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DBA/1 mice arthritis models have contributed to our understanding of human rheumatoid arthritis (RA) and spondyloarthritis (SpA) pathogenesis, as well as the exploration of therapeutic targets for treatment. Quantitative polymerase chain reaction (qPCR) is an indispensable tool in molecular research, which requires reference gene validation to obtain consistent and reliable results.To determine the stability of candidate reference genes for qPCR in the joint of collagen-induced arthritis (CIA) and spontaneous arthritis (SpAD) DBA/1 mice.The expression of eleven commonly used reference genes (ACTB, B2M, EF1a, GAPDH, HMBS, HPRT, PPIB, RPL13A, SDHA, TBP, and YWHAZ) was assessed by qPCR and the data were compared using delta-Ct methods and the geNorm, NormFinder, and RefFinder software packages. Genes identified as stable in each model were used for the quantification of inflammatory cytokines RESULTS: The gene stabilities differed between the two arthritis models in the DBA/1 mice. EF1a and RPL13A were the best reference genes for SpAD, while RPL13A and TBP were the best for the CIA. These genes allowed the data normalization for the quantification of the inflammatory cytokines in both models; these results showed an increase in the expression of IL-1B, IL-12B, IL-17A, and IL-6 in the inflamed joints. The use of different primer sequences for the same reference gene resulted in different relative quantification values.This study demonstrates that commonly used reference genes may not be suitable for arthritic tissues from DBA/1 mice, and strengthening the principle that meticulous validation of reference genes is essential before each experiment to obtain valid and reproducible qPCR data for analysis or interpretation.

Antinuclear antibodies (ANA) potentially play a role in the pathogenesis of connective tissue diseases (CTDs); however, they are also detected in healthy individuals. Our understanding of the physiological and pathological origin of ANA is incomplete. Both; female reproductive processes and deficiencies in DNA damage response (DDR) have been independently associated with ANA production. However, the link between these two factors and the presence of ANA is unclear METHOD OF STUDY: A cohort study was conducted on 87 non-pregnant and 51 healthy pregnant women. ANA and the DDR markers X-ray repair cross-complementing 1 (XRCC1) and recombinase (RAD51) were quantified in sera by enzyme-linked immunosorbent assay. Additionally, ANA was detected by indirect immunofluorescence in HEp-2 cells in 1:40 diluted sera during the three phases of the menstrual cycle in non-pregnant women and every trimester in pregnant women RESULTS: The prevalence of ANA+ in healthy women was 26.1%, with no significant differences between pregnant and non-pregnant women. ANA and DDR marker levels did not vary among the three phases of the menstrual cycle or the three trimesters of pregnancy. However, DDR marker levels were higher in pregnant women than in non-pregnant women (p lt; .001) and were found to be higher in ANA+ women (XRCC1, p = .025; RAD51, p = .006) CONCLUSIONS: The menstrual cycle and pregnancy did not influence the levels of DDR markers or ANA in healthy women; however, the DDR was higher in pregnancy and ANA+ women. The results suggest a potential role of DDR in the pathophysiology of ANA.

COVID-19 vaccination is recommended in patients with rheumatic diseases (RDs) to prevent hospitalized COVID-19 and worse outcomes. However, patients' willingness to receive a SARS-CoV-2 vaccine and the associated factors vary across populations, vaccines, and time. The objective was to identify factors associated with COVID-19 vaccine acceptance (VA) in Mexican outpatients with RDs. This multicenter study was performed between March 1 and September 30, 2021, and four national centers contributed with patients. Participants filled out a questionnaire, which included 32 items related to patients' perception of the patient-doctor relationship, the COVID-19 vaccine component, the pandemic severity, the RD-related disability, comorbid conditions control, immunosuppressive treatment impact on the immune system, and moral/civil position of COVID-19 vaccine. Sociodemographic, disease-related, and treatment-related variables and previous influenza record vaccination were also obtained. Multiple logistic regression analyses identified factors associated with VA, which was defined based on a questionnaire validated in our population. There were 1439 patients whose data were analyzed, and the most frequent diagnoses were Rheumatoid Arthritis in 577 patients (40.1%) and Systemic Lupus Erythematosus in 427 (29.7%). Patients were primarily middle-aged women (1235 [85.8%]), with (mean±SD) 12.1 (±4.4) years of formal education. Years of education, corticosteroid use, patient perceptions about the vaccine and the pandemic severity, patient civil/moral position regarding COVID-19 vaccine, and previous influenza vaccination were associated with VA. In Mexican patients with RDs, COVID-19 VA is associated with individual social-demographic and disease-related factors, patient´s perceptions, and previous record vaccination. This information is crucial for tailoring effective vaccine messaging in Mexican patients with RDs.

Objective To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi).

Introduction Complementary and alternative medicine (CAM) is frequently used by patients with rheumatic diseases (RD) to improve their symptoms; however, its diversity and availability have increased notably while scientific support for its effectiveness and adverse effects is still scarce. Objective To describe the prevalence and diversity of CAM in patients with RD in Chihuahua, Mexico. Methods A cross-sectional study was conducted in 500 patients with RD who were interviewed about the use of CAM to treat their disease. The interview included sociodemographic aspects, characteristics of the disease, as well as a description of CAM use, including type, frequency of use, perception of the benefit, communication with the rheumatologist, among others. Results The prevalence of CAM use was reported by 59.2% of patients, which informed a total of 155 different therapies. The herbal CAM group was the most used (31.4%) and included more than 50 different therapies. The use of menthol-based and arnica ointments was highly prevalent (35%). Most patients (62.3%) reported very little or no improvement in their symptoms. Only a fourth of the patients informed the rheumatologist of the use of CAM. The use of CAM was influenced by female sex, university degree, diagnosis delay, lack adherence to the rheumatologist’s treatment, family history of RD, and orthopedic devices. Conclusion The use of CAM in our population is highly prevalent and similar to reports in different populations suggesting a widespread use in many different societies. We found high use of herbal remedies; however, there were many different types suggesting a lack of significant effect. Patients continue using CAM despite a perception of no-effectiveness. Recurrent use of CAM is explained by factors other than its efficacy.

Aims To assess the effect of physical exercise (PE) on the histological and transcriptional characteristics of proteoglycan-induced arthritis (PGIA) in BALB/c mice. Methods Following PGIA, mice were subjected to treadmill PE for ten weeks. The tarsal joints were used for histological and genetic analysis through microarray technology. The genes differentially expressed by PE in the arthritic mice were obtained from the microarray experiments. Bioinformatic analysis in the DAVID, STRING, and Cytoscape bioinformatic resources allowed the association of these genes in biological processes and signalling pathways. Results Arthritic mice improved their physical fitness by 42.5% after PE intervention; it induced the differential expression of 2,554 genes. The bioinformatic analysis showed that the downregulated genes (n = 1,371) were significantly associated with cellular processes that mediate the inflammation, including Janus kinase-signal transducer and activator of transcription proteins (JAK-STAT), Notch, and cytokine receptor interaction signalling pathways. Moreover, the protein interaction network showed that the downregulated inflammatory mediators interleukin (IL) 4, IL5, IL2 receptor alpha (IL2rα), IL2 receptor beta (IL2rβ), chemokine ligand (CXCL) 9, and CXCL12 were interacting in several pathways associated with the pathogenesis of arthritis. The upregulated genes (n = 1,183) were associated with processes involved in the remodelling of the extracellular matrix and bone mineralization, as well as with the processes of aerobic metabolism. At the histological level, PE attenuated joint inflammatory infiltrate and cartilage erosion. Conclusion Physical exercise influences parameters intimately linked to inflammatory arthropathies. Research on the effect of PE on the pathogenesis process of arthritis is still necessary for animal and human models. Cite this article: Bone Joint Res. 2020;9(1):36–48.

Physical exercise (PE) is recommended for Rheumatoid Arthritis (RA), but the molecular and biological mechanisms that impact the inflammatory process and joint destruction in RA remain unknown. The objective of this study was to evaluate the effect of PE on the histological and transcriptional changes in the joints of adjuvant-induced arthritis (AIA) rat model. AIA rats were subjected to PE on a treadmill for eight weeks. The joints were subjected to histological and microarray analysis. The differentially expressed genes (DEGs) by PE in the arthritic rats were obtained from the microarray. The bioinformatic analysis allowed the association of these genes in biological processes and signaling pathways. PE induced the differential expression of 719 genes. The DEGs were significantly associated with pathogenic mechanisms in RA, including HIF-1, VEGF, PI3-Akt, and Jak-STAT signaling pathways, as well as response to oxidative stress and inflammatory response. At a histological level, PE exacerbated joint inflammatory infiltrate and tissue destruction. The PE exacerbated the stressed joint environment aggravating the inflammatory process, the hypoxia, and the oxidative stress, conditions described as detrimental in the RA joints. Research on the effect of PE on the pathogenesis process of RA is still necessary for animal models and human.

The aim of the study was to describe the oral health and orofacial function of Mexican patients with rheumatoid arthritis (RA) and their association with clinical and radiological aspects of the disease. Patients with RA received a complete odontological exam, which also included a clinical and radiographic assessment of the temporomandibular joint (TMJ). The rheumatologic assessment included detailed profiling of the disease and serological and radiographic parameters. The study included 62 RA patients; the median (min–max) age was 51 (18–72) years old and 8.5 (1–39) years of disease duration. The 63.6% of the patients had DAS28 ≥ 3.2, and a median (min–max) of Sharp/van der Heijde score (SvdHS) of 41 (0–214). 98.3% of the patients presented caries, which were severe in 53.3% of the cases. The 73.8% of the patients were missing teeth due to caries, with a median (min–max) of 4 (0–32) teeth missing per patient. Oral hygiene was classified as bad in 49.1% of patients and only 15.3% of them had a healthy periodontium. The TMJ function was abnormal in 98.4% of the patients and 62.9% of them presented moderate or severe TMJ disorder (TMD). The radiographic damage of the TMJ correlated positively with the SvdHS. No correlations were found between disease activity or structural progression and orofacial variables, including periodontitis. There are severe oral and orofacial health problems in RA patients despite having medical attention for their disease. Multidisciplinary management remains an area of opportunity for both the medical specialists and the health system in our country.

Objective.To assess 5-year safety, tolerability, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA).Methods.The Abatacept Comparison of sub[QU]cutaneous versus intravenous in Inadequate Responders to methotrexatE (ACQUIRE) phase IIIb, randomized, double-dummy, multinational trial compared efficacy and safety of SC and intravenous (IV) ABA in patients with RA. In the initial 6-month double-blind (DB) period, patients received IV or SC ABA, plus MTX, and in the subsequent open-label longterm extension (LTE) period, all patients received SC ABA (125 mg/wk). The final 5-year safety, tolerability, and efficacy analyses are reported.Results.Of 1385 patients who completed the DB period, 1372 entered LTE and 945 (68.8%) completed ≥ 5 years of treatment. During LTE, 97 (7.1%) patients discontinued treatment because of an adverse event (AE). Incidence rate (IR; event/100 patient-yrs of exposure; based on LTE data, 95% CI) for AE of interest were the following: serious AE 7.73 (6.96–8.58), infection 38.60 (36.24–41.12), serious infection 1.68 (1.35–2.07), malignancies 1.09 (0.84–1.42), and autoimmune disorders 1.33 (1.05–1.69), and were stable over time. No association between immunogenicity and either worsening of ABA safety or loss of efficacy was noted. Efficacy in the LTE was consistent with the DB period and was maintained to the end of the study.Conclusion.These 5-year data establish that SC ABA (125 mg/wk) has a consistent safety profile and durable efficacy for longterm treatment of patients with RA who had an inadequate response to MTX.

Objective To assess the efficacy and safety of decernotinib (VX-509), an oral selective inhibitor of JAK-3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate. Methods In this 24-week, double-blind, randomized phase IIb study, 358 patients with active RA received either placebo (n = 71) or VX-509 at dosages of 100 mg/day (n = 71), 150 mg/day (n = 72), 200 mg/day (n = 72), or 100 mg twice daily (n = 72). Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Results At week 12, the ACR20 response rates were 46.5%, 66.7%, 56.9%, and 68.1% in the groups receiving VX-509 at dosages of 100 mg/day, 150 mg/day, 200 mg/day, and 100 mg twice daily, respectively, and 18.3% in the placebo group (P < 0.001 for all comparisons). At week 12, the mean change from baseline in the DAS28-CRP was significantly greater in each VX-509 group compared with the placebo group (P < 0.001). Improvements were maintained at week 24, as shown by the ACR20, ACR50, and ACR70 response rates and mean change from baseline in the DAS28-CRP. The most common adverse event in the VX-509 group was headache (8.7%), and elevated levels of transaminases, lipoproteins, and creatinine were observed. Conclusion VX-509 significantly improved the signs and symptoms of RA at weeks 12 and 24 compared with the placebo group when it was administered in combination with methotrexate. Safety signals included infection and increases in liver transaminase and lipid levels.

The danger model was proposed by Polly Matzinger as complement to the traditional self-non-self- (SNS-) model to explain the immunoreactivity. The danger model proposes a central role of the tissular cells’ discomfort as an element to prime the immune response processes in opposition to the traditional SNS-model where foreignness is a prerequisite. However recent insights in the proteomics of diverse tissular cells have revealed that under stressful conditions they have a significant potential to initiate, coordinate, and perpetuate autoimmune processes, in many cases, ruling over the adaptive immune response cells; this ruling potential can also be confirmed by observations in several genetically manipulated animal models. Here, we review the pathogenesis of rheumatic diseases such as systemic lupus erythematous, rheumatoid arthritis, spondyloarthritis including ankylosing spondylitis, psoriasis, and Crohn’s disease and provide realistic approaches based on the logic of the danger model. We assume that tissular dysfunction is a prerequisite for chronic autoimmunity and propose two genetically conferred hypothetical roles for the tissular cells causing the disease: (A) the Impaired cell and (B) the paranoid cell. Both roles are not mutually exclusive. Some examples in human disease and in animal models are provided based on current evidence.

The Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire was developed directly from rheumatoid arthritis (RA) patients in the United Kingdom and the Netherlands to measure quality of life (QoL). Since then, it has become widely used in clinical studies and trials and has been adapted for use in 24 languages. The objective was to develop and validate 11 additional language versions of the RAQoL in US English, Mexican Spanish, Argentinean Spanish, Belgian French, Belgian Flemish, French, Romanian, Czech, Slovakian, Polish and Russian. The language adaptation and validation required three stages: translation, cognitive debriefing interviews and validation survey. The translation process involved a dual-panel methodology (bilingual panel followed by a lay panel). The validation survey tested the psychometric properties of the new scales and included either the Nottingham Health Profile (NHP) or the Health Assessment Questionnaire (HAQ) as comparators. Internal consistency of the new language versions ranged from 0.90 to 0.97 and test-retest reliability from 0.85 to 0.99. RAQoL scores correlated as expected with the HAQ. Correlations with NHP sections were as expected: highest with energy level, pain and physical mobility and lowest with emotional reactions, sleep disturbance, and social isolation. The adaptations exhibited construct validity in their ability to distinguish subgroups of RA patients varying by perceived disease severity and general health. The new language versions of the RAQoL meet the high psychometric standards of the original UK English version. The new adaptations represent valid and reliable tools for measuring QoL in international clinical trials involving RA patients.

Objective To evaluate effects of the anti-interleukin-6 receptor monoclonal antibody sarilumab administered with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on patient-reported outcomes (PROs) in the TARGET trial in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitors (TNF-IR). Methods 546 patients (81.9% female, mean age 52.9 years) were randomised to placebo, sarilumab 150 or 200 mg subcutaneously every 2 weeks + csDMARDs. PROs included patient global assessment (PtGA); pain and morning stiffness visual analogue scales; Health Assessment Questionnaire Disability Index (HAQ-DI); Short Form-36 Health Survey (SF-36); FACIT-Fatigue (FACIT-F); Work Productivity Survey-Rheumatoid Arthritis (WPS-RA) and Rheumatoid Arthritis Impact of Disease (RAID). Changes from baseline at weeks 12 and 24 were analysed using a mixed model for repeated measures; post hoc analyses included percentages of patients reporting improvements ≥ minimum clinically important differences (MCID) and scores ≥ normative values. Results Sarilumab + csDMARDs doses resulted in improvements from baseline at week 12 vs placebo + csDMARDs in PtGA, pain, HAQ-DI, SF-36 and FACIT-F that were maintained at week 24. Sarilumab improved morning stiffness and reduced the impact of RA on work, family, social/leisure activities participation (WPS-RA) and on patients9 lives (RAID). Percentages of patients reporting improvements ≥MCID and ≥ normative scores were greater with sarilumab than placebo. Conclusions In patients with TNF-IR RA, 150 and 200 mg sarilumab + csDMARDs resulted in clinically meaningful patient-reported benefits on pain, fatigue, function, participation and health status at 12 and 24 weeks that exceeded placebo + csDMARDs, and were consistent with the clinical profile previously reported. Trial registration number NCT01709578; Results.

To determine the rate and factors associated with ankylosing spondylitis in a cohort of patients with undifferentiated spondyloarthritides (SpA).62 consecutive patients with undifferentiated SpA seen between 1998 and 1999 underwent clinical and imaging evaluations throughout follow up. The main outcome measure was a diagnosis of ankylosing spondylitis.50 patients with peripheral arthritis (n = 35) and inflammatory back pain (n = 24) (26 male; mean (SD) age at onset, 20.4 (8.8) years; disease duration 5.4 (5.7) years) were followed up for 3-5 years. At baseline,90% of patients had axial and peripheral disease, while 38% had radiographic sacroiliitis below the cut off level for a diagnosis of ankylosing spondylitis (BASDAI 3.9, BASFI 2.9). At the most recent evaluation, 21 patients (42%) had ankylosing spondylitis. Two factors were associated with a diagnosis of ankylosing spondylitis in multivariate analysis: radiographic sacroiliitis grade2 bilateral, or grade3 unilateral (odds ratio (OR) = 11.18 (95% confidence interval, 2.59 to 48.16), p = 0.001), particularly grade 1 bilateral (OR = 12.58 (1.33 to 119.09), p = 0.027), and previous uveitis (OR = 19.25 (1.72 to 214.39), p = 0.001). Acute phase reactant levels, juvenile onset, and HLA-B27 showed a trend to linkage with ankylosing spondylitis (NS).Low grade radiographic sacroiliitis is a prognostic factor for ankylosing spondylitis in patients originally classified as having undifferentiated SpA. Low grade radiographic sacroiliitis should be regarded as indicative of early ankylosing spondylitis in patients with undifferentiated SpA.

Rheumatoid arthritis (RA) is considered an autoimmune disease, but the notion that the process may be triggered by an unknown infectious agent has been a longstanding concept in the pathogenesis of RA. After several decades searching for such causative agents in the joints, the direct evidence is still missing. In the June issue of Arthritis Care & Research, Chen et al provided new insights in this area searching with gas chromatography-mass spectrometry (GC-MS) for muramic acid, a component derived from bacterial cell walls, in the joint tissues of RA patients (1). In the case of reactive arthritis (ReA), infectious agents triggering joint inflammation have been well established (2,3). Gastrointestinal infections by enteric bacterial strains, such as Yersinia, Salmonella, Campylobacter, and Shigella species, and urogential infections by Chlamydia species are known to be associated with ReA. One of the strongest links is the demonstration of Chlamydial DNA in the joints of patients with post-Chlamydia ReA by polymerase chain reaction (PCR) (4,5). However, after a prolonged search for bacterial DNA in RA joints, it remains unresolved whether or not an organism or its antigenic fragments persist locally in these joints. It may still be argued that the causative agent is present at such a low concentration that it cannot be detected with current microbiology techniques. To date, many methods have been used in hunting for microbes in joints with RA, as well as those with ReA, ankylosing spondylitis, and osteoarthritis (OA) (Table 1). In their study, Chen et al screened for bacteria in joint tissues of RA patients using a sensitive pan-bacteria PCR, which can detect DNA of almost any bacterial species. However, no bacterial DNA was found in their study. Despite the absence of bacterial DNA, they probed for evidence of the bacterial cell wall, which represents the major constituent of bacteria. The skeleton of bacterial cell walls mainly consists of polysaccharide, peptidoglycan, and cell wall-associated proteins. Peptidoglycan is the major constituent of the gram-positive bacterial cell wall, whereas lipopolysaccharide (LPS) is the dominant component of the gram-negative bacterial cell wall. The schematic structure of the gram-positive bacterial cell wall is shown in Figure 1. In the current study, Chen et al selected muramic acid, a component of the peptidoglycan moiety of the bacterial cell wall. Muramic acid is unique to bacteria and is not present in the mammalian proteome, making it an ideal chemical marker for detecting bacteria (6). Chen et al detected muramic acid by using a GC-MS with a chemical ionization method sensitive enough to detect even picogram amounts (2 pg/injected amount). GC-MS has previously been used successfully to detect muramic acid in joints of septic arthritis patients) (7,8). Chen et al were able to demonstrate the presence of muramic acid in the joints of some RA patients, suggesting persistence of bacterial cell wall components, rather than bacterial DNA, in the joints of chronic RA (duration more than 5 years). Their findings are in line with earlier reports that bacterial cell wall components were present in RA joints by immunohistochemistry, using an antibody against bacterial cell wall peptidoglycan (9). However, this current study makes the important observation that the presence of bacterial cell wall components is not specific for RA, since they were also found in joint tissues of OA patients. The question has remained open how these bacterial cell wall components might play a biologic role if they persist in the joints for prolonged periods. Are they pathogenic? Several studies have implicated bacterial cell wall components as having multiple immunologic activities that may contribute to joint inflammation. 1) The recently discovered receptors of the first line of host defense—the Tolllike receptors (TLR)—recognize a range of microbes and their products. For example, TLR2 recognizes bacterial peptidoglycan (10). 2) Bacterial peptidoglycan is capable of stimulating synovial macrophages to express the costimulatory molecules CD80 and CD86, and to produce proinflammatory cytokines such as tumor necrosis factor and interleukin 6 (11). 3) Certain bacterial cell walls are able to induce experimental arthritis in rats with histopathologic features resembling RA (12,13). 4) Small fragments of the arthritogenic bacterial peptidoglycan, such as muramyl peptides, possess potent proinflammatory capacity (14). All these lines of evidence suggest that the bacterial cell wall components are potential arthritogenic Xiang Zhang, MD, PhD, Robert D. Inman, MD: University Health Network and University of Toronto, Toronto, Ontario, Canada; Cesar Pacheco-Tena, MD, MSc: Hospital Central Universitario, Universidad Autonoma de Chihuahua, and Hospital Clinica del Parque, Mexico. Address correspondence to R. D. Inman, MD, Arthritis Center of Excellence, ECW 8-005, Toronto Western Hospital, 399 Bathurst Street,Toronto, ON, M5T 2S8 Canada. Submitted for publication December 11, 2002; accepted December 22, 2002. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 49, No. 4, August 15, 2003, pp 479–482 DOI 10.1002/art.11186 © 2003, American College of Rheumatology

Objective: To investigate the role of HLA-B and HLA-DR genes as contributors to genetic susceptibility and clinical expression of the spondyloarthropathies (SpA) in the Mexican population. Methods: The study included 172 patients with SpA (undifferentiated SpA 83, ankylosing spondylitis (AS) 64, and reactive arthritis 25) and 99 healthy controls. The HLA-B and HLA-DR alleles were detected by the polymerase chain reaction with sequence-specific primers technique. Patient assessment included demographic data, diagnostic categories, and disease patterns. Statistical methods included the Mantel-Haenzel χ2 test, Fisher's exact test, and Woolf method for odds ratio (OR). Differences of continuous variables between HLA allele groups were calculated by Student's t test. Results: Increased frequencies of HLA-B27 (pCh10-3, OR=28.7), HLA-DR1 (pC=0.045, OR=2.77), and HLA-B15 (p=0.034, pC=NS, OR=2.04) alleles in the whole group were found. HLA-B27 strength of association (OR) was 41.4 in AS; 20.9 in undifferentiated SpA; 27.2 in reactive arthritis. HLA-DR1 and HLA-B15 were increased in undifferentiated SpA (pC=0.045, OR=2.98 and p=0.004, pC=NS, OR=2.75). By analysing 58 HLA-B27 negative patients it was found that HLA-B15 and HLA-DR1 associations with SpA were independent of HLA-B27; increased frequencies of HLA-B15 were found in the whole SpA group and in patients with undifferentiated SpA (pC=0.03, OR=3.09 and pCh0.01, OR=3.77) and of HLA-DR1 in the latter (p=0.04, pC=NS, OR=3.15). HLA-B27 positive patients were younger than HLA-B27 negative patients at onset (p=0.03), but HLA-DR1 positive patients were older than HLA-DR1 negative patients (p=0.03). Bath indices for disease activity and functioning were higher in HLA-B27 positive patients (p=0.006 and p=0.004 v HLA-B27 negative patients). In contrast, neither HLA-DR1 nor HLA-B15 influenced these indices. Conclusion: Apart from HLA-B27, there is a significant association of HLA-DR1 and HLA-B15 with SpA in Mexicans which is independent of B27. HLA-B27 is associated with younger age at onset and increased disease severity and HLA-DR1 with older age at onset. The strength of HLA-B15, HLA-B27, and HLA-DR1 associations varied in different forms of SpA.

Objective: To investigate the role of HSP70 genes as contributors to genetic susceptibility of the spondyloarthropathies (SpA) in the Mexican population. Methods: The study included 150 patients with SpA (undifferentiated spondyloarthropathy (uSpA) 68, ankylosing spondylitis (AS) 60, and reactive arthritis 22) and 158 healthy controls. HSP70-1, HSP70-2 and HSP70-hom genotypes were analysed by the polymerase chain reaction-restriction fragment length polymorphism technique. Statistical methods included the Mantel-Haenzel, χ2, Fisher's exact test, and Woolf's method for odds ratio (OR). Results: HSP70-2 B/B genotype frequency was increased in the whole group of patients with SpA (pC

Objective.Patients with juvenile-onset spondyloarthritis (SpA) may develop ankylosis of the midfoot resembling the spinal changes seen in patients with ankylosing spondylitis (AS). The study of the histopathology of the feet of patients with tarsitis could help us understand the pathogenesis of bone formation in affected structures in the SpA. The objective of our study was to describe the histopathologic characteristics of the midfoot in patients with tarsitis associated with SpA.Methods.We obtained synovial sheaths, entheses, and bone samples from 20 patients with SpA with midfoot pain/tenderness and swelling. Tissue samples underwent H&E staining; immunohistochemistry for CD3, CD4, CD8, CD68, and CD20 cell identification; and immunofluorescence for bone lineage proteins, including osteocalcin, osteopontin, parathyroid hormone-related protein, bone sialoprotein, and alkaline phosphatase.Results.Slight edema and hyalinization were found in some tendon sheaths, and few inflammatory cells were detected in the entheses. In bones, we found some changes suggesting osteoproliferation, including endochondral and intramembranous ossification, but no inflammatory cells. In entheses showing bone proliferation, we detected osteocalcin and osteopontin in cells with a fibroblast-mesenchymal phenotype, suggesting the induction of entheseal cells toward an osteoblast phenotype.Conclusion.Osteoproliferation and abnormal expression of bone lineage proteins, but no inflammatory infiltration, characterize midfoot involvement in patients with SpA. In this sense, tarsitis (or ankylosing tarsitis) resembles the involvement of the spine in patients with AS. Ossification may be in part explained by the differentiation of mesenchymal entheseal cells toward the osteoblastic lineage.

Objective, To identify bacterial DNA in synovial fluid cells of patients with active juvenile onset spondyloarthropathy (SpA). Methods. The main group of study constituted 22 patients with juvenile onset SpA. In addition, five patients with adult onset SpA and nine with rheumatoid arthritis (RA) were studied. Polymerase chain reaction (PCR) with either genus- or species-specific primers was performed on synovial fluid cells to detect DNA sequences of Chlamydia trachomatis, Yersinia enterocolitica, Salmonella sp., Shigella sp., Campylobacter sp. and Mycobacterium tuberculosis. The presence of antibacterial antibodies in sera and synovial fluid was also determined by enzyme-linked immunoassay. Results. The synovial fluid of nine patients with juvenile onset SpA, three with adult onset SpA and one with RA contained bacterial DNA. Five juvenile onset SpA samples had DNA of one single bacterium; two juvenile onset SpA and three adult onset SpA had DNA of two bacteria and two juvenile onset SpA had DNA of three bacteria. Overall, Salmonella sp. DNA was detected in seven synovial fluid samples, Shigella sp., Campylobacter sp. and M. tuberculosis were found in four samples each, and C. trachomatis was found in two. The bacterial DNA findings correlated with neither diagnosis nor disease duration. One RA synovial fluid had DNA of Campylobacter sp. Neither serum nor synovial fluid antibacterial antibodies correlated with DNA findings or clinical diagnosis. Conclusion. In this study, single and several combinations of bacterial DNA were identified in the synovial fluid of patients with long-term undifferentiated and definite juvenile onset SpA and adult onset SpA. Of relevance is that bacterial DNA corresponds to bacteria producing endemic disease in our population.

Objective To compare the efficacy of 2 low-dose oral methotrexate (MTX) schedules in maintaining remission in patients with rheumatoid arthritis (RA). Methods Patients with RA were included if they were receiving treatment with weekly MTX for at least 9 months and the RA was in remission (defined by American College of Rheumatology [ACR] criteria) for at least 6 months. Patients were stratified by treatment and randomly assigned to weekly or every-other-weekly (EOW; reducing their monthly dose by half) treatment with MTX. Patients were evaluated by a rheumatologist (blinded to the treatment schedule) at baseline and at 6, 12, and 24 weeks. The evaluations included joint counts, Ritchie Articular Index, Health Assessment Questionnaire Disability Index, physician's and patient's global health assessments, visual analog scale for pain, and incidence of adverse effects. Laboratory evaluations were done at baseline and at week 24. Results Fifty-one patients were included (26 taking weekly MTX, 25 taking EOW MTX). Baseline comparisons showed no differences between the groups. The mean duration of RA was 90% of the patients in both groups continued in remission. Evaluations of disease activity at 6 and 12 weeks showed no between-group differences. EOW MTX patients who experienced relapse were switched back to weekly MTX, and after a few weeks, their RA was again controlled. The incidence of adverse effects was slightly higher in the weekly MTX group, although the difference did not reach statistical significance. The observed laboratory values were very similar for both groups, except for the serum aspartate aminotransferase and alanine aminotransferase levels, which decreased in the EOW MTX group and were statistically significant at week 24 (P = 0.04 and P = 0.006, respectively). Conclusion EOW MTX represents a valid therapeutic alternative for a specific subgroup of RA patients, as outlined by the ACR remission criteria. Patients with a short disease duration who were treated early after disease onset with weekly MTX and who achieve sustained remission have a higher probability of success with the EOW MTX schedule.

Objective: To assess the relationship between disease activity and signs and symptoms of infection in Mexican patients with spondyloarthropathies (SpA). Methods: A cross sectional study of 95 non-selected patients with SpA (62 men; mean age 26.4 years), who were examined for signs and symptoms of infection and their association with disease activity. 52 had ankylosing spondylitis (AS), 32 undifferentiated SpA (uSpA), 6 chronic reactive arthritis (ReA), and 5 psoriatic arthritis (PsA). Categorical data were analysed by x 2 or Fisher’s tests. Results: 53 (56%) patients had infections: 41 (43%) upper respiratory tract (URT), 34 (36%) enteric, and 20 (21%) genitourinary infections. More infections occurred in HLAB27 positive patients as a whole (39 v 5; p = 0.003) and in uSpA (12 v 2; p = 0.005). In AS and uSpA, infections occurred in ,50%. 30/39 (77%) patients with active disease (group A) and 23/56 (41%) (group B) (p = 0.001) had infection. There were more enteric infections in group A (47%; p,0.001) and more URT infections in group B (52%; p = NS). 22/30 (73%) patients attributed disease activity to infection. Conclusion: Enteric, and less commonly, URT infections in Mexican patients with SpA, particularly those who were HLAB27 positive, seem to have a role in the active phase of AS and uSpA.

Background Clinical remission is an important treatment goal in rheumatoid arthritis (RA) and is associated with improved physical function and quality of life.1,2 In the phase 3 TARGET study (NCT01709578), sarilumab (150 or 200 mg subcutaneously every 2 weeks + conventional synthetic disease-modifying antirheumatic drugs [csDMARDs]) demonstrated efficacy in adults with active, moderate-to-severe RA and inadequate response to tumor necrosis factor (TNF) inhibitors.3 Infections, neutropenia, injection site reactions, and increased transaminases were among the most common treatment-emergent adverse events.3 Objectives This analysis assessed the proportions of patients achieving clinical remission measured by 4 different disease activity measures in a difficult-to-treat patient population with active RA and inadequate response or intolerance to ≥1 prior TNF inhibitor(s). Methods Four definitions of remission were used: 28-joint disease activity score by C-reactive protein (DAS28-CRP) Results Baseline demographic and disease characteristics were balanced among the 3 treatment groups. At week (wk) 12 and wk 24, the proportion of patients achieving DAS28-CRP Conclusions Sarilumab induced remission (using a broad range of definitions) as early as 12 weeks after initiation of therapy in patients with an inadequate response to TNF inhibitors. Patients with remission generally had improvements in physical function and fatigue as well. References Smolen et al. Ann Rheum Dis. 2014;73:492–509. Radner et al. Arthritis Res Ther. 2014;16:R56. Fleischmann et al. Presented at: ACR; November 7–11, 2015; San Francisco, CA. Acknowledgement This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Editorial assistance was provided by Kristi Porter, PhD, MedThink SciCom, and funded by Sanofi and Regeneron Pharmaceuticals, Inc. Disclosure of Interest G. Burmester Grant/research support from: AbbVie, Pfizer, Roche, and UCB, Consultant for: AbbVie, BMS, Pfizer, Merck, MedImmune, UCB, and Roche, Speakers bureau: AbbVie, BMS, Pfizer, Merck, UCB, and Roche, P. Hrycaj: None declared, C. Pacheco-Tena Consultant for: BMS, Janssen, Pfizer, Roche, and UCB, H. van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, E. Mangan Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, Y. Lin Shareholder of: Sanofi, Employee of: Sanofi, D. Bauer Shareholder of: Sanofi, Employee of: Sanofi, J. Fay Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, J. Parrino Shareholder of: Regeneron Pharmaceuticals, Inc, Employee of: Regeneron Pharmaceuticals, Inc, A. Kivitz Shareholder of: Sanofi and Regeneron Pharmaceuticals, Inc., Consultant for: Sanofi, Pfizer, Roche, and UCB

To the Editor: We thank The Journal for the opportunity to address some details in the editorial by Appel and Sieper1 about our recent paper “Bone Lineage Proteins in the Entheses of the Midfoot in Patients with Spondyloarthritis”2. As Appel and Sieper stated1, we reported the lack of inflammatory lesions in our set of tissue samples2. Yet in contrast to their interpretation, our findings did not result from the study of patients in the advanced stage of what we have called “ankylosing tarsitis”, but for reasons that were already mentioned in the paper. Figure 1 does not represent the population included in the study; it illustrates only the most advanced stage of ankylosing tarsitis2. In fact, there were only 3 … Address correspondence to Dr. R. Burgos-Vargas, Rheumatology Department, Hospital General de Mexico, Dr. Balmis 148, Mexico DF 06720, Mexico. E-mail: r.burgos.vargas{at}gmail.com

To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) gene as susceptibility marker for spondyloarthritis (SpA), two polymorphisms (-238 and -308 positions) were analyzed in 229 patients with SpA (113 with ankylosing spondylitis [AS], 92 with undifferentiated SpA [U-SpA], 24 with reactive arthritis), and 169 ethnically matched healthy control subjects. The HLA-B alleles were detected by PCR-SSP technique and the TNF-alpha polymorphism by PCR-RFLP. In comparison with healthy control subjects, the frequencies of TNF-238 in SpA were similar. In contrast, the analysis of -308 polymorphism showed increased frequencies of the T2(A) allele in the whole SpA group (p0.05, pC = NS, OR = 1.83) as well as the T2(A) allele (pC0.05, OR = 2.4) and T1T2(AG) genotype (p0.05, pC = NS, OR = 2.25) in U-SpA patients. Comparison of B27-negative patients and healthy control subjects yielded similar results. There was no significant correlation between TNF genotypes and clinical data. The present study demonstrates that TNF-alpha -308 polymorphism appears to be associated with the genetic susceptibility U-SpA. The association seems independent of the susceptibility conferred by the HLA-B27 in this group of patients.

To evaluate the role of LMP (low molecular weight protein) genes as susceptibility markers for spondyloarthritis (SpA), LMP gene polymorphisms were analyzed in 223 Mexican patients with SpA (81 undifferentiated SpA [U-SpA], 117 with ankylosing spondylitis [AS], 25 with reactive arthritis) and in 139 ethnically matched healthy individuals. LMP genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. The LMP2 and LMP7 allele frequencies were similar in patients and healthy controls. Genotype analysis revealed an increased frequency of LMP2 R/R genotype in the whole group of SpA (pC = 0.003, OR = 2.06, 95%CI = 1.3-3.25) and in the clinical subgroups of AS (pC = 0.039, OR = 1.88, 95%CI = 1.1-3.22) and U-SpA (pC = 0.003, OR = 2.56, 95%CI = 1.37-4.8) compared with healthy controls. Analysis in the LMP7 did not reveal significant differences in patients and healthy controls. The HLA-B27-negative AS subgroup also showed an increased frequency of LMP2 R/R genotype (pC = 0.027, OR = 4.81, 95%CI = 1.21-22.13). The LMP2-R/R AS patients were younger than LMP2-H/R and H/H patients at onset of the disease (16.0 +/- 6.8 years for R/R, 22.0 +/- 11.2 years for H/R and 28.6 +/- 10.9 years for H/H) (p0.05). The data suggest that, besides HLA-B27, LMP2 genotypes are also involved in the genetic susceptibility to develop AS in Mexicans. Furthermore, the age at onset of this disease might also be influenced by genotypes of this gene.

Objective: To develop and test an index to evaluate the radiographic changes that occur in the tarsus and adjacent areas of the foot in patients with spondyloarthropathies (SpA). Methods: The spondyloarthropathy tarsal radiographic index (SpA-TRI) was developed in three consecutive steps: (a) detection of descriptors after reviewing 70 radiographic files; (b) descriptor gradation and subsequent modifications performed by a consensus committee, and (c) interobserver variability assessed by three blinded and independent observers on 272 radiographs: anteroposterior 118, lateral 90, oblique 64 from 121 patients with SpA, and intraobserver variability on 75 radiographs from 25 patients with SpA. Statistical analysis included percentage of agreement and κ test. SpA-TRI score ranges from 0 to 4 (0=normal; 1=osteopenia or suspicious findings; 2=definite joint space narrowing, bony erosion(s), periosteal whiskering, or enthesophyte(s) in the plantar fascia or Achilleal tendon attachments; 3=para-articular enthesophyte(s); 4=bony ankylosis (joint space fusion or complete bridging)). Results: Complete agreement for every evaluation was >40%, and discordance >1 grade was

BACKGROUND—Because serious adverse reactions to allopurinol have been related to a reduce creatinine clearance rate and prolonged half life of oxypurinol, it has been recommended that the dose should be adjusted according to the rate of creatinine clearance. However, in some patients with gout the dose is not sufficient to reduce serum levels of uric acid (⩽390 µmol/l) and to halt disease progression. OBJECTIVE—To determine the prevalence of adverse reactions attributable to allopurinol in patients with primary gout according to dose and creatinine clearance rate. METHODS—Data on 120 patients with gout receiving allopurinol, in whom the starting dose was adjusted according to creatinine clearance rate and later increased in some patients to control the disease, were retrospectively reviewed. Two groups were compared: group A, 52 patients receiving creatinine clearance adjusted maintenance doses of allopurinol and group B, 68 patients receiving non-adjusted higher maintenance doses of allopurinol. RESULTS—During follow up 57% required higher allopurinol doses than those recommended according to their creatinine clearance rate. Only five (4%) of 120 consecutive patients developed allopurinol related adverse reactions: four minor skin reactions and one allopurinol hypersensitivity syndrome (AHS). Three of these (including the case of AHS) occurred in group A and two in group B (p=NS). The duration of allopurinol treatment was the same in both groups (group A: 2.3 (3.3) years; group B: 3.7 (4.8) years). No patient in group A, but 44% in group B had a creatinine clearance rate of

Background Although there is much discussion regarding when to initiate a biological agent in rheumatoid arthritis (RA) patients, data on when to stop these agents is scant. Disease activity outcomes after the ending of an industry sponsored clinical trials may provide useful information regarding the duration of drug-free remission for a given biological agent. Objectives To assess the length of remission and rate of relapse of disease activity after ending the open label, long-term extension study (5 yrs) using tocilizumab in RA patients enrolled in the OPTION trial. Methods Patients who no longer received tocilizumab because of the ending of the extension study (5 yrs) of the OPTION trial were analyzed. All patients were: a) in remission (DAS28 Results Forty patients were analyzed, 85% females with a mean age of 53.5 yrs. During the first 12 months of follow-up, 21 (52.5%) patients continued in remission. Relapses occurred in 19 (47.5%) patients, 11 (58%) of them during the first three months after the last tocilizumab administration. No variables were identified to predict length of remission. Conclusions Long-term remission is possible in a substantial number of RA patients after suspension of tocilizumab. Additional data are required to support recommendations for discontinuing a biological agent after achieving remission. These recommendations would impact in patients’ safety and the economic burden imposed by these treatments. References Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 2008;371:989–97. Disclosure of Interest None Declared

Alterations in tissue oxygen pressure contribute to a number of diseases, including rheumatoid arthritis (RA). Low partial pressure of oxygen, a condition known as hypoxia, is a relevant feature in RA since it is involved in angiogenesis, inflammation, apoptosis, cartilage degradation, energy metabolism, and oxidative damage. Therefore, alterations in hypoxia-related signaling pathways are considered potential mechanisms of disease pathogenesis. The objective of this review is to highlight and update our current knowledge of the role of hypoxia in the pathogenesis of RA. We describe the experimental evidence that RA synovial tissue exists in a hypoxic state, as well as the origin and involvement of synovial hypoxia in different aspects of the pathogenic process.