Atlas of axial spondyloarthritis in Spain 2017: Study design and population / Atlas de Espondiloartritis Axial en España 2017: diseño del estudio y descripción de la muestra

Objective: Atlas of Axial Spondyloarthritis in Spain 2017 aims to better understand the reality of the patients suffering from this disease from an integrated approach. Methods: The Atlas 2017 based its results on an extensive cross-sectional patient survey conducted in Spain (2016), validated by a multidisciplinary group of experts on spondyloarthritis. Results: Data from 680 patients with axSpA were obtained, most of them suffered from AS, were HLA-B27 positive, older than 45 years, and live as part of a couple. A large percentage had university studies, were disabled and members of a patient association. Patients reported a diagnostic delay of 8.5 years, high disease activity (BASDAI 5.5±2.2), moderate-important stiffness (61.0%), medium-high functional limitation (74.9%), and psychological distress (GHQ 5.7±4.5). A total of 54.7% reported taking NSAIDs, 28.4% DMARDs, 36.3% biological therapy and 32.2% were not receiving pharmacological treatment. Conclusions: The Atlas survey data reveals still a long diagnostic delay, high disease activity, psychological distress, while an important proportion could be undertreated

Objetivo: El Atlas de Espondiloartritis Axial en España 2017 tiene como objetivo comprender mejor la realidad de los pacientes que padecen esta enfermedad desde un enfoque integrado. Métodos: El Atlas 2017 basó sus resultados en una amplia encuesta transversal de pacientes realizada en España (2016), validada por un grupo interdisciplinar de expertos en espondiloartritis. Resultados: Se obtuvieron datos de 680 pacientes con EspAax. La mayoría de ellos sufría EA, eran HLA-B27 positivo, mayores de 45 años y vivían en pareja. Un gran porcentaje tenía estudios universitarios, discapacidad reconocida y era miembro de una asociación de pacientes. Los pacientes declararon un retraso diagnóstico de 8,5 años, alta actividad de la enfermedad (BASDAI 5,5±2,2), rigidez moderada-importante (61,0%), limitación funcional moderada-alta (74,9%) y problemas psicológicos (GHQ 5,7±4,5). Un total del 54,7% declaró estar tomando AINE, el 28,4% FAME, el 36,3% terapia biológica, mientras que el 32,2% no recibía ningún tipo de tratamiento farmacológico. Conclusiones: Los datos de la encuesta Atlas revelan todavía un enorme retraso diagnóstico, alta actividad de la enfermedad, problemas psicológicos, mientras que una proporción importante de pacientes podrían estar infratratados

Nefritis túbulo-intersticial aguda en paciente con espondiloartritis axial HLA-B27 en tratamiento con adalimumab / Acute tubulointerstitial nephritis in an HLA-B27-positive patient with axial spondyloarthritis being treated with adalimumab

Los antagonistas del factor de necrosis tumoral-alfa (ATNF) se utilizan en el tratamiento de múltiples enfermedades, como artritis psoriásica, enfermedad de Crohn, espondilitis anquilosante, artritis idiopática juvenil, generalmente, cuando son refractarias al tratamiento de primera línea1. La utilización de los ATNF se ha asociado con la inducción de enfermedades autoinmunes, como lupus eritematoso sistémico-like, vasculitis, sarcoidosis-like y, recientemente, nefritis túbulo-intersticial aguda granulomatosa. Describimos un caso de nefritis túbulo-intersticial aguda no granulomatosa en un paciente con espondiloartritis axial HLA-B27 positiva y enfermedad de Crohn en tratamiento con adalimumab

Antagonists of tumor necrosis factor-alpha (ATNF) are used for the treatment of multiple diseases such as psoriatic arthritis, Crohn's disease, ankylosing spondylitis and juvenile idiopathic arthritis, usually, when they are refractory to first-line treatment1. The use of ATNF has been associated with the induction of autoimmune diseases such as systemic lupus erythematosus-like disease, vasculitis, sarcoidosis-like diseases and, recently, acute granulomatous tubulointerstitial nephritis. We report a case of acute nongranulomatous tubulointerstitial nephritis in an HLA-B27-positive patient with axial spondyloarthritis and Crohn's disease being treated with adalimumab

Clinical characteristics of patients with spondyloarthritides and HLA-B27 positive antigen.

The aim of this study was to present our experiences in diagnosing spondyloarthritides (SpA), and to list the most common clinical features of HLA-B27 positive patients. The study included 65 HLA-B27 positive patients with confirmed diagnosis of ankylosing spondylitis (AS) and psoriatic arthritis (PsA) who were analyzed between 2009 and 2010 in Clinic of Internal Medicine in Osijek. The diagnosis of seronegative spondyloarthritides was based on the ASAS (Assessment in AS Working Group) classification criteria for axial and then supplemented with ASAS criteria for peripheral SpA and was confirmed by radiological techniques. For diagnosing the ankylosing spondylitis (AS), there have been applied the modified New York criteria. Radiological criteria for definite sacroiliitis according to the modified New York criteria is bilateral sacroiliitis, grade 2-4 (> or = 2) or unilateral sacroiliitis, grade 3-4. For diagnosing the psoriatic arthritis (PsA), there were used CASPAR diagnostic criteria. Other features of SpA are defined within the existing classification criteria. HLA-B27 antigen was determined by direct immune-fluorescence technique using flow cytometer. The average age of patients was 50.34 years, of whom 27 female (41.53%), 38 male (58.46%). Duration of illness was 15.79 years on average. With 75.38% of patients, there had been determined the diagnosis of AS; 24.62% of patients had the diagnosis of PsA. The most common clinical characteristics that patients had were: inflammatory back pain (pain Inflammation along the lumbosacral spine), peripheral arthritis, intermittent pain in the gluteus, sacroiliitis, enthesitis, uveitis, dactilitis.

LC MALDI-TOF MS/MS and LC ESI FTMS analyses of HLA-B27 associated peptides isolated from peripheral blood cells.

Peptides eluted from peripheral blood cells of HLA-B*2705 healthy donor were analyzed by LC MALDI MS/MS and LC ESI FTMS techniques. The sequences of 92 peptide ligands identified from one healthy blood donor by LC MALDI-TOF MS/MS were compared with those previously published from in vitro long-term cell cultures available in SYFPEITHI database and splenocytes. It was found that 18 sequences confirmed within 1ppm mass error by LC ESI FTMS were already described and 3 of them matched with those previously reported from HLA-B*2705 splenocytes. Another 38 sequences validated within the same mass error were not found in SYFPEITHI database and are identified here for the first time. Finally, 36 sequences (5 sequences already published in SYFPEITHI database) were evaluated by LC MALDI-TOF MS/MS but no matches in the list of monoisotopic masses obtained from LC ESI FTMS were found.

Espondiloartritis en la infancia: formas de presentación, diagnóstico y tratamiento / No disponible

No disponible

HLA-B27 y patogenia de las espondiloartropatías / No disponible

No disponible

¿Se trata de un caso de artritis reactiva? / No disponible

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Incapacidad motora en una paciente con artritis / Motor incapability in a patient with arthritis

No disponible

No disponible

Chronic synovitis and HLA B27 in patients with severe haemophilia.

Chronic synovitis affects about 10% of patients with severe haemophilia in India. This disease has some features in common with ankylosing spondylitis, which has been linked to HLA B27. We therefore aimed to test whether there is an association between HLA B27 and chronic synovitis. We studied 473 patients with severe haemophilia (33 of whom had chronic synovitis), and 1175 healthy controls using a standard serological technique and the reverse line strip assay. 64% (21 of 33) of patients with haemophilia and chronic synovitis were positive for HLA B27, compared with 5% (23 of 440) of those with severe haemophilia, but not chronic synovitis (odds ratio 31.6 [95% CI 9.28-39.38], p<0.0001), and 9% (100 of 1175) of healthy controls (18.81 [9.6-27.7], p<0.0001). We conclude that there is a strong association between HLA B27 and chronic synovitis in Indian patients with severe haemophilia and screening in this population could allow treatment and prevention of the complication.

Uniquely conformed peptide-containing beta 2-microglobulin-free heavy chains of HLA-B2705 on the cell surface.

The human class I MHC molecules are known to generally exist on the cell surface either as peptide-containing complexes of H chain (alpha-chain) and beta(2)-microglobulin (beta(2)m) or as beta(2)m-free H chains incapable of binding peptides. In this study, a uniquely conformed peptide-containing beta(2)m-free HLA-B2705 H chain has been isolated using the recently described highly efficient perfusion-affinity chromatography system for purification of class I MHC protein molecules. This form recognized by the mAb MARB4 is very closely associated with the remainder of the peptide containing HLA-B2705/beta(2)m complex reactive with mAb ME1 and is present to approximately 1-10% of mAb ME1 reactive forms on the cell surface. Also, HLA-B2705 purified using the mAb ME1 affinity column includes this unique mAb MARB4-reactive, unusually stable peptide-containing beta(2)m-free form. A peptide nonamer GRWRGWYTY was isolated and identified from this beta(2)m-free HLA-B2705 H chain and was used to assemble the mAb MARB4 reactive form efficiently on the surface of cells expressing HLA-B2705. The discovery of this form opens new avenues for further investigation of the role of HLA-B27 in spondyloarthropathies.

Destructive diskovertebral lesions in ankylosing spondylitis: appearance on magnetic resonance imaging.

We report magnetic resonance imaging findings of diskovertebral lesions in a case of ankylosing spondylitis mimicking metastatic and/or infectious disease. Multiple hypointense areas were seen on T1-weighted images corresponding to hyperintense areas on T2-weighted images in dorsal, lumbar, and sacral vertebral bodies and the manubriosternal joint, with accompanying soft tissue masses. Diagnosis was achieved through biopsy, regression of the paravertebral soft tissue masses, later detection of bilateral sacroiliitis on computed tomography, and presence of histocompatibility antigen HLA-B27.

Influence of infection of cells with bacteria associated with reactive arthritis on the peptide repertoire presented by HLA-B27.

Reactive arthritis (ReA) after infections with various gram-negative bacteria is strongly associated with the MHC class I molecule HLA-B27. It is supposed that the B27 molecule itself plays a role in the pathogenesis of ReA by presenting antigenic peptides to cytotoxic T lymphocytes. The peptide repertoires presented by Salmonella-, Shigella- and non-infected cells were compared to identify such peptides. From the peptides isolated from the B27 molecules of these cells, profiles were generated by reversed-phase chromatography and peaks present in the profiles from infected cells but not in profiles from non-infected cells were studied for their peptide compositions. Some sequences with identity to those in human histone H3, human ribosomal protein S17 and the heavy chain of HLA-B27 itself were detected only in profiles from infected cells. All peptides identified from infected cells contained the B*2705 peptide-binding motif. The data suggest that HLA-B27-positive cells infected with ReA-inducing bacteria show an increased presentation of certain self-peptides. There was no evidence for altered peptide-binding specificity of B27 after infection. However, the interpretations were hampered by the variation in peptide presentation between different experiments.

Quantitative and qualitative influences of tapasin on the class I peptide repertoire.

Tapasin is critical for efficient loading and surface expression of most HLA class I molecules. The high level surface expression of HLA-B*2705 on tapasin-deficient 721.220 cells allowed the influence of this chaperone on peptide repertoire to be examined. Comparison of peptides bound to HLA-B*2705 expressed on tapasin-deficient and -proficient cells by mass spectrometry revealed an overall reduction in the recovery of B*2705-bound peptides isolated from tapasin-deficient cells despite similar yields of B27 heavy chain and beta(2)-microglobulin. This indicated that a proportion of suboptimal ligands were associated with B27, and they were lost during the purification process. Notwithstanding this failure to recover these suboptimal peptides, there was substantial overlap in the repertoire and biochemical properties of peptides recovered from B27 complexes derived from tapasin-positive and -negative cells. Although many peptides were preferentially or uniquely isolated from B*2705 in tapasin-positive cells, a number of species were preferentially recovered in the absence of tapasin, and some of these peptide ligands have been sequenced. In general, these ligands did not exhibit exceptional binding affinity, and we invoke an argument based on lumenal availability and affinity to explain their tapasin independence. The differential display of peptides in tapasin-negative and -positive cells was also apparent in the reactivity of peptide-sensitive alloreactive CTL raised against tapasin-positive and -negative targets, demonstrating the functional relevance of the biochemical observation of changes in peptide repertoire in the tapasin-deficient APC. Overall, the data reveal that tapasin quantitatively and qualitatively influences ligand selection by class I molecules.

Perfusion chromatography for very rapid purification of class I and II MHC proteins.

Major histocompatibility complex (MHC) proteins are surface glycoproteins that are strongly associated with either self or foreign peptides. Their interaction with the T-cell receptor on the T-cells initiates an immune response and help in discriminating between self and non-self, respectively. We describe here a novel means of rapidly purifying human MHC molecules on either small scale or large scale from the cell lysate of lymphoblastoid B cell line and from insect cell culture supernatants by using affinity perfusion chromatography. As representative cases HLA-B2705, a class I MHC molecule, and HLA-DR1, a class II MHC molecule were purified from EBV-transformed human lymphoblastoid B cells, LG2. Soluble HLA-DR1 was also purified from the cell culture supernatant of insect cells. The peptides eluted from the purified HLA-B2705 were pool sequenced and found to have the same motif as has previously been published. This new method provides a very rapid means of purifying MHC protein molecules, applicable to both large scale and small scale purification, which in turn greatly enhances the accuracy of further analysis of the associated peptides through mass spectrometry.

Strong association of HLA-B27 heavy chain with beta 2-microglobulin.

Monoclonal antibody TG1 recognizes specifically antigens HLA-B27, B7, B22 and B17 on cell surface in cytotoxicity and cytofluorometry tests. When cell detergent extracts were subjected to SDS PAGE under mild conditions (no heating and no reduction of the sample) followed by Western blotting, TG1 detected exclusively a complex of B27 heavy chains with beta(2)-microglobulin (as a 50 kDa band) whereas the other B-locus antigens (B7, B22, B17) were detected as free 43 kDa heavy chains under the same conditions. When the samples were boiled prior to SDS PAGE, TG1 detected again the 43 kDa free heavy chains of B7, B22 and B17 but no zone corresponding to B27 could be detected indicating that the epitope in free B27 chains is more sensitive to denaturation by SDS. Thus, our main finding is that the interaction of HLA-B27 heavy chain with beta(2)-microglobulin appears to be stronger than that of the other HLA-B chains. The resistance of the HLA-B27/beta(2)-microglobulin complex to the SDS dissociation is strikingly similar to the behavior of MHC class II molecules under similar conditions. Thus, it may be speculated that HLA-B27 complexes can be also more stable than other MHC class I molecules under more physiological dissociative conditions (e.g. in endosomal compartments). This feature might potentially influence antigen presentation by HLA-B27 and contribute to the well known disease linkage of HLA-B27.

HLA-B27 subtypes positively and negatively associated with spondyloarthropathy.

OBJECTIVE: Eleven subtypes of HLA-B27 have been identified. If some of these subtypes had a stronger association with spondyloarthropathy (SpA) than others, this might tell us which peptides are of pathogenetic importance. A subtype preponderance has not been proved in Caucasians or in Asian Indians. Our objective was to determine whether some subtypes are positively or negatively associated with SpA in Indonesia. METHODS: Cells of 34 HLA-B27 positive patients with SpA (fulfilling the European Spondylarthropathy Study Group criteria) and 26 HLA-B27 positive controls, all living in Java, Indonesia, were sampled. Patients and controls were divided according to their presumed ethnic origin. HLA-B27 subtyping (B*2701-09) was performed by polymerase chain reaction in combination with sequence specific oligonucleotide probes to analyze polymorphism in exons 2 and 3 of HLA-B27. RESULTS: HLA-B*2701, *2702, *2703, *2708, and *2709 were found in neither group. HLA-B*2704 was found in 23/34 (68%) of the patients and in only 4/26 (15%) of the controls (p < 0.01). HLA-B*2706 was found in none of the 34 patients, but in 21/26 (81%) of the controls (p < 0.01). One drawback of the study was that most patients were of Chinese descent and most controls were native Javanese. Nevertheless, the absence of SpA among HLA-B*2706 positive individuals is noteworthy. CONCLUSION: HLA-B*2704 is positively associated with SpA (RR = 11.5), while *2706 is negatively associated with this disease (RR < 0.007). The results confirm the findings of Lopez-Larrea, et al in Thailand.

Discrimination of HLA-B27 alleles by group-specific amplification followed by solid-phase sequencing.

HLA-B27 is known to be highly associated with ankylosing spondylitis. Until now, nine B27 subtypes have been sequenced and may contribute in different fashions to ankylosing spondylitis. Additionally, the divergent subtypes may be of clinical importance in bone marrow transplantation with alternative donors. The purpose of this study was to determine the different subtypes of HLA-B27 by a direct sequencing approach. The typing strategy is based on a group-specific amplification of the second and third exon followed by automated fluorescence sequencing of the polymorphic regions. The extensive sharing of sequence motifs between the different B alleles made it impossible to specifically amplify the B27 group under the precondition of including all sequence variations necessary for a postamplification specificity step. Therefore, for setting up a direct sequencing approach of B27, co-amplified B alleles had to be taken into account. In order to get unambiguous sequencing chromatograms without any heterozygous positions, nested sequencing primers were used which selectively matched sequence motifs only present in the second and third exon of the amplified B27 alleles. This strategy allowed in all cases investigated a clear separation of the haplotypes, revealing unequivocal sequencing results. Using this method, we have investigated 93 B27-positive individuals. Sequencing identified the alleles B*2702, 2703, 2704, 2705, and 2707. B*2701, 2706, 2708, and 2709 were not represented in the population studied.

An unstable beta 2-microglobulin: major histocompatibility complex class I heavy chain intermediate dissociates from calnexin and then is stabilized by binding peptide.

Proper assembly of the class I heavy chain (HC), beta 2-microglobulin (beta 2m), and peptide must occur in the endoplasmic reticulum (ER) in order for MHC class I molecules to be expressed on the cell surface. Newly synthesized class I HC bind calnexin, an ER resident chaperone. These calnexin-associated class I HC appeared to lack the stable association with beta 2m in peptide transporter-deficient T2 cells since beta 2m-unassociated class I HC-specific HC10 antibody, but not beta 2m-associated class I HC-specific W6/32 antibody, coimmunoprecipitated calnexin. To determine the precursor-product relationship of the pool of HC that bind peptide, class I-restricted peptides were added to lysates of T2 cells in vitro. These peptides stabilized preexisting beta 2m-associated HC complexes (beta 2m+:HC:pep-), but had no significant effect on the preexisting pool of calnexin-associated HC that lack beta 2m. Release of HC from calnexin appeared to be controlled by the binding of beta 2m, since beta 2m-deficient FO-1 cells showed a prolonged association of class I HC with calnexin, while beta 2m-transfected FO-1 cells displayed a more rapid dissociation of class I HC from calnexin. Consistent with this result, the dissociation of class I HC from calnexin did not appear to be dependent on peptide binding since the dissociation rates were similar in peptide transporter-deficient T2 cells and in wild-type T1 cells. From these observations, we speculate that in the stepwise assembly of class I molecules, calnexin may mediate dimerization of class I HC with beta 2m, and that the unstable beta 2m+:HC:pep- complexes, after dissociation from calnexin, subsequently bind peptide to complete the assembly.

[Idiopathic retroperitoneal fibrosis and ankylosing spondylitis]. / Fibrose rétropéritonéale idiopathique et spondylarthrite ankylosante.

A case of ankylosing spondylarthritis in which retroperitoneal fibrosis developed 16 years after onset is reported. The patient also had aortic incompetence and cardiac conduction disorders. Eight other cases of ankylosing spondylitis with retroperitoneal fibrosis have been published. Potential relationships between the two conditions--including the possible role of indomethacin used by the patient for 16 years--are discussed.