Quantification of Bone Marrow Edema by Magnetic Resonance Imaging Only Marginally Reflects Clinical Neck Pain Evaluation in Rheumatoid Arthritis and Ankylosing Spondylitis.

OBJECTIVE: Neck pain is common in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). We investigated the correlation of bone marrow edema (BME) on magnetic resonance imaging (MRI) in RA and AS and its association with clinical complaints of neck pain. METHODS: Cervical spine short-tau inversion recovery-MRI and T1w-MRI of 34 patients with RA and 6 patients with AS complaining about neck pain were obtained. Clinical and laboratory data were available. BME was scored by 2 blinded readers using a modification of a published score, including various cervical sites. Degenerative changes were also quantified. RESULTS: Patients were predominantly women (82.5%), and mean ± SD age was 57.5 ± 11.8 years, C-reactive protein (CRP) was 0.8 ± 1.3 mg/dl, and pain score was 46.0 ± 17.5. BME was detected in 24/40 patients (60%) involving the atlantoaxial region (21%), vertebral bodies (75%), facet joints (29%), and spinous processes (46%). Degenerative changes were identified in 21/40 patients (52.5%), 13 (62%) of whom also had BME in vertebral bodies. No differences were found between patients with versus without cervical BME for clinical assessments: numeric rating scale pain (median ± interquartile range) 5.5 ± 3.0 vs 6.0 ± 4.0 (p = 0.69), Funktionsfragebogen Hannover 68.2 ± 41.0 vs 42.0 ± 55.5 (p = 0.19), Northwick pain score 44.4 ± 21.8 vs 47.2 ± 27.0 (p = 0.83), or CRP 0.40 ± 0.80 vs 0.60 ± 0.66 (p = 0.94). For patients with degenerative changes, symptom duration was longer than for patients without (10 ± 12.5 vs 5.0 ± 18.0 yrs, p = 0.73). CONCLUSION: In this small study of patients with RA and AS complaining about neck pain, BME was found in many different cervical sites, including the facet joints and the spinous processes. However, the occurrence and severity of BME did not correlate with the severity of neck pain.

Clinical experience with the European Ankylosing Spondylitis Infliximab Cohort (EASIC): long-term extension over 7 years with focus on clinical efficacy and safety.

OBJECTIVES: Knowledge on the long-term effects of anti-TNF therapy in patients with ankylosing spondylitis (AS) is still limited. Our objective was to study the long-term efficacy and safety of anti-TNF therapy in AS. METHODS: After having completed the first part of the EASIC trial a total of 71 patients were enrolled into this 96-week extension study. Patients were treated with the same dosages and dosing intervals of infliximab as in the EASIC core study. Efficacy was assessed by using standardised assessment tools such as BASDAI, BASFI, BASMI, patient global assessment, CRP levels and the proportion of patients without any sign of enthesitis or arthritis. Long-term safety was assessed by documenting adverse events (AE), serious adverse events (SAE) and reasons for dropping out. RESULTS: Of the 71 patients included, 64 (90.1%) completed the trial , and 7 discontinued: one was lost to follow-up, 3 withdrew informed consent and in 3 patients therapy was stopped for different reasons: secondary loss of response, recurrent infections and basal cell carcinoma of the skin. The completers showed rather stable low scores of BASDAI (mean 2.4, median 2.52), BASFI (mean 3.1, median 2.76) and BASMI (mean 3.2, median 3) as well as patients global assessment and CRP. The vast majority of patients did not have enthesitis or arthritis. A total of 476 AE were observed, 13 of which were SAE. The majority of these were infections and most of them affected the respiratory tract. Two malignancies occurred: one basal cell carcinoma and one malignant melanoma. These were the only SAE judged to be possibly related to the study drug. CONCLUSIONS: Anti-TNF treatment with infliximab is efficacious over long periods of time in patients with AS. The observation of two skin related malignancies, including one melanoma, during the whole study period of 7 years is in line with reports from previous large AS data sets.

Do patients with ankylosing spondylitis adapt to their disease? Evidence from a 'then-test' in patients treated with TNF inhibitors.

OBJECTIVE: To investigate whether patients with ankylosing spondylitis (AS) adapt to their disease, using the 'then-test'. METHODS: Data from patients participating in the AS Study for Evaluation of Recombinant Infliximab Therapy (ASSERT) and continuing in the European AS Infliximab Cohort (EASIC) were used. At 5 assessments in EASIC, patients were asked to rerate their global well-being before the start of infliximab in ASSERT. The patients evaluated their past situation by using a 'then-test' ('retrospective patient global'). Initial and retrospective patient global were compared using a paired t test, and mixed linear models investigated whether the retrospective score of well-being was stable at all follow-up assessments in EASIC. Linear regression analysis explored whether treatment response was associated with the difference between the initial and retrospective score ('gap') while adjusting for possible confounders. RESULTS: 86 patients (mean age 39.8 years (SD=10.4), mean disease duration 10.8 years (SD=8.5)) contributed to the current analyses. At the time of starting infliximab, patients judged their global at 7.0 (SD=1.6), and with the 'then-test' at 7.2 (SD=2.3) (p=0.45). Time elapsed did not influence the 'then-test' (p=0.13). Multivariably, the gap was irrespective of treatment response, but associated with initial patient global (p<0.01) and initial Bath AS Disease Activity Index (p=0.02). CONCLUSIONS: Patients with AS accurately judged their global well-being before starting treatment with tumour necrosis factor inhibition, even though substantial time had elapsed. The difference between initial and retrospective judgment was irrespective of treatment response. In this setting, the 'then-test' could not prove adaptation in AS. TRIAL REGISTRATION NUMBER: NCT01286545.

Emerging drugs for the treatment of axial and peripheral spondyloarthritis.

INTRODUCTION: The topic under discussion is of strong relevance to the field of spondyloarthritis (SpA) because, in addition to established biological, there are new promising compounds. The reason for the review is to put all available data together to allow for an overview on recent developments and to especially inform readers about emerging drugs, biologics and small molecules in the field of SpA. AREAS COVERED: This review on new therapies in axial and peripheral SpA comprising psoriatic arthritis (PsA) shows, that, in addition to the established anti-TNF agents infliximab, etanercept, adalimumab, golimumab, certolizumab and the first biosimilar approved in the EU, there are at least two emerging biologics in the field of SpA: ustekinumab, a compound targeting IL12/IL-23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn's disease, and the anti-IL-17 antibody secukinumab which has also been shown to work in psoriasis, both compounds seem to also work in ankylosing spondylitis. In addition, the potential of two small molecules, apremilast a phoshodiesterase4 inhibitor and tofacitinib, a januskinase inhibitor is discussed. EXPERT OPINION: Since, in contrast to rheumatoid arthritis, the therapeutic array in SpA is currently limited to TNF-blockers, and since there is still an unmet need because some patients do not respond to anti-TNF therapy at all or they loose response, new agents with a different mechanism of action are eagerly awaited.

Tumor necrosis factor alpha antagonists in the treatment of axial spondyloarthritis.

INTRODUCTION: The introduction of therapy with tumor necrosis factor antagonists (aTNF) was a cornerstone of treatment modalities in patients with ankylosing spondylitis (AS). After > 10 years of using aTNF, the introduction of aTNF therapy was a major step forward in the medical management of patients with spondyloarthritis (SpA), but there are still a number of scientific questions that have not been resolved. AREAS COVERED: This review includes both subtypes of axial spondyloarthritis (axSpA), non-radiographic axial SpA (nr-axSpA), and AS. It covers all five aTNF adalimumab, certolizumab, etanercept, golimumab, and infliximab, which are approved for patients with active AS. EXPERT OPINION: aTNF are efficacious and effective in reducing signs and symptoms of patients with axSpA. While aTNF reduce spinal inflammation, the effects on new bone formation are less clear. There may be a deceleration of radiographic progression in 4 years. The development of fatty lesions in vertebral edges seems to be relevant for that - especially when inflammation also persists. Reduction of aTNF doses seems to be possible in selected patients over time. In case of failure, switching to another aTNF works in the majority of cases. Long-term data suggest a favorable safety profile of aTNF.

Withdrawal of biologic therapy in axial spondyloarthritis: the experience in established disease.

Treatment of patients suffering from active ankylosing spondylitis (AS) with TNFα blockers, has been shown to result in clinically significant improvement of signs and symptoms of the disease. Long-term extension studies with these agents have shown sustained clinical efficacy for up to 10 years in patients who continued treatment. However, only a few studies have examined whether reduction of dosage of discontinuation of anti-TNF therapy is possible. In daily clinical practice, prolongation of treatment intervals is frequently tried in patients who are in clinical remission for longer periods of time, but no data on the success of that are available. Discontinuation of treatment is usually needed in patients who want to become pregnant, and in patients with severe infections. This review summarises what is known on the topic of discontinuation of biologic treatment in patients with AS.

Long-term outcome of patients with active ankylosing spondylitis with etanercept-sustained efficacy and safety after seven years.

INTRODUCTION: Data from clinical studies on the long-term efficacy and safety of anti-tumor necrosis factor (TNF)-α therapy in patients with ankylosing spondylitis (AS) are scarce. This is the first report on continuous treatment with the TNFα fusion protein etanercept over seven years (y). METHODS: Overall, 26 patients with active AS were initially treated with etanercept 2 × 25 mg s.c./week with no concomitant disease modifying anti-rheumatic drugs (DMARDs) or steroids. The clinical response was assessed by standardized parameters. The primary outcome was the proportion of patients in the Spondyloarthritis International Society (ASAS) partial remission at seven years. AS disease activity scores (ASDAS) for status and improvement were compared to conventional outcome measures. RESULTS: Overall, 21/26 patients (81%) completed two years of treatment and 16/26 patients (62%) completed seven years. In the completer analysis, 31% patients were in ASAS partial remission at seven years, while 44% patients showed an ASDAS inactive disease status. Mean Bath AS activity index (BASDAI) scores, which were elevated at baseline (6.3 ± 0.9), showed constant improvement and remained low: 3.1 ± 2.5 at two years and 2.5 ± 2.2 at seven years, while ASDAS also improved (3.9 ± 0.7 at baseline, 1.8 ± 0.9 at two years, 1.6 ± 0.8 at seven years), all P <0.001. From the 10 dropouts, only 5 patients discontinued treatment due to adverse events. Patients who completed the study had lower baseline Bath AS function index (BASFI) scores vs. patients who discontinued. No other clinical parameter at baseline could predict any long-term outcome. CONCLUSIONS: This study confirms the clinical efficacy and safety of etanercept in patients with active AS over seven years of continuous treatment. After seven years, more than half of the initially treated patients remained on anti-TNF therapy, and one-third were in partial remission. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01289743

Treatment of ankylosing spondylitis in patients refractory to TNF-inhibition: are there alternatives?

PURPOSE OF REVIEW: Axial spondyloarthritis (SpA) - including ankylosing spondylitis (AS) - is a frequent chronic inflammatory disease that affects mainly the axial skeleton. There is evidence that NSAIDs and tumor necrosis factor (TNF) α blockers are efficacious, but not all patients achieve remission or a major clinical response. A variety of new drug classes have been investigated during the last years for the treatment of patients with AS in whom TNF blockers have failed or are contraindicated. RECENT FINDINGS: Data for abatacept, anakinra, apremilast, bisphosphonates, rituximab, secukinumab, sulfasalazine, thalidomide and tocilizumab were found. All studies had problems with design and methodology. SUMMARY: Although some trends for efficacy were seen, there is at present insufficient evidence to support a recommendation for any of these compounds. So far, none of these new drugs has been shown to reach response rates compared to TNF-blockers.

Update on biologic therapy in the management of axial spondyloarthritis.

Axial spondyloarthritis, which includes ankylosing spondylitis and psoriatic spondyloarthritis, is an important subtype of the spondyloarthritides. Tumor necrosis factor (TNF) antagonists are effective therapies for this partially heterogeneous group of rheumatic diseases in terms of signs, symptoms, and functioning, but they do not seem to substantially inhibit radiographic progression, which is mainly new bone formation in ankylosing spondylitis. However, they clearly reduce inflammation, as shown by MRI. TNF blockers are also efficacious in the treatment of extraspinal features of spondyloarthritis. In addition, evidence indicates that anti-TNF therapy works well in early axial disease. Other biologics are currently being investigated, as alternatives are needed for patients who fail anti-TNF therapy.

Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two.

OBJECTIVE: To evaluate the efficacy and safety of the tumor necrosis factor (TNF) antagonist adalimumab in patients with axial spondylarthritis (SpA) without radiographically defined sacroiliitis refractory to conventional treatment. METHODS: Patients with active axial SpA (n = 46) were randomized to receive placebo or adalimumab at a dosage of 40 mg subcutaneously every other week for 12 weeks, followed by an open-label extension that continued up to week 52. The diagnosis of axial SpA required the presence of 3 of 6 diagnostic criteria, including 2 of the following 3 criteria: inflammatory back pain, HLA-B27 positivity, or acute inflammation of the spine or sacroiliac joints on magnetic resonance imaging, in the absence of radiographic evidence of sacroiliitis. The primary end point was a 40% response according to the improvement criteria of the Assessment of SpondyloArthritis international Society (ASAS40). RESULTS: All 46 patients (22 receiving adalimumab and 24 receiving placebo) completed the 12-week trial; 38 patients completed the extension period to week 52. At week 12, an ASAS40 response was achieved by 54.5% of the adalimumab-treated patients, as compared with 12.5% of the placebo-treated patients (P = 0.004). After switching to adalimumab, a similar degree of efficacy was also achieved by the patients who were initially treated with placebo. Efficacy was maintained in all patients until week 52. Young age at study entry and an elevated C-reactive protein concentration were the best predictors of achieving an ASAS40 response. Serious adverse events occurred in 5 patients, none of which was related to the study drug. CONCLUSION: Adalimumab is the first TNF antagonist to demonstrate good clinical efficacy and safety in patients with axial SpA without radiographically defined sacroiliitis.