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Background: The influence of sex on treatment outcomes during interleukin-12/23 therapy in patients with psoriatic arthritis (PsA) has not been explored., Objective: To conduct exploratory post hoc analyses of sex-stratified data from the MUST trial, an investigator-initiated, multicentre, phase 3b study in which patients with active PsA initiating treatment with open-label ustekinumab were randomised to treatment with placebo or methotrexate (MTX)., Methods: We evaluated baseline characteristics, key treatment outcomes and adverse events stratified by sex, with a focus on outcomes that did not include erythrocyte sedimentation rate (ESR) as a component due to the known elevation of ESR in females., Results: A total of 166 patients were treated with ustekinumab+MTX (37 female, 50 male) or ustekinumab+placebo (32 female, 47 male). At baseline, females had a significantly longer time since PsA diagnosis and greater impairment in physical function, but similar joint counts. At week 24, both females and males showed marked improvements to ustekinumab with or without MTX. Females generally had numerically reduced treatment responses compared with males, although differences did not achieve statistical significance. MTX did not show an overall effect on treatment outcomes, but was associated with faster enthesitis responses in males only. Adverse events were generally comparable, but females in the ustekinumab+MTX group had higher levels of gastrointestinal disorders., Conclusion: Females and males with PsA had differences in baseline characteristics, treatment responses and adverse events during therapy. A better understanding of sex-based differences in PsA may help optimise treatment., Competing Interests: Competing interests: MK received consulting fees or honoraria from Amgen, Janssen-Cilag, Lilly, Novartis and UCB and received travel support from UCB. UK received grant and research support and consultancy fees from AbbVie, Amgen, Biocad, Biogen, BMS, Chugai, Eli Lilly, Fresenius, Gilead, Grünenthal, GSK, Hexal, Janssen, MSD, Novartis, onkowissen.de, Pfizer, Roche, UCB and Viatris and participated on a data safety monitoring or advisory board for the COPAGO trial, conducted by the German Ministry of Health. GRB received fees or honoraria for serving as a speaker and/or consultant from Abbvie, Galapagos, Janssen, Lilly, Novartis and UCB, meeting or travel support from Abbvie and Lilly and is the editor-in-chief of RMD Open. DMK received honoraria for serving as a speaker for Sanofi-Aventis. SF received scientific grants from Novartis, honoraria or fees for serving as a speaker and/or consultant from Abbvie, AstraZeneca, Chugai, Galapagos, Novartis, NovoNordisc and UCB, and travel or meeting support from Abbvie, Galapagos, Janssen Cilag, Novartis, SOBI and UCB. RB received honoraria or fees for serving as a speaker and/or consultant from Abbvie, BMS, Chugai, GSK, Galapagos, Novartis, Roche and Vifor and meeting or travel support from Chugai and Galapagos. MS received research support from Charité. FB received research support for this study from Janssen Cilag, consulting fees or honoraria from Abbvie, Acelyrin, Amgen, Janssen Cilag, Lily, Novartis, Pfizer and UCB, and meeting or travel support from Abbvie and UCB. ACF, TR, HK and JB have no competing interests to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Objective: To analyze the safety and efficacy of the anti-tumor necrosis factor agent infliximab in patients with ankylosing spondylitis (AS) after discontinuation of longterm therapy over 1 year and readministration, using clinical and laboratory assessments including serum levels of antibodies to infliximab (ATI)., Methods: Altogether 42/43 patients with AS in a 3-year multicenter trial discontinued therapy after continuous treatment with infliximab (5 mg/kg/6 wks). Infliximab was only readministered in case of a clinical relapse [judged by Bath AS Disease Activity Index (BASDAI) and physician global assessment > 4]. ATI were measured at different timepoints. The primary outcome was safety, and efficacy outcomes were secondary., Results: One patient dropped out after the eighth infusion after retreatment due to repeated local infections. ATI were detected in this patient only. No other relevant adverse events were observed. One patient remained in clinical remission without therapy for more than 1 year. The other 40 patients (97.6%) were reinfused because of clinical relapse. There was no correlation between ATI and clinical measures. BASDAI 50% responses were seen in 25 (63%) and partial remission in 12 (30%) patients. The mean (+/- SD) BASDAI score dropped from 6.0 +/- 1.4 at the time of relapse to 2.6 +/- 2.0, and the median C-reactive protein from 11.2 to 1.8 mg/l after 1 year (all p < 0.05)., Conclusion: Readministration of infliximab after discontinuation of longterm treatment was generally safe and efficacious. Ongoing remission after discontinuation was rare. There was only one patient with relevant adverse events. ATI were detected only in this patient, but there was no correlation to clinical data. Formation of ATI seems to be rare after longterm infliximab therapy in AS.

Ankylosing spondylitis (AS) is a chronic and progressive inflammatory arthropathy that affects young adults. It is associated with increased morbidity and mortality, and can have a devastating effect on quality of life. Conventional therapeutic regimes have traditionally been insufficient to control symptoms and signs of disease, and have failed to halt disease progression. However, the outlook of AS has changed with the advent of biological agents that block pivotal inflammatory cytokines, such as tumour necrosis factor-alpha. Ongoing research has proven these agents to be efficacious and safe in the short and medium term. Further, longer-term trials are awaited to address the issue of whether these therapies are true disease modifiers in AS.

Objective: Anti-tumor necrosis factor-a (TNF-alpha) therapy has been successfully used in patients with active ankylosing spondylitis (AS) and other subtypes of spondyloarthritis (SpA). Treatment options for patients with severe forms of undifferentiated spondyloarthritis (uSpA), a rather frequent SpA subset, are limited. In this open study we examined the efficacy of the TNF-alpha receptor fusion protein etanercept in patients with uSpA., Methods: Ten patients classified to have uSpA according to modified European Spondylarthropathy Study Group criteria in a severe and active stage of disease were included in the study and received etanercept in a dosage of 25 mg two times a week for 12 weeks, followed by an observation period of 12 weeks. The following outcome variables were used: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Functional Index (BASFI), pain on a numerical rating scale, disability by the Funktionsfragebogen Hannover (FFbH), a validated questionnaire to assess functional disability, and quality of life (Medical Outcome Study Short Form-36, SF-36). The primary outcome variable was defined as >or= 50% improvement of the BASDAI., Results: Treatment with etanercept resulted in a >or= 50% regression of disease activity in 60% (95% CI 31-83%) of the patients. The mean BASDAI at baseline of 6.1 (range 3.7-9.2) dropped significantly to 3.5 at Week 12 (0.8-8.7; p = 0.01). Function, spinal pain, peripheral arthritis, enthesitis, quality of life, and acute phase reactants improved similarly. The FFbH improved from 62.8% to 69.7%. After cessation of anti-TNF therapy, 4 out of 8 patients relapsed after an average of 4.5 weeks (range 3-6). Two patients went into longstanding remission. No severe adverse events or major infections were observed., Conclusion: This study strongly suggests that treatment with etanercept has short term efficacy in patients with active and severe uSpA. Since it is known that 30-50% of uSpA patients develop AS over time, it will be important to study whether this can be prevented by anti-TNF-alpha therapy.

Therapeutic options for patients suffering from the more severe forms of spondyloarthritis have been rather limited in the last decades. There is now accumulating evidence that antitumor necrosis factor therapy is highly effective in spondyloarthritis, especially in ankylosing spondylitis and psoriatic arthritis. Based on the data recently published on more than 500 patients with ankylosing spondylitis and psoriatic arthritis, this treatment seems to be even more effective than in rheumatoid arthritis. The antitumor necrosis factor-alpha agents currently available, infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira), are approved for the treatment of rheumatoid arthritis in the United States and partly in Europe. The situation in spondyloarthritis is different from that of rheumatoid arthritis because there is an unmet medical need, especially in ankylosing spondylitis: no therapies with disease-modifying antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, tumor necrosis factor blockers may even be considered a first-line treatment in a patient with active ankylosing spondylitis and psoriatic arthritis whose condition is not sufficiently controlled with nonsteroidal antiinflammatory drugs in the case of axial disease, and sulfasalazine or methotrexate in the case of peripheral arthritis. For infliximab, a dose of 5 mg/kg was required, and intervals between 6 and 12 weeks were necessary to suppress disease activity constantly-also a major aim for long-term treatment. The standard dosage of etanercept is 2 x 25 mg subcutaneously per week. There are no studies yet on adalimumab (standard rheumatoid arthritis dose, 20-40 mg subcutaneously every 1-2 weeks) in spondyloarthritis. Infliximab was very recently approved for AS in Europe. The efficacy of etanercept was first demonstrated in psoriatic arthritis, and it is now approved for this indication. A double-blind study has also been performed in ankylosing spondylitis, with similarly clear efficacy. There is preliminary evidence that both agents do also work in other spondyloarthritis, such as undifferentiated spondyloarthritis. Ideally, both agents will be approved soon for the short-term treatment of severe, uncontrolled spondyloarthritis. In parallel, studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis may be preventable, but it remains to be shown whether patients benefit from long-term antitumor necrosis factor therapy and whether radiologic progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. These can be largely prevented by appropriate screening. At it stands now, the benefits of antitumor necrosis factor therapy in ankylosing spondylitis seem to outweigh these shortcomings.

Objective: Treatment of active ankylosing spondylitis (AS) with the monoclonal tumor necrosis factor alpha (TNF alpha) antibody infliximab is highly clinically effective. This study was undertaken to investigate the precise mechanism of action of anti-TNF alpha treatment in AS., Methods: Cytokine expression of CD4+ and CD8+ T cells was investigated before and 6 and 12 weeks after the start of treatment in 10 patients treated with infliximab, and before and after 6 weeks of treatment and 6 weeks after placebo was switched to infliximab in 10 patients treated initially with placebo. Peripheral blood mononuclear cells (PBMCs) were stimulated for 6 hours either nonspecifically with phorbol myristate acetate (PMA)/ionomycin or antigen specifically with a pool of 46 overlapping 18-mer peptides derived from the G1 domain of aggrecan. Cells were stained for T cell surface markers CD4 and CD8 and for the intracellular cytokines interferon-gamma (IFN gamma), TNF alpha, interleukin-4 (IL-4), and IL-10. Positive cells were quantified by flow cytometry. For monocyte-derived cytokines, PBMCs were stimulated with lipopolysaccharide (LPS) for 18 hours and TNF alpha and IL-10 in the supernatant were measured by enzyme-linked immunosorbent assay., Results: Compared with baseline, infliximab treatment induced a significant decrease at 12 weeks in the number of CD4+ and CD8+ T cells that were positive for IFN gamma and TNF alpha upon PMA/ionomycin stimulation (P = 0.005). A significant reduction had already begun to occur at 6 weeks. No change in the percent IFN gamma or TNF alpha positivity among CD4+ and CD8+ subpopulations was observed after 6 weeks in patients treated with placebo. However, when these patients began infliximab treatment after 6 weeks of receiving placebo, there was a similar significant decrease in IFN gamma and TNF alpha production by CD4+ and CD8+ T cells (P < 0.05). Furthermore, infliximab treatment induced a significant reduction in the number of IFN gamma+ and TNF alpha+ CD8+ T cells (P = 0.005 at week 6 and week 12) after antigen-specific in vitro stimulation with G1-derived peptides. Between-group analysis showed that the change in the expression of IFN gamma and TNF alpha in both CD4+ and CD8+ T cells was significantly different between the infliximab and placebo groups (P = 0.001 for all variables). There was no change in the number of IL-10+ or IL-4+ T cells during treatment. No significant change in the production of TNFalpha and IL-10 upon in vitro stimulation of PBMCs with LPS was detectable during infliximab treatment., Conclusion: Infliximab down-regulates both IFN gamma and TNF alpha secreted by T cells but does not induce a change in cytokines produced by monocytes during 3 months of treatment. This is likely to be a relevant mechanism for the clinical efficacy of this therapy.

Objective: Tumor necrosis factor-alpha (TNF-alpha) has been detected in sacroiliac joints of patients with spondyloarthropathies (SpA). Anti-TNF-a therapy has been efficacious in patients with active ankylosing spondylitis (AS) and psoriatic arthritis. Similar to these SpA subtypes, therapeutic options in undifferentiated SpA (uSpA) are also limited. We tested the efficacy of the monoclonal anti-TNF-alpha antibody infliximab in patients with active and severe uSpA in an open observation trial., Methods: Six patients with uSpA were treated with 3 infusions of infliximab in a dosage of 3 (n = 3) or 5 mg/kg (n = 3) at Weeks 0, 2, and 6. The total observational period was 12 weeks. The Bath AS Disease Activity Index (BASDAI), the Functional Index (BASFI), pain on a visual analog scale, the Bath AS Metrology Index (BASMI), and quality of life (SF-36) were assessed before, during, and after therapy., Results: Significant improvement at Day 1 after the first infusion lasting until Week 12 was reported by 5/6 patients. Improvement of > or = 50% in all activity, function, pain, and swollen joint scores was observed in the patients taking 5 mg/kg. The 3 mg/kg dose was less effective, resulting in > or = 15% improvement in outcome variables. Peripheral arthritis, enthesitis, and spinal symptoms improved equally. C-reactive protein dropped in 4 patients. Health related quality of life increased. No serious side effects or infections occurred., Conclusion: These observations suggest that anti-TNF-alpha therapy has significant short term efficacy in patients with severe uSpA.