results from the German Spondyloarthritis Inception Cohort

Background Functional status and spinal mobility in patients with axial spondyloarthritis (axSpA) are known to be determined both by disease activity and by structural damage in the spine. The impact of structural damage in the sacroiliac joints (SIJ) on physical function and spinal mobility in axSpA has not been studied so far. The objective of the study was to analyze the impact of radiographic sacroiliitis on functional status and spinal mobility in patients with axSpA. Methods In total, 210 patients with axSpA were included in the analysis. Radiographs of SIJ obtained at baseline and after 2 years of follow up were scored by two trained readers according to the modified New York criteria grading system (grade 0–4). The mean of two readers’ scores for each joint and a sum score for both SIJ were calculated for each patient giving a sacroiliitis sum score between 0 and 8. The Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) at baseline and after 2 years were used as outcome measures. Results Longitudinal mixed model analysis adjusted for structural damage in the spine (modified Stoke Ankylosing Spondylitis Spine Score - mSASSS), disease activity (Bath Ankylosing Spondylitis Disease Activity Index - BASDAI and C-reactive protein level) and gender, revealed an independent association of the sacroiliitis sum score with the BASFI: b = 0.10 (95% CI 0.01–0.19) and the BASMI: b = 0.12 (95% CI 0.03–0.21), respectively, indicating that change by one radiographic sacroiliitis grade in one joint is associated with BASFI/BASMI worsening by 0.10/0.12 points, respectively, independently of disease activity and structural damage in the spine. Conclusion Structural damage in the SIJ might have an impact on functional status and spinal mobility in axSpA independently of spinal structural damage and disease activity. Trial registration ClinicalTrials.gov, NCT01277419. Registered on 14 January 2011

Incorporation of the anteroposterior lumbar radiographs in the modified Stoke Ankylosing Spondylitis Spine Score improves detection of radiographic spinal progression in axial spondyloarthritis

Background: To evaluate the performance of the extended modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) incorporating information from anteroposterior (AP) lumbar radiographs as compared to the conventional mSASSS in detection of radiographic spinal progression in patients with axial spondyloarthritis (axSpA) Methods: A total of 210 patients with axSpA, 115 with radiographic axSpA (r-axSpA), and 95 with non-radiographic axSpA (nr-axSpA), from the GErman SPondyloarthritis Inception Cohort (GESPIC), were included in the analysis based on the availability of spinal radiographs (cervical spine lateral, lumbar spine lateral, and AP views), at baseline and year 2. Two trained readers independently scored lateral cervical and lumbar spine images according to the mSASSS system (0-3 per vertebral corner, 0-72 in total). In addition, all vertebral corners of vertebral bodies visible on lumbar AP radiographs (lower T12 to upper S1) were assessed according to the same scoring system that resulted in a total range for the extended mSASSS from 0 to 144. Reliability and sensitivity to detect radiographic spinal progression of the extended mSASSS as compared to the conventional mSASSS were evaluated. Results: The reliability of conventional and extended scores was excellent with intraclass correlation coefficients (ICCs) of 0.926 and 0.927 at baseline and 0.920 and 0.933 at year 2, respectively. The mean ± SD score for mSASSS and extended mSASSS at baseline were 4.25 ± 8.32 and 8.59 ± 17.96, respectively. The change score between baseline and year 2 was 0.73 ± 2.34 and 1.19 ± 3.73 for mSASSS and extended mSASSS, respectively. With the extended mSASSS, new syndesmophytes after 2 years were detected in 4 additional patients, new syndesmophytes or growth of existing syndesmophytes in 5 additional patients, and progression by ≥ 2 points in the total score in 14 additional patients meaning a 25%, 28%, and 46% increase in the proportion of patients with progression according to the respective definition as compared to the conventional score. Conclusions: Incorporation of lumbar AP radiographs in the assessment of structural damage in the spine resulted into detection of additional patients with radiographic spinal progression not captured by the conventional mSASSS score

High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis

Introduction: The molecular mechanisms of syndesmophyte formation in ankylosing spondylitis (AS) are yet to be characterised. Molecules involved in bone formation such as Wnt proteins and their antagonists probably drive syndesmophyte formation in AS. Methods: This study investigated sequential serum levels of functional dickkopf-1 (Dkk1), a potent Wnt antagonist involved in bone formation in arthritis, by capture ELISA with its receptor LRP6 in 65 AS patients from the German Spondyloarthritis Inception Cohort. Dkk1 levels were then related to structural progression (syndesmophyte formation) as well as sclerostin and C-reactive protein (CRP) levels. Results: Functional Dkk1 levels were significantly (p=0.025) higher in patients with no syndesmophyte growth (6.78±5.48 pg/ml) compared with those with syndesmophyte growth (4.13±2.10 pg/ml). Dkk1 levels were highly correlated to serum sclerostin levels (r=0.71, 95% CI 0.53 to 0.82; p<0.001) but not to CRP (r=0.15, 95% CI −0.10 to 0.38; p=0.23). Conclusion: AS patients with no syndesmophyte formation show significantly higher functional Dkk1 levels suggesting that blunted Wnt signalling suppresses new bone formation and consequently syndesmophyte growth and spinal ankylosis. Similar to serum sclerostin levels, the functional Dkk1 level thus emerges as a potential biomarker for structural progression in patients with AS

Deep learning for detection of radiographic sacroiliitis: achieving expert-level performance

Background: Radiographs of the sacroiliac joints are commonly used for the diagnosis and classification of axial spondyloarthritis. The aim of this study was to develop and validate an artificial neural network for the detection of definite radiographic sacroiliitis as a manifestation of axial spondyloarthritis (axSpA). Methods: Conventional radiographs of the sacroiliac joints obtained in two independent studies of patients with axSpA were used. The first cohort comprised 1553 radiographs and was split into training (n = 1324) and validation (n = 229) sets. The second cohort comprised 458 radiographs and was used as an independent test dataset. All radiographs were assessed in a central reading session, and the final decision on the presence or absence of definite radiographic sacroiliitis was used as a reference. The performance of the neural network was evaluated by calculating areas under the receiver operating characteristic curves (AUCs) as well as sensitivity and specificity. Cohen's kappa and the absolute agreement were used to assess the agreement between the neural network and the human readers. Results: The neural network achieved an excellent performance in the detection of definite radiographic sacroiliitis with an AUC of 0.97 and 0.94 for the validation and test datasets, respectively. Sensitivity and specificity for the cut-off weighting both measurements equally were 88% and 95% for the validation and 92% and 81% for the test set. The Cohen's kappa between the neural network and the reference judgements were 0.79 and 0.72 for the validation and test sets with an absolute agreement of 90% and 88%, respectively. Conclusion: Deep artificial neural networks enable the accurate detection of definite radiographic sacroiliitis relevant for the diagnosis and classification of axSpA

B Cell Numbers Predict Humoral and Cellular Response Upon SARS–CoV-2 Vaccination Among Patients Treated With Rituximab

Objective: Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy are at higher risk of poor COVID-19 outcomes and show substantially impaired humoral immune response to anti-SARS-CoV-2 vaccine. However, the complex relationship between antigen-specific B cells and T cells and the level of B cell repopulation necessary to achieve anti-vaccine responses remain largely unknown. Methods: Antibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B and CD4/CD8 T cell subsets were studied in 19 patients with rheumatoid arthritis (RA) or antineutrophil cytoplasmic antibody-associated vasculitis receiving RTX, 12 patients with RA receiving other therapies, and 30 healthy controls after SARS-CoV-2 vaccination with either messenger RNA or vector-based vaccines. Results: A minimum of 10 B cells per microliter (0.4% of lymphocytes) in the peripheral circulation appeared to be required for RTX-treated patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX-treated patients who lacked IgG seroconversion showed reduced receptor-binding domain-positive B cells (P = 0.0005), a lower frequency of Tfh-like cells (P = 0.0481), as well as fewer activated CD4 (P = 0.0036) and CD8 T cells (P = 0.0308) compared to RTX-treated patients who achieved IgG seroconversion. Functionally relevant B cell depletion resulted in impaired interferon-γ secretion by spike-specific CD4 T cells (P = 0.0112, r = 0.5342). In contrast, antigen-specific CD8 T cells were reduced in both RA patients and RTX-treated patients, independently of IgG formation. Conclusion: In RTX-treated patients, a minimum of 10 B cells per microliter in the peripheral circulation is a candidate biomarker for a high likelihood of an appropriate cellular and humoral response after SARS-CoV-2 vaccination. Mechanistically, the data emphasize the crucial role of costimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B cell and plasma cell differentiation

Therapy of axial spondyloarthritis

In der vergangenen Dekade haben sich neben der Erstellung neuer Klassifikationskriterien die Messinstrumente zur Evaluation der Erkrankung und die therapeutischen Optionen für die AS deutlich erweitert und neue Erkenntnisse aus klinischen Studien sind zu aktuellen Therapieempfehlungen zusammengefasst worden. In der vorliegenden Arbeit habe ich meinen Beitrag aus klinischen Studien bei Patienten mit AS und nr-axSpA zusammengefasst. In einer klinischen Studie mit Pamidronat konnte kein deutlicher Effekt des Medikaments auf die Besserung der Krankheitsaktivität gefunden werden [32]. Da sonstige klinische Studien gemeinsam mit der hier vorgestellten Arbeit inkonklusive Ergebnisse erbrachten [30, 31, 44, 46-50], wurde die Anwendung von Pamidronat nicht in die Theapieempfehlungen integriert [37]. Obwohl in der täglichen Praxis eine substantielle Gruppe von Patienten mit AS mit MTX behandelt wird, gibt es keine Beweise für dessen Effektivität bei dieser Erkrankung [13, 17, 18]. In der hier vorgestellten klinischen Studie wurde im Gegensatz zu vorangegangen Studien eine ausreichende Dosis (20mg s.c.) über 16 Wochen mit negativem Ergebnis für den axialen Befall verabreicht [55]. Diese Erkenntnisse flossen ebenfalls in die Therapieempfehlungen der ASAS/ EULAR ein [37]. Optional kann MTX für den peripheren Gelenkbefall eingesetzt werden, hierfür gab es Hinweise in meiner eigenen Arbeit, allerdings ohne Nachweis statistischer Signifikanz [55]. Bislang gab es keinerlei Studien zum Einsatz von Prednisolon per os bei Patienten mit AS [37]: In einer weltweit ersten Placebo- kontrollierten Studie untersuchte ich die Wirksamkeit von Prednisolon 20 mg versus 50 mg gegenüber Placebo bei Patienten mit NSAR-refraktärer AS über einen Zeitraum von 2 Wochen [56]. Es zeigte sich ein signifikanter Effekt für 50mg/Tag gegenüber Placebo. Dies könnte sinnvoll als Überbrückungstherapie für Patienten mit Schub der Erkrankung sein, die z.B. nicht (oder noch nicht) Kandidaten für eine Therapie mit TNF-Blocker sind. Weitere Erkenntnisse zu schon vorbekannten klinischen Erfolgen gemessen mittels Krankheitsaktivität und Funktion von TNF-Blockern bei AS konnten bezüglich Lebensqualität, gemessen mittels SF-36, und in der täglichen Praxis gewonnen werden [60]. Zudem konnte eine deutliche Verbesserung der Arbeitsproduktivität und täglichen Aktivität sowie eine deutliche Reduktion verpasster Arbeitsstunden, gemessen mittels WPAI, innerhalb des kurzen Studienzeitraums von 28 Wochen festgestellt werden. Diese Ergebnisse unterstützten die bisherigen Ergebnisse, dass der TNF-Blocker Infliximab ein gut wirksames Medikament in der Therapie der aktiven NSAR-refraktären AS ist. In aus Subgruppenanalysen gewonnenen Ergebnissen zur Prädiktion eines guten klinischen Ansprechens zeigte sich, dass eine Therapie früh im Krankheitsverlauf mit höheren Verbesserungen einhergeht. Die nr-axSpA wurde in der vergangenen Dekade neu definiert [39]. Eine klinische Studie mit dem TNF-Blocker Adalimumab wurde in dieser Patientengruppe weltweit erstmals in einer klinischen doppelblinden Placebo- kontrollierten Studie untersucht [64]. Hierbei konnte gezeigt werden, dass diese Patientengruppe ähnlich gut auf den TNF-Blocker anspricht wie Patienten mit AS. In Subgruppenanalysen konnte gezeigt werden, dass insbesondere Patienten mit kurzem Krankheitsverlauf profitieren. Auf Basis dieser Erkenntnisse wurde eine große multizentrische Studie in der Patientengruppe angeschlossen [73] und Adalimumab erhielt als erster TNF-Blocker die Zulassung in dieser Indikation. Eine weitere Frage, die in der Studie aufgegriffen wurde, war, ob Patienten, die gut auf die Therapie angesprochen haben, ohne weitere Therapie in gutem klinischem Zustand verbleiben können [67]. Hierbei stellte sich heraus, dass die Mehrheit der Patienten mit nicht- röntgenologischer axialer SpA einer kontinuierlichen Therapie bedürfen und es nach Absetzen des Medikaments nach einigen Wochen zum Krankheitsschub kommt. Nach Wiederaufnahme der Therapie spricht wiederum die Mehrheit der Patienten erneut gut an.During the past decade new classification criteria, outcome measures to evaluate the disease and treatment options for ankylosing spondylitis (AS) were developed. This knowledge was summarized to treatment recommendations. The present work concentrates on results of clinical trials in patients with AS and nonradiographic axial Spondyloarthritis (nr-axSpA) I conducted and published. A small clinical trial in patients with active AS could not detect a clear clinical effect of therapy with pamidronate on disease activity [32]. Because other clinical trials [30, 31, 44, 46-50], together with my contribution on this topic showed inconclusive results, the treatment recommendations did not integrate pamidronate as an option for patients with active SpA [37]. While in daily practice a substantial group of patients with AS are treated with methotrexate (MTX), there is no evidence for efficacy of MTX in patients with active AS [13, 17, 18]. In the present clinical trial in contrast to previous trials we used a adequate dosage (20 mg subcutaneously) over 16 weeks in patients with active axial disease with negative result. [55]. These results were also integrated in the ASAS/ EULAR recommendations for axial SpA [37]. For peripheral joint disease in patients with SpA MTX could be an option, as it was shown in the present study, but for this subgroup no statistical significance was reached [55]. Until recently no clinical trials using oral prednisolone in patients with AS [37]: In a worldwide first clinical trial investigating oral prednisolone 20 mg versus 50 mg versus placebo in patients with NSAID-refractory AS over 2 weeks a significant effect of 50 mg per day was seen when compared to placebo [56]. This could be used as a bridging therapy in patients with flare of the disease, who are not (or not yet) candidates for therapy with biologicals. In addition to the already known high efficacy of TNF-blockers in patients with active AS further knowledge could be added regarding quality of life, as measured with SF-36, in daily practice [60]. Furthermore, in this clinical trial a clear improvement of work productivity, daily activity and a clear reduction of missed working hours as measured with WPAI could be found over the relatively short study time of 28 weeks. These results supported previous results of efficacy of the TNF-blocker infliximab in patients with active NSAID-refractory AS. In subgroup analyses predictors of a good clinical response among others, treatment start in early disease stages leads to higher improvement rates. Nonradiographic axial Spondyloarthritis (nr-axSpA) was new defined in the past decade [39]. A worldwide first double blind placebo controlled clinical trial with the TNF-blocker adalimumab was conducted in this group [64]. We showed that the response to the TNF-blocker is as good as it was seen in patients with active AS. In subgroup analyses we showed, that especially patients with short disease duration reach higher response rates. Based on the results a large multi-center trial in this group of patients was conducted and confirmed our results [73]. Adalimumab was the first TNF-blocker licensed in this indication. Another question of our trial was, if good responders of the therapy can stop treatment and remain in good clinical condition without further treatment [67]. We found that most of the patients relapsed within weeks after discontinuation of adalimumab and need reintroduction of therapy. Most patients responded well after reintroduction of therapy

Therapy of ankylosing spondylitis with Leflunomide, Anakinra and Adalimumab - three open pilot studies

GesamtdissertationHintergrund Die therapeutischen Optionen der aktiven ankylosierenden Spondylitis (AS), einer chronisch-entzündlichen rheumatischen Erkrankung, sind limitiert. Die krankheits-modifizierenden Antirheumatika Leflunomid und Anakinra haben sich als sicher und wirksam in der Therapie der rheumatoiden Arthritis erwiesen und stellen potentielle Kandidaten für die Therapie der AS dar. Der TNF-alpha Blocker Adalimumab ist ebenfalls etabliert für die Therapie der rheumatoiden Arthritis. Da die TNF-alpha Blocker Etanercept und Infliximab sehr effektiv in der Therapie der AS sind, liegt der Parallelschluss nahe, auch die Wirksamkeit und Sicherheit von Adalimumab, einem vollständig humanisierten monoklonalen TNF-alpha Blocker, bei aktiver AS zu überprüfen. Methoden In drei offenen Pilotstudien wurden Patienten mit aktiver AS entsprechend den modifizierten New York-Kriterien von 1984 mit Leflunomid 20 mg per os täglich über 24 Wochen, mit Anakinra 100 mg sc. täglich über 24 Wochen bzw. Adalimumab 40 mg sc. aller 2 Wochen behandelt. Die Evaluation der Patienten erfolgte mittels Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) als Maß für die Krankheitsaktivität, der für Leflunomid zu Studienbeginn ³ 3, für die Studien mit Anakinra und Adalimumab ³ 4 sein sollte, mittels Bath Ankylosing Spondylitis Functional Index (BASFI) für die Funktionsfähigkeit, mittels Bath Ankylosing Spondylitis Metrology Index (BASMI) für die Beweglichkeit, mittels einer numerischen Ratingskala für Schmerz, für allgemeines Patienten- und Arzturteil und mittels des Short Form (SF)-36 Fragebogens für die Lebensqualität. Es wurden die Entzündungsparameter CRP und Blutsenkungsgeschwindigkeit gemessen, unerwünschte Ereignisse wurden dokumentiert. MRT-Untersuchungen erfolgten in Short tau inversion recovery (STIR)-Technik zur Untersuchung der Wirbelsäule und der Ileosakralgelenke mit der Frage nach akut entzündlichen Veränderungen. Für die Auswertung wurden Intention to treat-Analysen zu Grunde gelegt. Der primäre Endpunkt der Leflunomidstudie war eine Verbesserung des BASDAI um 25%, der Anakinrastudie eine Verbesserung der ASsessment in Ankylosing Spondylitis (ASAS) 20% Response Kriterien nach 6 Monaten und bei der Adalimumabstudie eine Verbesserung um mindestens 50% des initialen BASDAI nach 12 Wochen. Ergebnisse In die offenen Pilotstudien mit Leflunomid und Anakinra wurden je 20 Patienten, in die mit Adalimumab 15 Patienten mit aktiver AS eingeschlossen. Im Gegensatz zu Adalimumab zeigten weder Leflunomid noch Anakinra einen deutlichen therapeutischen Effekt bezüglich der axialen Symptomatik über die erwartete Plazeboresponse hinaus. Zehn der 20 in die Leflunomidstudie eingeschlossenen Patienten brachen die Studie wegen Ineffektivität und/oder Nebenwirkungen vorzeitig ab. Es fand sich eine 25%-ige Besserung des initialen BASDAI bei 25% (n = 5) der Patienten. Die Anzahl geschwollener Gelenke in der Subgruppe der 10 Patienten mit peripherer Gelenkbeteiligung zu Studienbeginn nahm von 1,7 auf 0,2 geschwollene Gelenke ab (p 0 0.039). In der Anakinrastudie beendeten 65% der Patienten die Studie protokollgemäß nach 24 Wochen. Zu Studienende erreichten 26% der Patienten ASAS 20, 21% ASAS 40 und 10,5% ASAS 70. Dagegen zeigte die Therapie mit Adalimumab eine deutliche Besserung. Den Zeitpunkt Woche 12 erreichten 14/15 Patienten (93%) in der Adalimumabstudie. Eine Verbesserung um 50% des initialen BASDAI wurde von 46,6% der Patienten erreicht. Die anderen Outcomeparameter reagierten in gleicher Weise, das CRP sank bereits von im Mittel 15,1 mg/l ab Woche 2 in den Normbereich ab und blieb in diesem Bereich stabil über den Beobachtungszeitrum. Zusammenfassung und Beurteilung Die offenen Pilotstudien mit Leflunomid, und Anakinra zeigten keinen eindeutigen Effekt bezüglich der axialen Symptomatik und weiterführende Studien scheinen in dieser Hinsicht nicht lohnenswert. Von Anakinra könnte eine noch nicht näher definierte Subgruppe profitieren. Im Gegensatz dazu zeigten die Patienten, die mit Adalimumab behandelt wurden, eine gute Effektivität und Sicherheit. Während in der Leflunomidstudie die Hälfte der Patienten vorzeitig aus der Studie ausschied, wurden die Biologicals Anakinra und Adalimumab besser toleriert. Da Leflunomid einen positiven Effekt auf die Therapie der peripheren Gelenkbeteiligung zu haben scheint, könnten hier weitere Untersuchungen interessant werden. Adalimumab ist, wie von den anderen TNF-alpha-Blockern Etanercept und Infliximab bekannt, das wirksamste und verträglichste der 3 hier getesteten Medikamente. Da diese Therapie ähnlich effektiv wie die mit den anderen TNF-alpha-Blockern Infliximab und Etanercept war, ist ein TNF-alpha-Blocker-Klassen-Effekt anzunehmen. Weiterführende Studien mit dem Ziel der Zulassung sind derzeit zu diesem Medikament im Gange.Background The therapeutic options for ankylosing spondylitis (AS), a chronic inflammatory rheumatic disease, are limited. The disease modifying antirheumatic drugs (DMARDs) leflunomide and anakinra were shown to be effective and safe for the therapy of rheumatoid arthritis (RA) and are potential therapeutic options for patients with AS. Because the TNF-alpha blockers etanercept and infliximab are very effective in treatment of AS, in the potential therapeutic effects of adalimumab should be tested in patients with active AS. Methods Patients with active AS according to the modified New York Criteria from 1984 were enrolled in three pilot open label studies with leflunomide 20 mg every day orally for 24 weeks, with anakinra 100 mg subcutaneous every day for 24 weeks or adalimumab 40 mg subcutaneous every other week for 12 weeks. Patients were evaluated using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for disease activity, which had to be ³ 3 for leflunomide and ³ 4 for anakinra and adalimumab, the Bath Ankylosing Spondylitis Functional Index (BASFI) for function, the Bath Ankylosing Spondylitis Metrology Index (BASMI) for spinal mobility, numeric rating scales for pain, patient´s and physician s global assessment and the Short form-36 questionnaire for quality of life. CRP and erythrocyte sedimentation rate were measured, adverse events were documented. MRI examinations were conducted using the Short Tau Inversion Recovery (STIR) technique to analyze spine and sacroiliac joints for active inflammatory lesions. For statistical analyses an intention to treat analysis was used. The primary endpoint for leflunomide was a 25% improvement of BASDAI, for anakinra an improvement according to the ASessments in AS (ASAS) 20% response criteria at 6 months and for Adalimumab a 50% improvement of the BASDAI after 12 weeks. Results Twenty patients were included in both the leflunomide and anakinra study and 15 patients in the adalimumab trial. In contrast to adalimumab, leflunomide and anakinra did not show efficacy superior to an assumed placebo response on the axial symptoms in patients with active AS. Ten out of the 20 patients who were included in the leflunomide trial stopped therapy earlier because of inefficacy and/or side effects. Only 25% (n = 5) of the patients showed a 25% improvement of the BASDAI. However, the number of swollen joints in patients with peripheral arthritis at study start was reduced from 1.7 to 0.2 after 6 months (p = 0.039). For the anakinra study 65% of the patients were treated for 6 months. ASAS20 was reached by 26%, ASAS 40 by 21% and ASAS 70 by 10.5% of patients after 24 weeks of therapy. For adalimumab 93% of patients were treated for 12 weeks. An improvement of 50% of the BASDAI was reached by 46.6% of patients. Similar reductions were seen for the other outcome parameters. Likewise the CRP fell from 17.1 mg/l (mean) to normal ranges already from week 2 on remaining stable up to week 12. Conclusions The open pilot studies with leflunomide, anakinra showed no efficacy on axial symptoms in patients with active ankylosing spondylitis, only a small subgroup might benefit from treatment with anakinra. While half of the patients treated with leflunomide stopped therapy earlier, the biologicals anakinra and adalimumab were better tolerated by the patients. Because leflunomide seems to be effective for the peripheral arthritis further studies could be conducted for peripheral Spondyloarthritides. Adalimumab is the only clearly effective therapy among the three drugs tested, as as shown for the other TNF-alpha blocking agents infliximab and etanercept. A class effect for the TNF-alpha- blockers can be assumed

Relevance of structural damage in the sacroiliac joints for the functional status and spinal mobility in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort

Abstract Background Functional status and spinal mobility in patients with axial spondyloarthritis (axSpA) are known to be determined both by disease activity and by structural damage in the spine. The impact of structural damage in the sacroiliac joints (SIJ) on physical function and spinal mobility in axSpA has not been studied so far. The objective of the study was to analyze the impact of radiographic sacroiliitis on functional status and spinal mobility in patients with axSpA. Methods In total, 210 patients with axSpA were included in the analysis. Radiographs of SIJ obtained at baseline and after 2 years of follow up were scored by two trained readers according to the modified New York criteria grading system (grade 0–4). The mean of two readers’ scores for each joint and a sum score for both SIJ were calculated for each patient giving a sacroiliitis sum score between 0 and 8. The Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) at baseline and after 2 years were used as outcome measures. Results Longitudinal mixed model analysis adjusted for structural damage in the spine (modified Stoke Ankylosing Spondylitis Spine Score - mSASSS), disease activity (Bath Ankylosing Spondylitis Disease Activity Index - BASDAI and C-reactive protein level) and gender, revealed an independent association of the sacroiliitis sum score with the BASFI: b = 0.10 (95% CI 0.01–0.19) and the BASMI: b = 0.12 (95% CI 0.03–0.21), respectively, indicating that change by one radiographic sacroiliitis grade in one joint is associated with BASFI/BASMI worsening by 0.10/0.12 points, respectively, independently of disease activity and structural damage in the spine. Conclusion Structural damage in the SIJ might have an impact on functional status and spinal mobility in axSpA independently of spinal structural damage and disease activity. Trial registration ClinicalTrials.gov, NCT01277419 . Registered on 14 January 2011

Good correlation between changes in objective and subjective signs of inflammation in patients with short- but not long duration of axial spondyloarthritis treated with tumor necrosis factor-blockers

INTRODUCTION: The aim of this study was to investigate the influence of symptom duration on treatment response and on the correlation between improvements in patient reported outcomes (PRO) and objective inflammation in patients with axial spondylarthritis (SpA) treated with etanercept (ETA) or adalimumab (ADA). METHODS: Data from 112 patients with axial SpA originally enrolled in two randomized controlled clinical trials were pooled and analyzed after one year of treatment with ETA (n = 66) or ADA (n = 46). Patients with <4 years and ≥4 years of disease were compared for improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS), C-reactive protein (CRP) and magnetic resonance imaging (MRI) score for sacroiliac joints (SIJ). RESULTS: Patients with <4 years of disease showed a significantly better improvement than longer diseased patients in BASDAI (3.2 (95% confidence interval (CI): 2.7 to 3.7) vs. 1.7 (1.1 to 2.2)), BASFI, BASMI and ASDAS (1.6 (1.4 to 1.8) vs. 0.9 (0.7 to 1.1)). The change in BASDAI showed a significant correlation with the change in SIJ score (Spearman’s rank correlation coefficient (rho) = 0.37, P = 0.01) and the change in CRP (rho = 0.45, P = 0.001) in patients with <4 years of disease. For long diseased patients this correlation was poor and did not achieve statistical significance (rho = 0.13, P = 0.46; rho = 0.22, P = 0.13 respectively). CONCLUSION: The low correlation between change of PROs and change of objective signs of inflammation seen in axial SpA patients with longer symptom duration treated with tumor necrosis factor-blocker seems to indicate that inflammation is not the only cause of the patients’ symptoms, while inflammation seems to be the major cause in short diseased patients. TRIAL REGISTRATION: Clinical Trials.gov NCT00844142 (Trial 1); NCT00235105 (Trial 2