of response or intolerance than for patients who discontinued because of lack of response. Median changes in swollen-joint count and in enthesitis score were similar in patients with and without prior TNF-antagonist treatment. Modified PsA response criteria were fulfilled by 71.2% of 66 patients with PsA, with prior exposure to TNF antagonists, and by 78.8% of 376 patients with no history of anti-TNF therapy. The percentages of patients with PsA attaining a Physician's Global Assessment of psoriasis of "Clear/Almost clear" increased from 33.3% to 61.0% for patients with prior IFX and/or ETN treatment and from 34.6% to 69.7% for patients without anti-TNF therapy. The median change in the Nail Psoriasis Severity Index was -6 for both groups. In both studies, patterns of adverse events were similar for patients with and without prior anti-TNF therapy and were consistent with the known safety profile of adalimumab.
Patients with AS or PsA previously treated with IFX and/or ETN experienced clinically relevant improvements of their diseases after 12 weeks of adalimumab.
ClinicalTrials.gov NCT00478660 and NCT00235885.
As long-term treatment with antitumour necrosis factor (TNF) drugs becomes accepted practice, the risk assessment requires an understanding of anti-TNF long-term safety. Registry safety data in rheumatoid arthritis (RA) are available, but these patients may not be monitored as closely as patients in a clinical trial. Cross-indication safety reviews of available anti-TNF agents are limited.
To analyse the long-term safety of adalimumab treatment.
This analysis included 23 458 patients exposed to adalimumab in 71 global clinical trials in RA, juvenile idiopathic arthritis, ankylosing spondylitis (AS), psoriatic arthritis, psoriasis (Ps) and Crohn's disease (CD). Events per 100 patient-years were calculated using events reported after the first dose through 70 days after the last dose. Standardised incidence rates for malignancies were calculated using a National Cancer Institute database. Standardised death rates were calculated using WHO data.
The most frequently reported serious adverse events across indications were infections with greatest incidence in RA and CD trials. Overall malignancy rates for adalimumab-treated patients were as expected for the general population; the incidence of lymphoma was increased in patients with RA, but within the range expected in RA without anti-TNF therapy; non-melanoma skin cancer incidence was raised in RA, Ps and CD. In all indications, death rates were lower than, or equivalent to, those expected in the general population.
Analysis of adverse events of interest through nearly 12 years of adalimumab exposure in clinical trials across indications demonstrated individual differences in rates by disease populations, no new safety signals and a safety profile consistent with known information about the anti-TNF class.
The introduction of tumor necrosis factor-α (TNF-α) inhibitors represented a significant advance in the management of rheumatoid arthritis (RA) and other chronic inflammatory diseases. Although three TNF-α inhibitors have been approved for the treatment of RA by the US Food and Drug Administration (FDA) and the European Medicinal Products Evaluation Agency (EMEA), not all patients achieve a satisfactory clinical improvement with these therapeutic agents. The mode of administration of these medications is inconvenient for some patients.
Golimumab is a novel anti-TNF-α monoclonal antibody that is in clinical development for the treatment of RA, psoriatic arthritis (PsA), and ankylosing spondylitis (AS), either as a first-line biologic therapy or an alternative after other TNF-α inhibitors have been discontinued. This review summarizes the development of, and clinical evidence achieved with, golimumab.
Golimumab has demonstrated significant efficacy in randomized, double-blind, placebo-controlled trials when administered subcutaneously once every four weeks. It has been generally well tolerated in clinical trials and demonstrates a safety profile comparable with currently available TNF-α inhibitors.
Golimumab has been confirmed to be an effective treatment for patients with RA, PsA, and AS in phase III clinical trials as evaluated by traditional measures of disease activity, such as signs and symptoms, as well as measures of physical function, patient reported outcomes, and health economic measures. The efficacy and safety profile of golimumab in RA, PsA, and AS appears to be similar to other anti-TNF agents. However, golimumab has the potential advantage of once monthly subcutaneous administration and the possibility of both subcutaneous and intravenous administration.
golimumab; TNF-α inhibitors; rheumatoid arthritis; psoriatic arthritis; ankylosing spondylitis
Treatment of rheumatoid arthritis (RA) with infliximab (Remicade®) has been associated with the induction of antinuclear autoantibodies (ANA) and anti-double-stranded DNA (anti-dsDNA) autoantibodies. In the present study we investigated the humoral immune response induced by infliximab against organ-specific or non-organ-specific antigens not only in RA patients but also in patients with ankylosing spondylitis (AS) during a two-year followup. The association between the presence of autoantibodies and clinical manifestations was then examined. The occurrence of the various autoantibodies was analyzed in 24 RA and 15 AS patients all treated with infliximab and in 30 RA patients receiving methotrexate but not infliximab, using the appropriate methods of detection. Infliximab led to a significant induction of ANA and anti-dsDNA autoantibodies in 86.7% and 57% of RA patients and in 85% and 31% of AS patients, respectively. The incidence of antiphospholipid (aPL) autoantibodies was significantly higher in both RA patients (21%) and AS patients (27%) than in the control group. Most anti-dsDNA and aPL autoantibodies were of IgM isotype and were not associated with infusion side effects, lupus-like manifestations or infectious disease. No other autoantibodies were shown to be induced by the treatment. Our results confirmed the occurrence of ANA and anti-dsDNA autoantibodies and demonstrated that the induction of ANA, anti-dsDNA and aPL autoantibodies is related to infliximab treatment in both RA and AS, with no significant relationship to clinical manifestations.
ankylosing spondylitis; anti-β2-glycoprotein I autoantibodies; antiphospholipid autoantibodies; infliximab; rheumatoid arthritis.
Objective. To describe working status in patients with RA, AS and PsA treated with anti-TNF therapy registered with the British Society for Rheumatology Biologics Register.
Methods. Patients with RA (n = 3291), AS (n = 229) and PsA (n = 254) treated with anti-TNF therapy were included in this study. In addition, biologic-naive patients with RA (n = 379) were included. At baseline and 3 years after registration, all patients reported their working status. Baseline characteristics between working and work-disabled patients were compared. Logistic regression analysis was applied to identify factors associated with new work disability in patients with RA.
Results. At baseline, work disability rates were already high: 49% for RA, 39% for PsA, 41% for AS and 36% for biologic-naive patients. Work-disabled patients had a higher HAQ score and worse disease activity than working patients. Working patients with a high HAQ score [odds ratio (OR) 2.79; 95% CI 1.89, 4.12] and a manual job (OR 2.31; 95% CI 1.52, 3.52) at baseline were more likely to become work disabled at follow-up, while those patients in remission 6 months after commencing anti-TNF therapy were less likely to become work disabled. However, use of anti-TNF therapy did not prevent patients with RA from becoming work disabled (OR for RA control patients vs RA anti-TNF patients 0.80; 95% CI 0.36, 1.81, adjusted for baseline variables).
Conclusion. A high percentage of patients with RA, AS and PsA were already work disabled at the start of anti-TNF therapy. There is less future work disability in working patients with RA who responded to anti-TNF therapy.
Rheumatoid arthritis; Ankylosing spondylitis; Psoriatic arthritis; Work disability; Anti-TNF therapy
To evaluate the clinical response after switching from one tumour necrosis factor (TNF)α antagonist to another in patients with ankylosing spondylitis (AS) and psoriatic arthritis (PsA).
In this ongoing, longitudinal, observational study, data were prospectively collected on efficacy and safety since 2000 for patients starting biological treatments. The present analysis was restricted to patients with a diagnosis of spondyloarthropathy (SpA) who switched from one TNFα antagonist to another because of inadequate efficacy or adverse events.
In total, 589 anti‐TNFα‐naive patients were registered, of whom 165 had a diagnosis of SpA; 7 patients with AS and 15 with PsA received >1 TNFα antagonist. Two patients with PsA were treated with all the drugs. In all, 16 subjects switched from infliximab to etanercept, 7 from etanercept to adalimumab and 1 from etanercept to infliximab. Overall, a clinical response was seen in 75% of patients who changed from infliximab to etanercept, and in 57.1% who switched from etanercept to adalimumab.
The findings of this study on a selected population of patients with SpA indicate that the failure of an initial TNFα antagonist does not preclude the response to another one. Further trials are needed to confirm this preliminary observation.
spondyloarthropathy; ankylosing spondylitis; psoriatic arthritis; TNFα antagonists; switching
The conventional approach to treatment of patients with spondyloarthritis (SpA), particularly ankylosing spondylitis (AS), has serious limitations, adding a sense of urgency to the evaluation of new treatments for these rheumatic disorders. Tumour necrosis factor α (TNFα) is a cytokine that has been shown to mediate inflammatory and regulatory activities in SpA and other immune mediated diseases, including other arthritides and inflammatory bowel disease. Positive results have been reported in several international open label and randomised controlled trials of infliximab and etanercept, the two main biological agents targeting TNFα, which have included approximately 300 patients with SpA. Specifically, TNFα-directed therapy resulted in significant improvements in disease activity, function, and quality of life in these patients, most of whom had AS and received infliximab. Preliminary evidence from open label, long term extension trials suggests clinical benefit with continued use. Serious side effects were rare and consistent with experience from patient groups receiving infliximab or etanercept treatment for inflammatory bowel disease or rheumatoid arthritis. Together, these findings herald an age of more effective treatment of patients with AS with anti-TNFα and other emerging biological agents.
New developments in the field of targeted therapies or biologic agents led more effective management of ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Recommendations for the management of rheumatic diseases propose to reduce inappropriate use of medications, minimize variations among countries, and enable cost-effective use of health care resources.
The aim this study was to evaluate conceptual agreement of ASsessment in SpondyloArthritis International Society (ASAS) and the EUropean League Against Rheumatism (EULAR) recommendations for the management of AS and EULAR recommendations for RA and to assess the rate of application among Turkish physiatrists in daily clinical practice.
An online survey link has been sent to 1756 Turkish physiatrists with e-mails asking to rate agreement on 11-item ASAS/EULAR AS recommendations and 15-item EULAR RA recommendations with synthetic and biological disease-modifying anti-rheumatic drugs. Also barriers and difficulties for using biologic agents were assessed.
Three hundred nine physiatrists (17.5%) completed the survey. The conceptual agreement with both recommendations was very high (Level of agreement; mean 8.35±0.82 and 8.90± 0.67 for RA and AS recommendations, respectively), and the self-declared application of overall recommendations in the clinical practice was also high for both RA and AS (72.42% and 75.71%, respectively).
Turkish physiatrists are in good conceptual agreement with the evidence-based recommendations for the management of AS and RA. These efforts may serve to disseminate the knowledge and increase the current awareness among physicians who serve to these patients and also implementation of these recommendations is expected to increase as well.
Rheumatoid arthritis; ankylosing spondylitis; recommendations; agreement; physiatrist.
Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA).
To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy.
Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail.
Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient's status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9–10 (10: maximum agreement) for all recommendations. A research agenda was formulated.
The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.
Treat-to-target; spondyloarthritis; ankylosing spondylitis; psoriatic arthritis; therapy
Background: There is currently no universal consensus on nomenclature for spondyloarthropathy (SpA), or on activity and severity criteria for ankylosing spondylitis (AS).
Method: Points of agreement and majority opinions among 28 international experts in the field were identified by questionnaire. Agreement was defined as >80% concurrence, clear majority as >60% concurrence, and a majority or trend as >50% concurrence.
Results: Respondents agreed on the need for one term that reflects the inflammatory nature of the disease, but no agreement was reached on a specific term. Agreement included subdivision of patients with SpA into AS, psoriatic arthritis, inflammatory bowel disease associated arthritis, and undifferentiated spondyloarthritis/spondyloarthropathy. A majority of experts defined active disease as fulfilling classification criteria for AS and/or a SpA, and disease activity measured by a Bath AS Disease Activity Index (BASDAI) score >4 determined by two patient visits during a two month period, but no maximum radiographic score. The majority of participants considered failure of treatment response to non-steroidal anti-inflammatory drugs (NSAIDs) alone to be a prerequisite for active/severe AS, and 15/28 (54%) thought that NSAID treatment failure should be defined as lack of response to two or more NSAIDs.
Conclusions: Respondents agreed that a two to five year study is the ethical method to demonstrate effects of anti-tumour necrosis factor α (TNFα) therapy on radiographic progression of AS, and that inclusion criteria should include a certain level of disease activity (measured by BASDAI) and failure of certain treatments. After the efficacy of anti-TNFα therapy in AS and psoriatic arthritis is proved, respondents agreed that more studies will be needed to show efficacy for other SpA subsets.
The aim of the present study was to emphasize the collagen turnover in 2 of the most common chronic inflammatory rheumatic diseases by evaluating serum prolidase activity (SPA) in ankylosing spondylitis (AS) and rheumatoid arthritis (RA). 30 patients who met the modified New York Criteria for the classification of AS, 29 patients who met the 2010 Rheumatoid Arthritis Classification Criteria for the classification of RA, and 31 healthy controls were enrolled in the study. Serum samples of the patients and the controls were collected and SPA was measured by a spectrophotometric method. The comparison of the SPA in these 3 groups was statistically examined. In both patient groups, the SPA was lower than in the control group. SPA in patients with AS was statistically significantly lower than in the control and RA groups (P < 0.001/P = 0.002). No statistically significant difference was found between the RA and the control groups (P = 0.891). In conclusion, lower SPA is presumably associated with decreased collagen turnover and fibrosis, leading to decreased physical functions in both chronic inflammatory musculoskeletal diseases.
ankylosing spondylitis; rheumatoid arthritis; serum prolidase activity
Background: Anti-tumour necrosis factor (TNF) treatment is clinically efficacious in patients with active ankylosing spondylitis (AS) and leads to improvement of spinal inflammation, as assessed by magnetic resonance imaging. It is unclear whether anti-TNF treatment affects chronic spinal changes in AS.
Objectives: To analyse the effect of infliximab on the radiographic course of AS over 2 years.
Methods: Complete sets of lateral radiographs of the cervical spine and lumbar spine were available from 82 patients from two sources: 41 patients (group 1) had been treated with infliximab (5 mg/kg/6 weeks) as part of a recent randomised controlled trial and 41 patients (group 2) were part of the early German AS cohort (GESPIC), without controlled interventions. Radiographs were obtained at baseline and after 2 years and scored by the modified Stokes AS Spinal Score (mSASSS).
Results: Patients in the infliximab group were older, had a longer disease duration, and more radiographic damage at baseline. The mean (SD) mSASSS change was 0.4 (2.7) and 0.7 (2.8) for groups 1 and 2, respectively (p = NS). Radiographic damage at baseline was a predictor for more radiographic progression. Patients with baseline damage who were treated with infliximab showed a trend for less radiographic progression. No correlations between clinical parameters and radiographic progression were found.
Conclusions: Patients with AS treated with infliximab had less radiographic progression after 2 years. Patients with prevalent radiographic damage are prone to develop more damage over time. Infliximab may decelerate radiographic progression in such patients. Larger studies are needed to prove that anti-TNF treatment inhibits structural damage.
Objectives: To investigate whether anti-Saccharomyces cerevisiae antibodies (ASCA), a marker for Crohn's disease (CD), are present in spondyloarthropathies (SpA) and in the subgroups ankylosing spondylitis (AS), undifferentiated SpA (uSpA), and psoriatic arthritis (PsA), in comparison with healthy and inflammatory controls (patients with rheumatoid arthritis (RA)).
Methods: ASCA IgA and IgG levels were measured with an enzyme linked immunosorbent assay (ELISA) kit (Medipan, Germany) in 26 patients with CD, 108 patients with SpA (43 patients with AS, 20 patients with uSpA, 45 patients with PsA), 56 patients with RA and 45 healthy controls. Gut biopsy samples were available in 18 AS and 10 patients with uSpA, these samples were screened for the presence of inflammation.
Results: Both ASCA IgG and IgA levels were raised in CD compared with healthy controls and patients with RA. ASCA IgA, but not IgG levels, were higher in SpA than in both healthy and RA controls. ASCA IgA levels were raised in AS and uSpA, but not in PsA. No significant differences in ASCA IgA levels were noted between patients with SpA with and without histological gut inflammation.
Conclusion: ASCA IgA levels are significantly higher in SpA, and more specifically in AS, than in healthy controls and patients with RA. This is the first serum marker associated with SpA. No correlation between the presence of subclinical bowel inflammation and ASCA IgA levels was noted. However, it remains to be evaluated whether patients with SpA with ASCA have an increased risk of developing CD.
There is no consensus on whether it is safe to re-administer tumor necrosis factor-alpha (TNFα) inhibitors in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) flared after withdrawal of TNFα inhibitors due to active tuberculosis (TB). We evaluated the safety of restarting anti-TNFα therapy in patients with TNFα-associated TB. We used data of 1,012 patients with RA or AS treated with TNFα inhibitors at Seoul St. Mary's Hospital between January 2003 and July 2013 to identify patients who developed active TB. Demographic and clinical data including the results of tuberculin skin tests (TST) and interferon-γ releasing assays (IGRA) were collected. Fifteen patients developed active TB. Five cases were occurred in RA and 10 cases in AS. Nine of 15 patients had a negative TST or IGRA and 6 TST-positive patients had received prophylaxis prior to initiating anti-TNFα therapy. All patients discontinued TNFα inhibitors with starting the treatment of TB. Eight patients were re-administered TNFα inhibitors due to disease flares and promptly improved without recurrence of TB. TNFα inhibitors could be safely resumed after starting anti-TB regimen in patients with RA or AS.
TNFα Inhibitor; Tuberculosis; Arthritis, Rheumatoid; Spondylitis, Ankylosing
To date, anti-tumor necrosis factor alfa (anti-TNF-α) therapy is the only alternative to nonsteroidal anti-inflammatory drugs for the treatment of ankylosing spondylitis. Etanercept is a soluble TNF receptor, with a mode of action and pharmacokinetics different to those of antibodies and distinctive efficacy and safety. Etanercept has demonstrated efficacy in the treatment of ankylosing spondylitis, with or without radiographic sacroiliitis, and other manifestations of the disease, including peripheral arthritis, enthesitis, and psoriasis. Etanercept is not efficacious in inflammatory bowel disease, and its efficacy in the treatment of uveitis appears to be lower than that of other anti-TNF drugs. Studies of etanercept confirmed regression of bone edema on magnetic resonance imaging of the spine and sacroiliac joint, but failed to reduce radiographic progression, as do the other anti-TNF drugs. It seems that a proportion of patients remain in disease remission when the etanercept dose is reduced or administration intervals are extended. Etanercept is generally well tolerated with an acceptable safety profile in the treatment of ankylosing spondylitis. The most common adverse effect of etanercept treatment is injection site reactions, which are generally self-limiting. Reactivation of tuberculosis, reactivation of hepatitis B virus infection, congestive heart failure, demyelinating neurologic disorders, hematologic disorders like aplastic anemia and pancytopenia, vasculitis, immunogenicity, and exacerbation or induction of psoriasis are class effects of all the anti-TNF drugs, and have been seen in patients with ankylosing spondylitis. However, etanercept is less likely to induce reactivation of tuberculosis than the other anti-TNF drugs and it has been suggested that etanercept might be less immunogenic, especially in ankylosing spondylitis. Acute uveitis, Crohn’s disease, and sarcoidosis are other adverse events that have been rarely associated with etanercept therapy in patients with ankylosing spondylitis.
ankylosing spondylitis; etanercept; spondyloarthritis; efficacy; safety
Whether physical functioning in patients with rheumatoid arthritis (RA) differs from that in patients with ankylosing spondylitis (AS) is presently uncertain. Such a comparison poses challenges, not only because the two diseases differ in the domains of functioning affected, but also because of the different instruments used to measure functional limitations. Limiting our analysis to studies using similar self-report questionnaires, we examined published observational studies of unselected cohorts of patients with RA and patients with AS to compare and contrast the severity of functional limitations. Available studies from a few direct comparisons, and mostly indirect comparisons, suggested that patients with RA are generally more severely limited in physical functioning throughout the disease course than patients with AS. Since most studies did not adjust adequately for potentially important confounders, such as age, gender, comorbidity, and disease duration, reported differences in functional disability between patients with RA and patients with AS must be interpreted cautiously.
Rheumatoid arthritis; ankylosing spondylitis; physical function; functional limitation
OBJECTIVES—To investigate the occurrence of and risk factors for focal sialadenitis in patients with rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), ankylosing spondylitis (AS), and spondyloarthropathy (SpA).
METHODS—A total of 85 patients (25 with RA, 19 with MCTD, 19 with AS, 22 with SpA) participated in the study. Each patient filled out a questionnaire for eye and oral symptoms and for the use of medication, and was interviewed; other tests included Schirmer's test, laboratory tests, collection of unstimulated and stimulated whole saliva, and minor salivary gland biopsy. A focus score of ⩾1 was regarded as an indicator of focal sialadenitis.
RESULTS—Focal sialadenitis was observed in 68% (57/84) of all patients. It affected 80% (20/25) of the patients with RA, 94% (17/18) of those with MCTD, 58% (11/19) of those with AS, and 41% (9/22) of those with SpA (χ2 test, p=0.0013). Salivary secretion correlated negatively with the focus scores—that is, severity of focal sialadenitis. Patients with focal sialadenitis had both decreased salivary secretion and decreased tear secretion significantly more often than did patients without (χ2 test, p=0.0074 and p=0.048 respectively). Patients with positive rheumatoid factor (RF), antinuclear antibodies (ANA), or SSA or SSB antibodies had sialadenitis significantly more often than did patients with negative antibodies. In the subgroup of patients with AS or SpA, no associations were found between focal sialadenitis and the presence of these antibodies.
CONCLUSION—In addition to patients with RA or MCTD, focal sialadenitis also affects a very high proportion of patients with AS or SpA. Focus scores are significantly higher in patients with RA or MCTD than in those with AS or SpA. A significant association exists between focal sialadenitis and RF, ANA, SSA and SSB. However, in the subgroup of patients with AS or SpA, no associations were found between focal sialadenitis and serological markers or clinical symptoms.
The purpose of this study was to investigate the effectiveness of adalimumab in enthesitis and peripheral arthritis in patients with ankylosing spondylitis (AS).
Adults with active AS (Bath ankylosing spondylitis disease activity index [BASDAI] ≥ 4) received adalimumab 40 mg every other week with standard antirheumatic therapies in a 12-week, open-label study. Effectiveness in enthesitis was assessed using the Maastricht ankylosing spondylitis enthesitis score (MASES, 0-13) and by examining the plantar fascia in patients with enthesitis (≥ 1 inflamed enthesis) at baseline; effectiveness in peripheral arthritis was evaluated using tender and swollen joint counts (TJC, 0-46; SJC, 0-44) in patients with peripheral arthritis (≥ 1 swollen joint) at baseline. Overall effectiveness measures included Assessment of SpondyloArthritis International Society 20% response (ASAS20).
Of 1,250 patients enrolled, 686 had enthesitis and 281 had peripheral arthritis. In 667 patients with MASES ≥ 1 at baseline, the median MASES was reduced from 5 at baseline to 1 at week 12. At week 12, inflammation of the plantar fascia ceased in 122 of 173 patients with inflammation at baseline. The median TJC in 281 patients with SJC ≥ 1 at baseline was reduced from 5 at baseline to 1 at week 12; the median SJC improved from 2 to 0. ASAS20 responses were achieved by 70.5% of 457 patients with no enthesitis and no arthritis; 71.0% of 512 patients with only enthesitis; 68.0% of 107 patients with only arthritis; and 66.7% of 174 patients with both.
Treatment with adalimumab improved enthesitis and peripheral arthritis in patients with active AS.
Inflammation driven connective tissue turnover is key in rheumatic diseases, such as ankylosing spondylitis (AS). Few biomarkers are available for measuring disease prognosis or the efficacy of interventions applied in these tissue-related conditions. Type II collagen is the primary structural protein of cartilage and type III collagen of connective tissues, and obvious targets for the collagenalytic, which increase during tissue inflammation. The objective of the study was to investigate the diagnostic and prognostic utility of cartilage, C2M, and synovial, C3M, turnover biomarkers in AS. Serum samples were retrieved from patients suffering from AS (n = 103), RA (n = 47) and healthy controls (n = 56). AS progressors were defined as having new vertebral syndesmophytes or more that 3 unit change in mSASSS over a two-year period. Type II collagen degradation markers in serum were measured by the C2M ELISA, and type III collagen degradation by the C3M ELISA. Logistic regression and dichotomized decision tree were used to analyze the prognostic value of the markers individually or in combination. Both C2M and C3M levels were significantly higher in RA patients than in healthy controls (p<0.0001). Diagnostic utility was analyzed by ROC and areas under the curve (AUCs) were 72% and 89% for C2M and C3M, respectively. Both C2M and C3M, were significantly higher in serum samples from AS patient than from healthy controls (p<0.0001). The AUCs of C2M and C3M, respectively, were 70% and 81% for AS. A combination of C2M and C3M, dichotomized according to best cut-offs for individual markers, could correctly identify 80% of the progressors and 61% of the non-progressors. The present study is the first to show that specific biomarkers of cartilage and connective tissue degradation facilitate both diagnosis and prediction of progression of RA and AS.
Non-steroidal anti-inflammatory agents (NSAIDs) remain the mainstay of treatment for ankylosing spondylitis (AS) though one recent trial suggests that continuous as opposed to on-demand use may be superior in preventing progression of structural damage. One particular NSAID, which is a highly selective cyclo-oxygenase 2 inhibitor, etoricoxib, may be superior to standard NSAIDs for AS. Second-line agents typically used for rheumatoid arthritis appear to lack efficacy. Salazopyrin is only moderately effective in the subgroup of AS patients with concomitant peripheral arthritis and not in those with purely axial disease. A recent trial showed that there is no greater efficacy in patients presenting early in their disease course. Three anti-tumor necrosis factor alpha agents, infliximab, etanercept, and adalimumab, are now available for the treatment of AS, the latest being adalimumab. All possess similar clinical efficacy in phase III trials with response rates of about 60%. Imaging studies using magnetic resonance show substantial amelioration of inflammatory lesions in the spine and sacroiliac joints. There is as yet no evidence that any of these agents prevent progression of structural damage. One study that evaluated etanercept demonstrated no impact on damage progression. Increasing evidence points to the superiority of the two monoclonal antibodies, infliximab and adalimumab, over etanercept for the treatment of extra-articular manifestations typically seen in AS such as acute anterior uveitis and inflammatory bowel disease. All three agents can be used as monotherapy and concomitant methotrexate appears to offer no advantages although insufficient doses have been used to date. Future studies should target patients earlier in their disease course as well as those with adverse prognostic factors such as elevated serum metalloproteinase 3 levels and radiographic evidence of spinal ankylosis.
infliximab; etanercept; adalimumab; ankylosing spondylitis; NSAIDs
Structural changes of bone and cartilage are a hallmark of inflammatory joint diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Despite certain similarities – in particular, inflammation as the driving force for structural changes – the three major inflammatory joint diseases show considerably different pathologies. Whereas RA primarily results in bone and cartilage resorption, PsA combines destructive elements with anabolic bone responses, and AS is the prototype of a hyper-responsive joint disease associated with substantial bone and cartilage apposition. In the present review we summarize the clinical picture and pathophysiologic processes of bone and cartilage damage in RA, PsA, and AS, we describe the key insights obtained from the introduction of TNF blockade, and we discuss the future challenges and frontiers of structural damage in arthritis.
Acetylation or deacetylation of histone proteins may modulate cytokine gene transcription such as TNF alpha (TNF). We evaluated the balance between histone deacetytlase (HDAC) and histone acetyltransferase (HAT) in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) compared to healthy controls (HC) and determined the influence of HDAC inhibitors (trichostatin A -TSA- or Sirtinol -Sirt-) on these enzymatic activities and on the PBMC production of TNF.
52 patients with RA, 21 with AS and 38 HC were evaluated. HAT and HDAC activities were measured on nuclear extracts from PBMC using colorimetric assays. Enzymatic activities were determined prior to and after ex vivo treatment of PBMC by TSA or Sirt. TNF levels were evaluated in PBMC culture supernatants in the absence or presence of TSA or Sirt.
HAT and HDAC activities were significantly reduced in AS, while these activities reached similar levels in RA and HC. Ex vivo treatment of PBMC by HDACi tended to decrease HDAC expression in HC, but Sirt significantly reduced HAT in RA. TNF production by PBMC was significantly down-regulated by Sirt in HC and AS patients.
HAT and HDAC were disturbed in AS while no major changes were found in RA. HDACi may modulate HDAC and HAT PBMC expression, especially Sirt in RA. Sirtinol was able to down regulate TNF production by PBMC in HC and AS. An imbalance between HAT and HDAC activities might provide the rationale for the development of HDACi in the therapeutic approach to inflammatory rheumatic diseases.
The health-related quality of life (HRQL) is an important indicator of the burden of musculoskeletal disease. The Medical Outcome Study Short-Term 36 (SF-36) is the most used tool that evaluates HRQL as a subjective perception about psychological and physical limitations due to an underlying illness. The purpose of this study was to compare the HRQL scores among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) and a selected sample of health people and determine their relationship with measures of clinical condition.
799 patients (469 with RA, 164 with AS, 65 with axial PsA and 101 with peripheral PsA) accepted the invitation to participate. 1579 healthy controls were used for the comparison. We calculated scores for the eight SF-36 subscales, the Physical Component Summary (PCS) score, and the Mental Component Summary (MCS) score, according to published algorithms. Disease-related characteristics included disease duration, comorbidity, a measure for disease activity and for radiographic damage. The presence of comorbidity was ascertained through patient's self-reports by the Self-Administered Comorbidity Questionnaire (SCQ). Comparison were performed with respect to sex and age, and s-scores were calculated for comparison with the norm. Multivariate analyses were used to assess the relationship between HRQL and radiographic damage, disease activity, and socio-demographic data.
The four inflammatory rheumatic diseases (IRD), compared to controls, significantly impaired all eight health concepts of the SF-36 (p < 0.0001) in both component PCS and MCS scores (p < 0.0001). Overall, the dimensions typically affected were physical functioning, limitations due to physical function, and bodily pain. The disease with the worst HRQL for those dimensions was RA. The multivariate analyses revealed that the physical component was influenced by a high disease activity and comorbidity. The severity of psoriatic lesions was associated with poor mental functioning in patients with PsA.
Chronic IRD have a clearly detrimental effect on the HRQL in both sex and in age groups, and physical domain is more impaired than mental and social ones.
To estimate and compare the direct and indirect costs of illness in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis (PsA) and systemic lupus erythematosus (SLE), and to evaluate the effect of sex, disease duration and functional status on the various cost domains.
Data of outpatients, aged 18–65, with rheumatoid arthritis (n = 4351), ankylosing spondylitis (n = 827), PsA (n = 908) or SLE (n = 844), who were enrolled in the national database of the German collaborative arthritis centres in 2002, were analysed. Data on healthcare consumption, out‐of‐pocket expenses and productivity losses were derived from doctors and patients. For the calculation of indirect costs, the human capital approach (HCA) and the friction cost approach (FCA) were applied.
Mean direct costs amounted to €4737 a year in rheumatoid arthritis, €3676 in ankylosing spondylitis, €3156 in PsA and €3191 in SLE. By using the HCA, total costs were calculated at €15 637 in rheumatoid arthritis, €13 513 in ankylosing spondylitis, €11 075 in PsA and €14 411 in SLE, whereas with the FCA the numbers were €7899, €7204, €5570 and €6518, respectively. Costs increased with disease duration and were strongly dependent on functional status. In patients with the highest disability (<50% of full function), the total costs on applying the HCA were €34 915 in rheumatoid arthritis, €29 647 in alkylosing spondylitis, €37 440 in PsA and €32 296 in SLE.
The costs of illness are high in all four diseases, with a strong effect of functional status on total costs. Indirect costs differ by the factor 3, based on whether the HCA or the FCA is used.
Objective. Few data exist on the use of anti-TNF drugs for AS during routine clinical use in the UK. This report describes an improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) after 6 months of therapy in 261 patients enrolled in a national prospective observational register.
Methods. The British Society for Rheumatology Biologics Register (BSRBR) recruited patients starting anti-TNF therapy for AS between 2002 and 2006. Multivariable linear regression models were used to estimate the predictors of absolute improvement in BASDAI and BASFI at 6 months. Covariates included age, gender, disease duration, baseline BASDAI and BASFI, presence of raised inflammatory markers (defined as twice the upper limit of normal) and DMARD therapy.
Results. The cohort was young (median age 43 years) and 82% were males. Median baseline BASDAI was 7.6 and BASFI 7.9. At 6 months, the mean improvements in BASDAI and BASFI were 3.6 and 2.6 U, respectively; 52% reached a BASDAI50. Patients with raised inflammatory markers at the start of therapy had a 0.9-U (95% CI 0.2, 1.5) better improvement in BASDAI compared with those without. Lesser responses were seen in those with higher baseline BASFI scores. Women had a 1.1-U (95% CI 0.3, 2.0) greater improvement in BASFI at 6 months, as did those who were receiving concurrent DMARD therapy [0.9 U (95% CI 0.2, 1.7)].
Conclusions. The majority of patients receiving anti-TNF therapy for AS during routine care demonstrated an improvement in disease activity. Raised inflammatory markers at the start of therapy predicted a greater improvement in BASDAI, identifying a group of patients who may be more responsive to anti-TNF therapies, although the results were not confined to this group.
Anti-TNF; Etanercept; Infliximab; Adalimumab; Ankylosing spondylitis; Treatment response; Treatment effectiveness; Disability