ObjectiveTo evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX).MethodsIn this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study.ResultsA total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies.ConclusionsTreatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed.Trial registration numberNCT02760368.

In this study, we analyzed the putative association between the −308 G/A polymorphism in the promoter region of the tumor necrosis factor (TNF) α gene (rs1800629) and chronic inflammatory arthritis in the Bulgarian population. A case-control study was carried out on 58 patients with ankylosing spondylitis (AS), 108 rheumatoid arthritis (RA) patients and 177 healthy subjects. −308 G/A TNF-α genotypes of patients and controls were determined by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). No significant association between the rs1800629 polymorphism and RA risk in the study cohort was observed. However, there were significant differences in the genotype and allele frequencies of the −308 G/A TNF-α polymorphism between AS patients and the healthy subjects. In logistic regression analysis, the presence of the TNF-α −308A allele in the genotype (AA + AG vs. GG) was associated with a 3.298 times lower risk of developing AS. In addition, in AS, there were associations for age at disease onset (<29 years; odds ratio (OR) = 0.222), disease severity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score > 4; OR = 0.152) and response to anti-TNF treatment (OR = 2.25) under a dominant model (AA + AG vs. GG). In conclusion, our results suggested that the promoter polymorphism −308 G/A in the TNF-α gene had no significant effect on RA development, but could play a role in AS development and in determining the age of disease onset, disease severity and therapeutic outcome of AS in the Bulgarian patients who participated in our study.

To cite this article: Manolova I, Gerenova J, Ivanova M. Serum levels of transforming growth factor-␤1 (TGF-␤1) in patients with systemic lupus erythematosus and Hashimoto's thyroiditis. ABSTRACT. Background:Transforming growth factor-␤1 (TGF-␤1) exerts broad anti-inflammatory and immunosuppressive effects and plays a key role in self-tolerance. Complete knockout of TGF-␤1 in mice results in autoimmunity and multi-organ inflammatory syndrome. The aim of the present study was to determine TGF-␤1 serum levels in healthy individuals and in patients with typical systemic or organ-specific autoimmune disorders such as systemic lupus erythematosus (SLE) and Hashimoto's thyroiditis (HT) in an attempt to elucidate the importance of TGF-␤1 in human autoimmunity. Patients and methods: Serum concentrations of TGF-␤1 were determined using an enzyme-linked immunosorbent assay in a group of 53 patients with SLE (87% women) and 123 with HT (95% women). Results were compared with those from 66 healthy controls (HC; 80% women). Results: Significantly lower levels of serum TGF-␤1 were found in patients with SLE and HT than those found in HC (mean ± SD: SLE: 8.7 ± 2.5 ng/mL; HT: 18.74 ± 8.2 ng/mL; HC: 33.01 ± 2.4.8 ng/mL; SLE versus HC: p<0.001; HT versus HC: p<0.001). Also, serum levels of TGF-␤1 were significantly lower in patients with SLE compared to patients with HT (p<0.001). The serum levels TGF-␤1 were significantly higher in men than in women in the HC group (63.4 ± 28.1 ng/mL versus 26.6 ± 17.5 ng/mL, P<0.001), but were similar for men and women in both patients groups (p>0.05). Conclusions: Our data demonstrate that altered TGF-␤1 levels are associated with the presence of autoimmune disorders, and that TGF-␤1 concentrations seem to be more profoundly depressed in systemic autoimmune diseases than in autoimmune thyroid disorders. Autoimmunity may have been triggered as a result of a decreased immunosuppressive effect induced by depressed TGF-␤1 levels in patients with SLE and Hashimoto's thyroiditis.

Osteoarthritis (OA) is characterized by deterioration of the joints and associated with considerable pain and disability. OA is a chronic disease that requires intervention with both non-pharmacological and pharmacological treatment modalities and, inevitably, disease progression may necessitate successive treatments throughout the course of the disease. There is increasing data on the shortfalls of current pharmacological treatment of OA, and safety concerns associated with analgesic therapy use in OA arising from increasing evidence of gastrointestinal, cardiovascular, hepatic and renal adverse events with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). Consequently, symptomatic slow-acting drugs for OA (SYSADOAs) may now be considered as a first-line treatment for knee OA, with a particular emphasis placed on the outstanding benefit: risk ratio of pharmaceutical-grade glucosamine and chondroitin sulfate formulations. In this short communication we review recent publications concerned with the safety of paracetamol, NSAIDs and SYSADOAs. Greater understanding of the benefits and limitations of current medications will lead to better disease management in OA. Furthermore, adherence to guideline recommendations across Europe and internationally, such as those from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), will promote evidence-based medicine and patient-centric care, ultimately leading to greater physician and patient satisfaction.

We aimed to analyze serum pro-inflammatory profiles of female rheumatoid arthritis (RA) patients and compare them with healthy women to establish the relative importance of pro-inflammatory cytokines in RA and their relation with different treatment regimens. Levels of six cytokines were determined by ELISA assays. A supervised dimensionality reducing approach (PLS-DA Analysis) was applied. All of the cytokines assayed were significantly elevated in the sera of RA female patients than healthy controls with fold change: 21-fold for IL-6; 6.1-fold for IL-17A; 2.5-fold for IL-23; 2.3-fold for IL-18; 1.94-fold for TNF-α; 1.7-fold for IL-12p40. According to the results of the PLS-DA analysis, IL-17A, IL-18, and TNF-α were of higher importance rank compared to IL-23 and IL-12p40. Women in the early stage of RA displayed significantly elevated IL-17A levels than those with longer disease duration: 8.04 pg/ml [8.04–175.3] vs 4.64 pg/ml [2.95–13.31], p = 0.007. IL-6 serum levels were related to higher disease activity. We have demonstrated altered cytokine production within female RA patients on different treatment regimens. Those on Tocilizumab therapy showed elevated IL-6 levels and decreased IL-17A versus the rest of the patients’ subgroups. In conclusion, our data support the pivotal role of IL-18 in addition to IL-6, IL-17A, and TNF-α as the hierarchical cytokines in the pathogenesis of RA, particularly valid for women. Therapy with biological agents targeting IL-18 in addition to the Th17 axis may be an adequate approach in RA patients.