F. Heldmann

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.

Different response to rituximab in tumor necrosis factor blocker–naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: A twenty‐four–week clinical trial

OBJECTIVE Histologic studies have shown B cell clusters in the subchondral bone marrow of the spine of patients with ankylosing spondylitis (AS). An immunotherapy targeting B cells in AS is therefore of interest. We undertook this study to examine the efficacy and safety of rituximab in patients with AS refractory to nonsteroidal antiinflammatory drugs in whom previous treatment with tumor necrosis factor alpha (TNFalpha) blockers either had not been tried or had failed. METHODS In this phase II clinical trial, 1,000 mg rituximab was administered intravenously at baseline and at week 2 in 20 patients with active AS. Ten of these patients had never received TNF blockers, and treatment with TNF blockers had failed in the other 10 patients. The primary end point was a 20% improvement in disease activity at week 24 according to the criteria of the Assessment of SpondyloArthritis international Society (an ASAS20 response). RESULTS Seventy-five percent of the patients were male, 90% were HLA-B27 positive, their mean age was 39.7 years, and their mean disease duration was 16.8 years. Patients had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >or=4. While there was no clear response at week 24 in the group in whom TNF blockers had failed (30% had achieved an ASAS20 response, 10% had achieved an ASAS40 response, none had achieved partial remission according to the ASAS criteria, and none had achieved 50% improvement on the BASDAI [a BASDAI50 response] beyond an expected placebo response), we observed a good improvement in the TNF blocker-naive group at week 24 (50% had achieved an ASAS20 response, 40% had achieved an ASAS40 response, 30% had achieved partial remission according to the ASAS criteria, and 50% had achieved a BASDAI50 response). CONCLUSION Although rituximab does not seem to be effective in patients with AS that does not respond to TNF blockers, it had significant efficacy in TNF blocker-naive patients. Therefore, further controlled trials with B cell-directed therapies should be performed in TNF blocker-naive AS patients in the future.

Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study

Objective To prospectively explore the short-term efficacy and safety of abatacept in patients with ankylosing spondylitis (AS). Methods In this prospective open-label pilot study, abatacept (10 mg/kg) was administered intravenously on days 1, 15, 29 and every 28 days thereafter up to week 24 in 15 tumour necrosis factor α (TNFα)-inhibitor naive patients (group 1) and 15 patients with inadequate response to TNFα inhibitors (group 2) with active AS. The primary end point was the proportion of patients with 40% improvement according to the Assessment of SpondyloArthritis international Society criteria (ASAS40) in both groups at week 24. Results At week 24, ASAS40 was reached by 13% of group 1 and 0% of group 2; 20% improvement (ASAS20) was reached by 27% and 20%, respectively. There was no significant change of Bath Ankylosing Spondylitis Disease Activity Index score, patient global assessment or C reactive protein. Overall, abatacept was well tolerated. Conclusions In this pilot open-label AS study a major response was not observed.

Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography

Objective To study the relationship of spinal inflammation and fatty degeneration (FD) as detected by MRI and new bone formation seen on conventional radiographs (CRs) in ankylosing spondylitis (AS). Methods CRs at baseline, 2 years and 5 years and spinal MRIs at baseline and 2 years of 73 AS patients treated with infliximab in European AS Infliximab Cohort were available. Relative risks (RR) were calculated with a general linear model after adjustment for within-patient variation. Results In a total of 1466 vertebral edges (VEs) without baseline syndesmophytes, 61 syndesmophytes developed at 5 years, the majority of which (57.4%) had no corresponding detectable MRI lesions at baseline. VEs with both inflammation and FD at baseline had the highest risk (RR 3.3, p=0.009) for syndesmophyte formation at 5 years, followed by VEs that developed new FD or did not resolve FD at 2 years (RR=2.3, p=0.034), while inflammation at baseline with no FD at 2 years had the lowest risk for syndesmophyte formation at 5 years (RR=0.8). Of the VEs with inflammation at baseline, >70% resolved completely, 28.8% turned into FD after 2 years, but only 1 syndesmophyte developed within 5 years. Conclusions Parallel occurrence of inflammation and FD at baseline and development of FD without prior inflammation after 2 years were significantly associated with syndesmophyte formation after 5 years of anti-tumour necrosis factor (TNF) therapy. However, the sequence ‘inflammation–FD–new bone formation’ was rarely observed, an argument against the TNF-brake hypothesis. Whether an early suppression of inflammation leads to a decrease of the risk for new bone formation remains to be demonstrated.

One-year follow-up of ankylosing spondylitis patients responding to rituximab treatment and re-treated in case of a flare

Recently we reported on a good clinical response at week 24, especially in tumour necrosis factor (TNF)-blocker-naive patients with ankylosing spondylitis (AS) who were treated with a first course of rituximab (two infusions of each 1000 mg of rituximab with 100 mg methylprednisolone at baseline and week 2).1 Here we report on the follow-up of these patients with a special focus on the good responders. At week 24, patients regarded as responders were offered to be followed up and to receive a second course of rituximab in case of flare. A response was defined as reaching 20% improvement in disease activity according to the Assessment of SpondyloArthritis international Society criteria (ASAS20)2 compared with screening on at least two consecutive visits (out of four visits: week 12, week 16, week 20 and week 24). Flare was defined as a 1.5-point worsening of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) compared to the lowest BASDAI between week 12 and week 24. Flare patients were then followed for another 48 weeks (between the flare visit (=R-baseline) and R-week …

High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis

Objectives The pathogenesis of axial spondyloarthritis (axSpA) is still unclear. There is a strong association with HLA-B27 and other genes. Recently, anti-CD74 antibodies with specificity to a class II-associated invariant chain peptide (anti-CLIP-ABs) were found in axSpA patients. We examined the prevalence, sensitivity and specificity of anti-CLIP-ABs in axSpA in comparison with controls. Methods Sera of axSpA and non-SpA patients were analysed for IgG-antibodies against CD74 by ELISA with specificity for CLIP developed in cooperation with AESKU Diagnostics (Germany). A cut-off of ≥4 SDs of arbitrary units (AU) from mean serum levels was used to differentiate the results. The laboratory workers were completely blinded for clinical data. Results We analysed 145 sera from 94 axSpA and 51 non-SpA patients. AxSpA patients were more often male and younger. HLA-B27 status was available in 72 patients. Anti-CLIP-ABs were detected in 85.1% in axSpA but in only 7.8% in non-SpA patients (p≤0.0001). AxSpA patients showed higher levels of anti-CLIP-ABs versus non-SpA: mean 14.5 versus 0.8 AU (p≤0.0001). The sensitivity of anti-CLIP-ABs for diagnosing axSpA was 85.1%, specificity 92.2%, likelihood ratio (LR) LR+ was 10.8 and LR− was 0.08. Anti-CLIP-ABs and HLA-B27 were positive in 87.5% patients with axSpA, but only 14.9% were anti-CLIP-negative, while 23.6% were HLA-B27-negative. Conclusions Anti-CLIP antibodies were strongly associated with axSpA. The LR for confirming axSpA by using anti-CLIP was even higher than by using HLA-B27. More studies using this promising new method in patients with non-radiographic axial SpA or peripheral SpA are needed to establish its usefulness in clinical practice.

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

IntroductionData 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).MethodsOverall, 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.ResultsOverall, 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.ConclusionsThis 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 RegistrationClinicalTrials.gov: NCT01289743

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

Purpose of reviewAxial 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) &agr; 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 findingsData for abatacept, anakinra, apremilast, bisphosphonates, rituximab, secukinumab, sulfasalazine, thalidomide and tocilizumab were found. All studies had problems with design and methodology. SummaryAlthough 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.

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.

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.