To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a ...pragmatic model to predict development of IA in this patient group.
In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation.
100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1-69.0); 50 developed IA after a median 7.9 months (range 0.1-52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1-2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0-1; 0/11 progressed).
In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention.
NCT02012764 at ClinicalTrials.gov.
Biologic therapies in rheumatoid arthritis are now part of standard practice for disease that proves difficult to control with conventional disease-modifying anti-rheumatic drugs. While anti-tumor ...necrosis factor therapies have been commonly used, other targeted biologic therapies with different mechanisms of action are becoming increasingly available. Abatacept is a recombinant fusion protein that inhibits the T-cell costimulatory molecules required for T-cell activation. Intravenous abatacept has good clinical efficacy with an acceptably low toxicity profile in rheumatoid arthritis, but the subcutaneous mode of delivery has only recently become available. In this article, we examine key efficacy and safety data for subcutaneous abatacept in rheumatoid arthritis, incorporating evidence from five large Phase III studies that included people with an inadequate response to methotrexate and an inadequate response to biologic disease-modifying anti-rheumatic drugs. The results demonstrate that subcutaneous abatacept has efficacy and safety comparable with that of intravenous abatacept and adalimumab. In addition, inhibition of radiographic progression at year 1 in relatively early rheumatoid arthritis is consistent with that of adalimumab. Subcutaneous abatacept is well tolerated, with very low rates of discontinuation in both short-term and long-term follow-up.
BACKGROUND: B cell depletion therapy (BCDT) using rituximab, a monoclonal antibody targeting CD20, was first used for systemic lupus erythematosus (SLE) in 2000 for patients refractory to ...conventional immunosuppressants. Although the successful use of BCDT has been reported in open label studies randomized controlled trials in SLE have not met their endpoints. SLE is a heterogeneous disease and it is possible that variation in response to BCDT might be due to differences in the rate of B cell repopulation and/or serological and cellular factors in treated patients. The aim of this study was to correlate the repopulation of B cells with disease relapse after BCDT and to identify any differences in B cell numbers and phenotype between patients with active disease according to other disease parameters. METHODS: Fifty-nine patients with refractory SLE treated with BCDT using a combination of rituximab, cyclophosphamide and methylprednisolone were followed up for a minimum of 18 months or until relapse if this occurred within 18 months. Patients were assessed with the 'classic' British Isles Lupus Assessment Group (BILAG) activity index. Relapse was defined as a new BILAG 'A' or two new 'B's in any organ system. Anti-dsDNA antibody titres, complement and leukocyte numbers were measured at baseline and relapse. B cell phenotypes were measured at relapse by flow cytometry using the markers CD19, IgD and CD27. RESULTS: The median time to relapse following BCDT was 16 months. During repopulation B cell numbers remained below baseline numbers for up to 9 months (p < 0.01). B cell numbers (normal range 0.11-0.50 x109 cells/L) increased more rapidly in patients that relapsed (within 18 months) compared to those that remained in remission (p < 0.01). At relapse, B cell numbers were lower than at baseline (p < 0.05). Patients that relapsed with very low B cell numbers (<0.01x10 super(9) cells/L) had the lowest B cell numbers at baseline (P < 0.05) and the highest anti-dsDNA antibody titres (normal range 0-50 IU/mL) at relapse (P < 0.05). Relapse with high anti-dsDNA antibody titres (>100 IU/mL) was associated with an increased percentage of IgD-CD27hi switched plasmablasts (p < 0.05) whereas relapse with low anti-dsDNA antibody titres was associated with an increased percentage of IgD-CD27- memory B cells (p < 0.05). CONCLUSIONS: Whilst clinical trials have not confirmed the reported benefit of BCDT in SLE this study shows that early relapse was associated with faster rates of B cell repopulation despite similar levels of depletion. The number of B cells and the B cell phenotype found at relapse differed according to the anti-dsDNA antibody titres. This data suggest that different pathologies might exist in patients with low anti-dsDNA antibody titres compared to those with high titres, possibly governed by specific B cell subsets. Future clinical trials in SLE should take into account serological and cellular variation between patients. Disclosure statement: D.I. has received honoraria from Roche, Vifor, GlaxoSmithKline, Teva and Merck Serono; these were donated to a local arthritis charity. All other authors have declared no conflicts of interest.
Background: Anti-CD20 (rituximab) therapy has been very successful in SLE patients resistant to conventional therapy, with about 80% of patients responding in most open label case series. However, ...about 30% of patients develop anti-drug antibodies (ADA), which may have a detrimental effect on the efficacy of the drug. Identifying ADA is, therefore, important to predict non-responders and to explain loss of efficacy, but low levels of ADA may be missed because of formation of immune complexes with the drug. A novel approach to this problem is the acid disruption of immune complexes immediately before analysis, which has been implemented by GE Healthcare in the Immunogenicity Package on the T100 BIAcore instrument. We have used this technology to characterize anti-rituximab responses in a series of SLE patients. Methods: We identified 9 patients treated with rituximab in dedicated lupus clinics in Birmingham, all with a confirmed diagnosis of SLE. All were treated with rituximab after failing to respond to one or more conventional immunosuppressants. Standardized doses of either 750 mg or 1 g of rituximab were given on two occasions, 2 weeks apart. 9 patients had undergone more than one course of rituximab treatment. Blood samples were collected for up to 51 months. A BIAcore CM5 chip was prepared by coupling rituximab to one flow cell and a rat anti-rituximab to another. Using the Immunogenicity Package on the BIAcore T100, samples were acidified with hydrochloric acid and then neutralized with Tris-HCl simultaneously with their injection over the coupled chip. In paired analyses the HCl and Tris-HCl were replaced with Hepes/saline pH 7.4, so that the same analysis occurred without acid disruption. Results: 25 serum samples from the 9 patients were assessed. When the analysis was done without acid pre-treatment 2 samples from one patient were positive for ADA against rituximab and 5 samples from 4 patients were positive for the drug. However, when acid disruption was used 5 samples from 2 patients were shown to be positive for ADA while 8 samples were positive for rituximab. Most notably, one patient was negative for both drug and ADA when assessed at pH 7 but were positive for both when acid treatment was used. One patient had high levels of ADA on three separate occasions and in each case this was masking the presence of drug which was revealed by the acidification. Conclusions: We have shown that two patients from this small cohort of 9 had developed antibodies against rituximab. The presence of immune complexes had masked the detection of these in one case. Furthermore, acid treatment revealed the presence of drug in 4 extra samples which was not detectable without acidification. These data show that immune complexes between ADA and rituximab may prevent accurate determination of drug levels and ADA. The acid disruption made possible by the BIAcore T100 may prove valuable in more accurate assessment of drug levels and ADA. Disclosure statement: S.P.Y., GE Healthcare - Loan of T100 equipment. All other authors have declared no conflicts of interest.
PDF
