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Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease?

Background: Recent studies with infliximab indicate the therapeutic potential of tumour necrosis factor α blockade in spondyloarthropathy (SpA). Because defective host defence is implicated in the pathogenesis of SpA, the potential side effects of this treatment due to impact on the antimicrobial defence are a major concern. Objective: To report systematically the adverse events seen in a large cohort of patients with SpA treated with infliximab, with special attention to bacterial infections. Patients and methods: 107 patients with SpA were treated with infliximab for a total of 191.5 patient years. All serious and/or treatment related adverse events were reported. Results: Eight severe infections occurred, including two reactivations of tuberculosis and three retropharyngeal abscesses, and six minor infections with clear bacterial focus. One patient developed a spinocellular carcinoma of the skin. No cases of demyelinating disease or lupus-like syndrome were seen. Two patients had an infusion reaction, which, however, did not relapse during the next infusion. Finally, three patients with ankylosing spondylitis developed palmoplantar pustulosis. All patients recovered completely with adequate treatment, and infliximab treatment had to be stopped in only five patients with severe infections. Conclusions: Although the global safety of infliximab in SpA is good compared with previous reports in rheumatoid arthritis and Crohn’s disease, the occurrence of infections such as tuberculosis and retropharyngeal abscesses highlights the importance of careful screening and follow up. Focal nasopharyngeal infections and infection related symptoms, possibly induced by streptococci, occurred frequently, suggesting an impairment of specific host defence mechanisms in SpA.

Repeated infusions of infliximab, a chimeric anti-TNFα monoclonal antibody, in patients with active spondyloarthropathy: one year follow up

Background: In a pilot study, the anti-tumour necrosis factor α monoclonal antibody, infliximab, induced a rapid and significant improvement in global, peripheral, and axial disease manifestations of patients with active spondyloarthropathy. Objective: To determine whether repeated infusions of infliximab would effectively and safely maintain the observed effect. Methods: Safety and efficacy of a maintenance regimen (5 mg/kg infliximab every 14 weeks) was evaluated using the measurements reported in the pilot study. Of the 21 patients, 19 completed the one year follow up for efficacy; two patients changed to another dosing regimen after week 12 owing to partial lack of efficacy. However, they are still being followed up for safety analysis. Results: After each re-treatment a sustained significant decrease of all disease manifestations was observed. Before re-treatment, symptoms recurred in 3/19 (16%) at week 20, in 13/19 (68%) at week 34, and in 15/19 (79%) at week 48. No withdrawals due to adverse events occurred. Twelve minor infectious episodes were observed. Twelve patients (57%) developed antinuclear antibodies; in four of them (19%) anti-dsDNA antibodies were detected. However, no lupus-like symptoms occurred. Conclusion: In this open study of infliximab in patients with active spondyloarthropathy, the significant improvement of all disease manifestations was maintained over a one year follow up period without major adverse events. Although recurrence of symptoms was noted in a rising number of patients before each re-treatment, no loss of efficacy was observed after re-treatment.

Histopathology of intestinal inflammation related to reactive arthritis.

This study has identified a group of patients with inflammatory chronic, or relapsing acute arthritis who even in the absence of gastrointestinal symptoms have histological evidence of ileocolitis. At colonoscopy simultaneous biopsies of the terminal ileum and colon were taken from 108 patients with reactive arthritis (n = 55) or ankylosing spondylitis (n = 53), 47 patients with other rheumatic diseases and 19 control patients suffering from colonic polyps, adenocarcinoma, or chronic constipation. All control patients and all but one patient with rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus, lumbar back ache, and psoriatic arthritis did not have histological evidence of acute or chronic inflammatory bowel disease. In contrast, in 30 of 35 (56.6%) patients with ankylosing spondylitis, and in 37 of 55 (67%) patients with reactive arthritis, regardless of HLA B27 phenotype, there was histological evidence of inflammatory bowel disease with features either of acute enterocolitis, or early Crohns disease. Only 18 of 67 (27%) of the patients with histological gut inflammation, however, had intestinal symptoms.

Needle Arthroscopy of the Knee with Synovial Biopsy Sampling: Technical Experience in 150 Patients

Abstract: Needle arthroscopy is an office-based technique allowing direct visualisation of the knee cavity and selective sampling of the synovial membrane. We performed needle arthroscopy in 150 patients with synovitis of the knee (1) to evaluate the diagnostic potential in early arthritis, (2) to perform therapeutic lavage in persistent inflammatory synovitis and (3) to assess the balance between technical feasibility, safety and patient comfort on the one hand, and the relevance of the obtained macro- and microscopic information for diagnosis and research purposes on the other. After disinfection of the leg and local anaesthesia of the skin and joint, a 1.8–2.7 mm needle arthroscope was introduced into the knee. Synovial fluid was aspirated and lavage of the joint cavity was performed to allow macroscopic evaluation of hyperaemia and hypertrophy of the synovial membrane. Biopsies were taken at inflamed sites, followed by another lavage to remove blood and debris. Needle arthroscopy of the knee is a simple and easy to perform technique made particularly attractive by the local anaesthesia and the ambulatory setting. It allows good macroscopic evaluation of synovial inflammation and selective sampling of the synovial membrane. Biopsies are suitable for RNA and DNA extraction, bacterial or lymphocyte culture, and cell isolation. Because samples were sometimes too small for representative histology, we switched from a 1.8 mm to a 2.7 mm biopsy forceps with good results. In nearly all cases the arthroscopy was well tolerated. Moreover, some patients reported relief of symptoms and even improvement of mobility after lavage of the inflamed joint. No major complications were noted. It was concluded that needle arthroscopy of the knee is a simple, safe and well-tolerated technique, with promising perspectives as a diagnostic, scientific and possibly therapeutic tool in rheumatic diseases.

Anti-perinuclear factor compared with the so called “antikeratin” antibodies and antibodies to human epidermis filaggrin, in the diagnosis of arthritides

OBJECTIVE Antiperinuclear factor (APF), “antikeratin antibodies” (“AKA”), and antibodies to human epidermis filaggrin (AFA), are highly specific serological markers of rheumatoid arthritis (RA), which recognise epitopes on various isoforms of (pro)filaggrin. It was proposed that these antibodies are globally named antifilaggrin autoantibodies. Here the diagnostic value of the detection of each one is compared and the overlap between the three tests evaluated. METHODS 492 serum samples were tested, including 279 RA serum samples, taken from patients in France and Belgium. APF and “AKA” titres were estimated by indirect immunofluorescence, and AFA titres by immunoblotting on filaggrin enriched human epidermis extracts. RESULTS By a convenient choice of the positivity thresholds, the diagnostic sensitivity and specificity of the tests were shown to be similar (0.52 and 0.97, respectively). Although the antibody titres were strongly correlated, the associations APF-AFA or AFA-“AKA” permitted more than 52% or 55% of RA to be diagnosed, with a specificity of 0.99. CONCLUSION APF, “AKA”, and AFA detection have a similar diagnostic value. However, because the three tests do not totally overlap, associating APF with “AKA” or AFA with “AKA” can improve diagnostic sensitivity. None of the three antigens used bear all the epitopes recognised by anti-filaggrin autoantibodies.

Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNFα

OBJECTIVES To evaluate the effect of anti-TNFα on the Th1 and Th2 cytokines in patients with spondyloarthropathy (SpA). METHODS Peripheral blood mononuclear cells (PBMC) were obtained from 20 patients with active SpA treated with infliximab (5 mg/kg). For comparison, PBMC were also obtained from 15 healthy controls and 19 patients with active rheumatoid arthritis (RA). After stimulation with PMA/ionomycin, the intracellular cytokines interleukin (IL)2, IL4, IL10, and interferon (IFN)γ were determined in CD3+ T cells and in CD3+/CD56+ natural killer (NK) T cells by flow cytometry. RESULTS At baseline the percentage of T cells positive for IFNγ (p=0.020) and IL2 (p=0.046) was decreased in patients with SpA compared with healthy controls, while IL10 (p=0.001) was increased. This cytokine profile, confirmed by the mean fluorescence intensities (MFI), was more pronounced in CD3+/CD8– cells and contrasted with higher IL2 production in RA. NK T cells, characterised by high IL4 and IL10 numbers, were also increased in patients with SpA (p=0.017). Treatment with infliximab induced a significant and persistent increase in IFNγ and IL2 in patients with SpA. Moreover, there was a transient decrease in IL10 and NK T cells in patients with high baseline values, resulting in values comparable with those of healthy controls. This switch in cytokine profile was seen in both the CD3+/CD8– and CD3+/CD8+ subsets. CONCLUSIONS Before treatment patients with SpA had an impaired Th1 cytokine profile compared with healthy controls and patients with RA. TNFα blockade induced restoration of the Th1 cytokines, resulting in a normal cytokine balance. These data confirm the effect of anti-TNFα on the immune changes in SpA, and provide insights into the mechanisms involved in TNFα blockade.

Detection and identification of antinuclear antibodies (ANA) in a large and consecutive cohort of serum samples referred for ANA testing

OBJECTIVE To provide data on (a) the probability of detecting antinuclear antibodies (ANA) in a large and consecutive cohort of serum samples referred for ANA testing and (b) the probability of detecting more specific antinuclear reactivities (anti-DNA and anti-extractable nuclear antigens (anti-ENA)) in serum samples with a positive screening test (indirect immunofluorescence on HEp-2 cells). METHODS Serum samples from 10 550 consecutive patients sent to the laboratory for ANA detection were analysed. In ANA positive serum samples (23.5% of referred serum samples), ANA were identified by indirect immunofluorescence on Crithidia, by immunodiffusion, and by line immunoassay. Because anti-SSA antibodies were the most frequently identified ANA, sensitively detected by line immunoassay, additional immunoassays were developed to confirm the specificity of the line immunoassay result. RESULTS At least one fine reactivity could be identified in 21.1% of ANA positive serum samples: anti-dsDNA in 3.2%; anti-ENA (anti-SSA 10.5%, anti-SSB 6.7%, anti-RNP 2.7%, anti-Sm 1.8%, anti-Scl70 1.2%, anti-Jo-1 0.2%) in 15.8%, rRNP and anti-Cenp-B in respectively 0.5% and 4.0%. Multiple reactivities were found in 7.9%. For anti-ENA antibodies, line immunoassay was more sensitive than immunodiffusion (15.4%v 7.7%; p<0.0001). The sensitive detection of anti-SSA antibodies by line immunoassay was confirmed by additional assays. CONCLUSIONS The data from this analysis are useful in estimating the probabilities of detecting specific ANA. Line immunoassay was shown to be a sensitive test for the detection of anti-ENA antibodies.

M‐cells are damaged and increased in number in inflamed human ileal mucosa

Ileocolonoscopy and biopsies of patients with spondylarthropathy reveal gut inflammation in 62% of cases. In order to better understand the pathogenetic mechanisms of spondylarthropathy‐related gut inflammation, the follicle‐associated epithelium was examined. Biopsies from nine controls and 18 patients with spondylarthropathy were studied by electronmicroscopy. Membranous (M) cells were investigated in normal and inflamed ileum. In normal mucosa, M‐cells were scarce whereas in inflamed mucosa their number was increased (up to 24% of follicle‐associated epithelial cells). They showed a thin rim of cytoplasm covering groups of lymphocytes. In chronic ileitis, necrotic M‐cells, rupture of M‐cells and lymphocytes entering the gut lumen were observed. The bursting of M‐cells at the top of the lymphoid follicles leads to interruption of the gut epithelial lining and gives the luminal content access to the lymphoid tissue. This pathogenetic mechanism may cause aphthoid ulcers.

Anti-Ro52 reactivity is an independent and additional serum marker in connective tissue disease

Objective: To determine whether anti-Ro52 is an independent serum marker in connective tissue disease. Methods: Over a two year period, 1727 consecutive antinuclear antibody (ANA) positive serum samples were analysed in parallel by double immunodiffusion with thymus/spleen nuclear extract and by line immunoassay with recombinant Ro52, recombinant La/SSB, and natural Ro60. Sera that were only reactive towards Ro52 were further analysed by a variety of additional anti-SSA/Ro detection methods and by specific anti-Ro52 and anti-Ro60 assays. Natural purified SSA/Ro was analysed by immunoblot and protein sequencing. Results: Analysis of natural purified SSA/Ro (Immunovision, Springdale, AR) showed only Ro60 and no immunoreactive Ro52. Consequently, assays based on this substrate only identify sera with anti-Ro60 reactivity. Twenty serum samples showed anti-Ro52 without anti-Ro60 and anti-SSB/La on line immunoassay. By additional testing, 2/20 sera were found positive for anti-Ro60 reactivity. The remaining 18 sera were not identified by any of the classical anti-SSA/Ro assays and were considered to be reactive only with Ro52 and not with Ro60. This anti-Ro52 reactivity was confirmed by natural and recombinant Ro52 in 16/18 cases. 12/18 sera corresponded to connective tissue diseases. Conclusion: Anti-Ro52 positive sera without any evidence of anti-Ro60 and anti-La/SSB reactivity can be considered as an independent group that is systematically missed by classical anti-SSA/Ro detection methods owing to a bias towards anti-Ro60 reactivity. The anti-Ro52 sera are precipitin negative, not retrieved by SSA/Ro enzyme linked immunosorbent assays (ELISAs) based on natural SSA/Ro, and show no specific ANA fluorescence staining pattern. These findings together with the clinical data indicate that anti-Ro52 should be considered as an additional and independent serum marker.

Rheumatoid nodules: differential diagnosis and immunohistological findings.

The presence of nodules in para-articular subcutaneous tissue in patients with peripheral rheumatoid arthritis (RA) is commonly regarded as an extra-articular manifestation of rheumatoid disease. Generally in these cases the presence of chronic inflammatory subcutaneous nodules does not create diagnostic problems for the clinician. Occurring in 20 to 30% ofwhite patients with definite RA,1 nodules are found most commonly on extensor surfaces at sites of frequent mechanical irritation2: proximal ulna, on the olecranon process (where they must be differentiated from a bursitis olecrani with enlargement of the synovial layer), extensor tendons of the hand (at the level of the metacarpophalangeal or the proximal interphalangeal joint), the back of the head and ears, the back of the heels, and the ischial tuberosities. When mechanical irritation is suppressed the nodules may disappear within a few days. Nodules vary in consistency from firm immovable masses when they are small to soft mobile masses when they are large. Nodules may also develop in tendons or in visceral organs. They may ulcerate or may become gangrenous. Rheumatoid factor is almost always found at a high titre in the serum of patients with rheumatoid nodules.3 The presence of subcutaneous nodules in a patient with an active inflammatory joint disease in the absence of rheumatoid factor makes the diagnosis of RA extremely improbable and it is necessary to look for other connective tissue and vasculitic diseases rather than RA. Generally there is a discrepancy between the presence of extensive extra-articular manifestations (subcutaneous nodules, necrotising vasculitis, etc...) and the inflammatory state of the joints. Explosive manifestation of extra-articular activity is often accompanied by regression of the joint inflammation. The reverse of this phenomenon