Peripheral disease contributes significantly to the level of disease activity in axial spondyloarthritis.

Objective: Spondyloarthritis (SpA) can encompass axial, peripheral and extra-articular disease manifestations. Patients are classified as axial or peripheral SpA depending on the presence or absence of current back pain, independently of the other disease manifestations. Therefore, we aimed to assess the percentage of patients with axial SpA with peripheral disease and how this peripheral disease contributes to the overall disease activity. Methods: Prevalence and disease activity of peripheral disease manifestations were assessed in a real-life observational cohort of 314 patients with the clinical diagnosis of SpA and fulfilling the Assessment of SpondyloArthritis international Society (ASAS) criteria. Results: Of the 314 patients fulfilling the ASAS criteria, 230 fulfilled the axial and 84 the peripheral SpA criteria. Of the 230 patients with axial SpA, 49% had purely axial disease without peripheral disease manifestations whereas 51% had combined axial (back pain) and peripheral (arthritis, enthesitis and/or dactylitis) disease. The latter group had the highest disease activity in comparison with pure axial SpA as well as with peripheral SpA. Conclusion: Half of the patients classified as axial SpA according to the ASAS criteria also have peripheral disease manifestations such as arthritis, enthesitis and/or dactylitis. These peripheral disease manifestations contribute significantly to overall disease activity.

A proof-of-concept study with the tyrosine kinase inhibitor nilotinib in spondyloarthritis.

BACKGROUND: To evaluate the immunomodulating and clinical effects of nilotinib, a tyrosine kinase inhibitor, in a proof-of-concept study in spondyloarthritis (SpA) assessing the mast cell as potential novel therapeutic target in this disease. METHODS: Twenty eight patients with active peripheral (pSpA) and/or axial SpA (axSpA) were included in a randomized, double-blind, placebo-controlled clinical trial (Trial registration: Trialregister.nl NTR2834). Patients were treated 1:1 with nilotinib or placebo for 12 weeks, followed by an open label extension for another 12 weeks. Paired synovial tissue biopsies, serum sampling and assessment of clinical symptoms were performed serially. RESULTS: In pSpA (n = 13) synovial inflammation appeared to diminish after 12 weeks of nilotinib treatment as evidenced by histopathology (decrease in number of infiltrating CD68+ and CD163+ macrophages and mast cells). Compared to placebo mRNA expression of c-Kit as mast cell marker (p = 0.037) and of pro-inflammatory cytokines such as IL-6 (p = 0.024) were reduced. The reduction of synovial inflammation was paralleled by a decrease in serum biomarkers of inflammation such as C-reactive protein (p = 0.024) and calprotectin (p = 0.055). Also clinical parameters such as patient's global assessment of disease activity (p = 0.031) and ankylosing spondylitis disease activity score (p = 0.031) showed improvement upon 12 weeks of nilotinib but not placebo treatment. This improvement was further augmented at week 24. In contrast to pSpA, neither serum biomarkers of inflammation nor clinical parameters improved upon nilotinib treatment in axSpA. During the trial one serious adverse event occurred, which was considered unrelated to the study drug. CONCLUSIONS: This small proof-of-concept study suggests that nilotinib treatment modulates inflammation and clinical symptoms in pSpA. A similar effect was not seen in axSpA. TRIAL REGISTRATION: trialregister.nl registration code NTR2834 registered 31 March 2011.

A psychometric analysis of outcome measures in peripheral spondyloarthritis.

OBJECTIVES: To assess the discriminatory capacity of various outcome measures and response criteria in patients with peripheral spondyloarthritis (pSpA). METHODS: Data originated from two randomised controlled trials, ABILITY-2 and Tnf Inhibition in PEripheral SpondyloArthritis (TIPES). Continuous outcome measures included patient's global assessment (PGA)/physician's global assessment of disease (PhGA), C-reactive protein (CRP), tender joint counts (TJC)/swollen joint counts (SJC), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and the Ankylosing Spondylitis Disease Activity Score (ASDAS). Dichotomous response criteria included Peripheral SpondyloArthritis Response Criteria (PSpARC), American College of Rheumatology (ACR), ASDAS and BASDAI response criteria. The capacity to discriminate between adalimumab and placebo groups was assessed by standardised mean differences (SMD) for continuous variables, and Pearson's χ(2) for dichotomous response criteria. RESULTS: Within each trial, the composite indices for axial SpA assessment, ASDAS-CRP (SMD: -0.63 and -0.89 in ABILITY-2 and the TIPES trial, respectively) and BASDAI (SMD: -0.50 and -0.73), and the single-item measures PGA (SMD: -0.47 and -1.12) and PhGA (SMD: -0.64 and -0.87) performed better than other single-item measures, such as CRP (SMD: -0.18 and -0.53), SJC or TJC. In general, the PSpARC and ACR response criteria discriminated better than ASDAS and BASDAI response criteria. CONCLUSIONS: The axial SpA-specific ASDAS-CRP and BASDAI, but also PGA and PhGA, demonstrated good discriminatory ability in patients with pSpA. The pSpA-specific pSpARC response criteria and the rheumatoid arthritis-specific ACR response criteria also discriminated well. To fully capture typical pSpA manifestations, it may be worth developing new pSpA-specific indices with better performance and face validity. TRIAL REGISTRATION NUMBERS: ABILITY-2: NCT01064856; TIPES: EUDRACT 2008-006885-27.

Calprotectin (S100A8/9) as serum biomarker for clinical response in proof-of-concept trials in axial and peripheral spondyloarthritis.

INTRODUCTION: Biomarkers complementing clinical evaluations may help to reduce the length and size of proof-of-concept (PoC) trials aimed to obtain quick "go/no go" decisions in the clinical development of new treatments. We aimed to identify and validate serum biomarkers with a high sensitivity to change upon effective treatment in spondyloarthritis (SpA) PoC trials. METHODS: The candidate biomarkers high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), pentraxin-3 (PTX-3), alpha-2-macroglobulin (alpha-2-MG), matrix metalloproteinase-3 (MMP-3), calprotectin, and vascular endothelial growth factor (VEGF) were determined by enzyme-linked immunosorbent assay (ELISA) in healthy controls (n = 20) and SpA patients before and after 2 weeks of infliximab (n = 18) or placebo (n = 19) treatment in cohort 1. Clinical outcome was evaluated at week 12. Results were validated in ankylosing spondylitis (AS) with infliximab (cohort 2, n = 21) and peripheral SpA with etanercept (cohort 3, n = 20). RESULTS: Serum levels of calprotectin, hs-CRP, PTX-3, VEGF (all P < 0.001) and MMP-3 (P = 0.062), but not IL-6 and alpha-2-MG, were increased in SpA versus healthy controls. Treatment with infliximab, but not placebo, significantly decreased calprotectin (P < 0.001) and hs-CRP (P < 0.001) levels, with a similar trend for MMP-3 (P = 0.063). The standardized response mean (SRM), which reflects the ability to detect changes over time, was high for calprotectin (-1.26), good for hs-CRP (-0.96) and moderate for MMP-3 (-0.52). Calprotectin and hs-CRP, but not MMP-3, were good biomarkers for treatment response in axial and peripheral SpA as evaluated and confirmed in cohort 2 and 3 respectively. CONCLUSIONS: Calprotectin and hs-CRP are good serum biomarkers with high sensitivity to change upon effective treatment at the group level in small-scale, short term PoC trials in SpA.

Adalimumab serum levels and antidrug antibodies towards adalimumab in peripheral spondyloarthritis: no association with clinical response to treatment or with disease relapse upon treatment discontinuation.

INTRODUCTION: In this study, we evaluated the clinical relevance of serum drug levels and antidrug antibodies (ADAbs) with regard to response to treatment, as well as to relapse upon treatment discontinuation, in peripheral spondyloarthritis (pSpA) patients treated with adalimumab. METHODS: The study included 26 pSpA patients treated with adalimumab for either 12 weeks (n = 12) or 24 weeks (n = 14) in a randomized controlled trial. Patients achieving inactive disease measured by Ankylosing Spondylitis Disease Activity Score (ASDAS) at the end of the treatment period were classified as responders. Clinical characteristics, serum trough adalimumab levels and ADAbs were assessed at the end of the treatment period and at follow-up (upon relapse or, in absence of relapse, at 16 weeks after discontinuation). RESULTS: Serum adalimumab levels measured 2 weeks after the last adalimumab administration ranged from <0.002 to 23.0 µg/ml, with a median of 11.5 µg/ml. These levels were associated with neither response to treatment or disease activity measurements at the end of treatment nor with the occurrence of relapse and time to relapse after discontinuation of treatment. Antiadalimumab ADAbs were present in 23% of the patients at end of treatment and in 35% at follow-up after treatment discontinuation, indicating that ADAbs were masked by the presence of the drug in some patients. However, ADAbs at the end of treatment and at follow-up were not different between responders and nonresponders and were not associated with relapse upon discontinuation of treatment. CONCLUSIONS: There is no clear association between adalimumab serum levels or antiadalimumab ADAbs with clinical response to treatment or with relapse upon treatment discontinuation in pSpA. TRIAL REGISTRATION: Netherlands Trial Register ID: NTR1806 (registered 7 May 2009).

The interleukin-23/interleukin-17 immune axis as a promising new target in the treatment of spondyloarthritis.

PURPOSE OF REVIEW: Various novel therapies for spondyloarthritis (SpA) are currently under development. In this review, we discuss the scientific rational to target the interleukin (IL)-23/IL-17 axis in SpA and give an overview of the proof-of-concept trials with drugs directed towards this axis. RECENT FINDINGS: Cumulative evidence from genetics (e.g. the strong genetic association with the IL-23 receptor gene), in-vitro models (e.g. the increased IL-23 production upon HLA-B27 misfolding), human expression studies (e.g. the expansion of IL-17 producing innate cells in SpA) and animal models (e.g. the increased IL-17 production in HLA-B27 transgenic rats) strongly supports the involvement of the IL-23/IL-17 axis in the pathogenesis of SpA. Ustekinumab (a monoclonal antibody directed against the common p40 subunit of IL-23 and IL-12), secukinumab, ixekizumab (both monoclonal antibodies directed against IL-17A), and brodalumab a monoclonal antibody against the IL-17RA receptor) have been recently used in proof-of-concept and randomized trials in the ankylosing spondylitis and/or psoriatic arthritis subforms of SpA, with overall very promising clinical efficacy. SUMMARY: The first results for novel drugs blocking key cytokines in the IL-23/IL-17 axis are promising in SpA and more novel compounds are upcoming. This will teach us more on the role of the IL-23/IL-17 axis in the pathophysiology of SpA.

Peripheral joint inflammation in early onset spondyloarthritis is not specifically related to enthesitis.

OBJECTIVES: A pivotal MRI study of knee arthritis indicated that enthesitis was more frequently observed in established spondyloartritis (SpA) than rheumatoid arthritis (RA). Subsequent MRI and ultrasound studies, however, failed to consistently demonstrate primary synovitis in RA versus primary enthesitis in SpA. Therefore, the current study aimed to reassess enthesitis versus synovitis in peripheral arthritis by a combined imaging and histopathological study in early untreated disease. METHODS: MRI and mini-arthroscopic synovial biopsy sampling were performed in 41 patients with early untreated knee or ankle arthritis, who were diagnosed with SpA (n=13), RA (n=20) or crystal arthropathy (n=8) at follow-up. MRI evaluation of enthesitis and synovitis, and immunohistochemical characterisation of synovitis were performed by two observers blinded to diagnosis. RESULTS: MRI showed similar prevalence of perientheseal fluid/oedema (67% vs 75%), perientheseal bone marrow oedema (0% vs 10%) and entheseal enhancement (46% vs 47%) in SpA versus RA, respectively. The number and distribution of affected entheseal sites were not different between both diseases. The MRI synovitis score was significantly higher in SpA (median 1.4; IQR 1.1-1.5) compared with RA (median 0.5; IQR 0.0-1.3) (p=0.028). Synovial histopathology showed a numerical increase in infiltrating cells in SpA versus RA synovitis which reached significance for CD163 macrophages in the synovial sublining (p=0.030). There were no differences compared with the crystal arthropathy control group. CONCLUSIONS: Enthesitis on MRI is not a specific feature of peripheral arthritis in recent onset SpA versus RA. Synovitis is prominent in both diseases as evaluated by MRI and immunohistochemistry.

Spondyloarthritis: from unifying concepts to improved treatment.

Spondyloarthritis (SpA) is a chronic immune-mediated inflammatory disease with diverse phenotypic manifestations including spondylitis, arthritis, enthesitis and extra-articular manifestations (psoriasis, uveitis, inflammatory bowel disease). The common genetic risk factors, the strong familial aggregation and the overlapping immunopathology suggest that these different phenotypic manifestations share common pathogenic pathways. This concept is further strengthened by the good clinical response of all different SpA manifestations to TNF-blocking therapies. However, the phenotypic diversity of SpA is still a major challenge in properly diagnosing, classifying and monitoring the disease and may lead to undertreatment of less typical SpA cases such as undifferentiated SpA. The optimal use of current treatments and the development of novel therapies, including compounds targeting the IL-23/IL-17 axis, thus requires a detailed understanding of both the clinical presentation and the underlying pathogenic pathways in SpA.

Undifferentiated spondyloarthritis vs ankylosing spondylitis and psoriatic arthritis: a real-life prospective cohort study of clinical presentation and response to treatment.

OBJECTIVE: SpA is a phenotypically heterogeneous disease, with AS and PsA as its best studied subtypes. This study aimed to investigate whether, despite a different phenotypic presentation, patients with undifferentiated SpA (uSpA) have similar disease activity and response to treatment to those with AS and PsA. METHODS: 175 patients presenting at a dedicated SpA outpatient clinic were recruited in a real-life prospective cohort with follow-up every 3 months. Clinical characteristics, disease activity at presentation and response to treatment of uSpA were compared with AS and PsA. RESULTS: Twenty-three per cent (n = 40) of the patients were classified as uSpA. These patients were younger and tended to have a shorter disease duration than AS and PsA patients. uSpA patients exhibited a mixed axial (inflammatory back pain in 87.5%) and peripheral (peripheral arthritis in 62.5%) phenotype, with almost half of the patients having low-grade sacroiliitis on conventional X-ray. The overall disease activity in uSpA was similar to AS and higher than in PsA, also when analysing only anti-TNF naive patients. Initiation of TNF blockade significantly decreased disease activity in uSpA, with a similar amplitude to that in AS and PsA. CONCLUSION: uSpA is a frequent, severe and anti-TNF-responsive phenotypic subtype of SpA. In agreement with the new ASAS classification criteria for axial and peripheral SpA and emerging data on TNF blockade in non-radiographic axial SpA and peripheral uSpA, these data emphasize the need for early diagnosis and optimal treatment of not only AS and PsA but also other SpA subforms.

Anti-TNF treatment blocks the induction of T cell-dependent humoral responses.

OBJECTIVE: Experimental and human data suggest that tumour necrosis factor (TNF) blockade may affect B cell responses, in particular the induction of T cell-dependent (TD) humoral immunity. This study aimed to assess this hypothesis directly in patients with arthritis by analysing longitudinally the effect of TNF blockade on B cell activation and the maturation of humoral responses against TD and T cell-independent vaccines. MATERIALS AND METHODS: Peripheral blood samples were obtained from 56 spondyloarthritis patients before and after treatment with either non-steroidal anti-inflammatory drug (NSAID) alone or TNF blockers and analysed for B cell activation, plasma cell differentiation, germinal centre versus extra-follicular B cell maturation, and somatic hypermutation. Vaccine responses to hepatitis B and Streptococcus pneumoniae were measured by ELISA. RESULTS: TNF blockade augmented B cell activation as reflected by the expression of early activation markers, CD40, and costimulatory molecules, without affecting differentiation towards plasmablasts. This was associated with a specific increase of the unswitched fraction of circulating memory B cells and a decreased level of somatic hypermutation in anti-TNF treated patients, indicating an impairment of the germinal centre-dependent B cell maturation. In agreement with these findings, TNF blockade profoundly suppressed the response to the TD vaccination against hepatitis B, whereas the T cell-independent response against pneumococcal polysaccharides was only modestly affected. CONCLUSIONS: These data indicate that TNF blockade severely impedes the induction of primary TD humoral responses, probably by interfering with the germinal centre reaction.

Efficacy and safety of adalimumab for the treatment of peripheral arthritis in spondyloarthritis patients without ankylosing spondylitis or psoriatic arthritis.

OBJECTIVES: To evaluate the efficacy and safety of adalimumab in patients with peripheral spondyloarthritis (SpA) not fulfilling the criteria for ankylosing spondylitis (AS) or psoriatic arthritis (PsA). METHODS: 40 patients with active peripheral SpA fulfilling the European Spondyloarthropathy Study Group or Amor criteria but not the criteria for AS or PsA were included in a randomised, double-blind, placebo-controlled clinical trial. Patients were treated 1 : 1 with adalimumab or placebo for 12 weeks, followed by an open label extension up to week 24. Safety and efficacy measurements were performed every 6 weeks, with the patient's global assessment of disease activity at week 12 as the primary endpoint. RESULTS: At week 12, the patient's and physician's global assessment of disease activity, swollen joint count, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS) and erythrocyte sedimentation rate improved significantly in the adalimumab group compared with the baseline values and compared with placebo. A similar improvement was seen upon adalimumab treatment from weeks 12 to 24 in the patients originally randomised to placebo, whereas the clinical response was maintained or even augmented at week 24 in the patients who received adalimumab from the start. ASDAS inactive disease and BASDAI50 responses were met in 42% of the adalimumab group versus 0%-5% in the placebo group at week 12 (p=0.001 and p=0.008, respectively), and were further increased at week 24. The number of adverse events was not different between the adalimumab and placebo groups. CONCLUSIONS: Adalimumab appears to be effective and well tolerated in SpA patients with peripheral arthritis, also in those patients not fulfilling the AS or PsA criteria.

Synovial Tissue Response to Treatment with TNF Blockers in Peripheral Spondyloarthritis.

This review describes the synovial response to treatment in peripheral spondyloarthritis (SpA). A series of recent studies demonstrates that the synovial histopathology is largely homogenous between different SpA subtypes and can be strongly modulated by effective treatment such as tumor necrosis factor (TNF) blockade. This includes a dramatic reduction of the infiltration with inflammatory cells (with the intriguing exception of B lymphocytes and plasma cells), a modulation of structural features such as vascularity, intimal lining layer hyperplasia, and ectopic lymphoid neogenesis, and a down-regulation of a variety of mediators involved in tissue damage. The analysis of tissue response to targeted therapies appears to be a novel and elegant approach to study the immunopathology of human peripheral SpA in vivo. Moreover, detailed cellular and molecular analysis of synovial features allows to identify synovial biomarkers of clinical response to therapeutic interventions which can be used in future early phase clinical trials in SpA.