Novel optical spectral transmission (OST)-guided versus conventionally disease activity-guided treatment: study protocol of a randomized clinical trial on guidance of a treat-to-target strategy for early rheumatoid arthritis.

BACKGROUND: Assessment of disease activity is a critical component of tight-control, treat-to-target treatment strategies of rheumatoid arthritis (RA). Recently, the HandScan has been validated as a novel method for objectively assessing RA disease activity in only 1.5 min, using optical spectral transmission (OST) in hands and wrists. We describe the protocol of a randomized controlled clinical trial (RCT) to investigate whether HandScan-guided treatment aimed at 'HandScan remission' (HandScan arm) is at least as effective as and more cost-effective than clinically guided treatment aimed at ACR/EULAR 2011 Boolean remission (DAS arm). METHODS/DESIGN: The study is a multi-center, double-blind, non-inferiority RCT of 18 months duration. Patients ≥ 18 years with newly diagnosed, disease-modifying antirheumatic drug (DMARD)-naïve RA according to the ACR 2010 classification criteria, will be randomized to the DAS arm or the HandScan arm. The efficacy of the arms will be compared by evaluating Health Assessment Questionnaire (HAQ) scores (primary outcome) after 18 months of DMARD therapy, aimed at remission. The equivalence margin in HAQ scores between study arms is 0.2. Secondary outcomes are differences in cost-effectiveness and radiographic joint damage between treatment arms. The non-inferiority sample size calculation to obtain a power of 80% at a one-sided p value of 0.05, with 10% dropouts, resulted in 61 patients per arm. In both arms, DMARD strategy will be intensified monthly according to predefined steps until remission is achieved; in both arms DMARDs and treatment steps are identical. If sustained remission, defined as remission that persists consistently over three consecutive months, is achieved, DMARD therapy will be tapered. DISCUSSION: The study protocol and the specifically designed decision-making software application allow for implementation of this RCT. To test a novel method of assessing disease activity and comparing (cost-)effectiveness with the contemporary method in treat-to-target DMARD strategies in early RA patients. TRIAL REGISTRATION: Dutch Trial Register, NTR6388. Registered on 6 April 2017 ( NL50026.041.14 ). Protocol version 3.0, 19-01-2017.

Can optical spectral transmission assess ultrasound-detected synovitis in hand osteoarthritis?

OBJECTIVE: To determine whether optical spectral transmission (OST) can be used to assess synovitis in hand and wrist joints of patients with hand osteoarthritis (OA). DESIGN: Hand and wrist joints of 47 primary hand OA patients with at least one clinically inflamed hand or wrist joint were assessed for synovitis by OST and ultrasound (US). Associations between standardized OST and US synovitis were studied in linear mixed effects models, across all joint types together and individually for wrist, proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints, and were adjusted for OA features that showed associations with US synovitis. Diagnostic performance was determined using receiver operator characteristic (ROC) curves analysis, with US as reference standard. RESULTS: Altogether, 6.7% of joints showed US synovitis. Statistically significant associations between OST scores and US synovitis were found for all joints combined (Δ0.37SD, p<0.001) and PIP joints (Δ0.81SD, p<0.001), but not for DIP (Δ0.14SD, p = 0.484) or wrist joints (Δ0.37SD, p = 0.178). All associations were independent of other OA features, i.e. osteophytes and dorsal vascularity. Analysis of diagnostic performance of OST, revealed an area under the ROC curve (AUC-ROC) of 0.74 for all joints together (p<0.001), 0.69 for PIP joints (p<0.001), 0.54 for DIP joints (p = 0.486), and 0.61 for wrist joints (p = 0.234). CONCLUSIONS: OST scores and US synovitis are statistically significantly associated, independent of osteophytes and dorsal vascularity. At this stage, OST performs fair in the assessment of synovitis in PIP joints of hand OA patients.

Assessment of disease activity in patients with rheumatoid arthritis using optical spectral transmission measurements, a non-invasive imaging technique.

OBJECTIVES: In rheumatoid arthritis (RA), treat-to-target strategies require instruments for valid detection of joint inflammation. Therefore, imaging modalities are increasingly used in clinical practice. Optical spectral transmission (OST) measurements are non-invasive and fast and may therefore have benefits over existing imaging modalities. We tested whether OST could measure disease activity validly in patients with RA. METHODS: In 59 patients with RA and 10 patients with arthralgia, OST, joint counts, Disease Activity Score (DAS) 28 and ultrasonography (US) were performed. Additionally, MRI was performed in patients with DAS28<2.6. We developed and validated within the same cohort an algorithm for detection of joint inflammation by OST with US as reference. RESULTS: At the joint level, OST and US performed similarly inproximal interphalangeal-joints (area under the receiver-operating curve (AUC) of 0.79, p<0.0001) andmetacarpophalangeal joints (AUC 0.78, p<0.0001). Performance was less similar in wrists (AUC 0.62, p=0.006). On the patient level, OST correlated moderately with clinical examination (DAS28 r=0.42, p=0.001), and US scores (r=0.64, p<0.0001). Furthermore, in patients with subclinical and low disease activity, there was a correlation between OST and MRI synovitis score (RAMRIS (Rheumatoid Arthritis MRI Scoring) synovitis), r=0.52, p=0.005. CONCLUSIONS: In this pilot study, OST performed moderately in the detection of joint inflammation in patients with RA. Further studies are needed to determine the diagnostic performance in a new cohort of patients with RA.

[Eosinophilic fasciitis; the importance of early detection for optimal outcomes]. / Eosinofiele fasciitis, het belang van een tijdige herkenning voor de genezing.

Eosinophilic fasciitis (EF) is a disease with unknown aetiology, although an immunologic pathogenesis is suspected. The characteristic features of this inflammatory disease include scleroderma-like skin indurations, predominantly on the extremities, and peripheral blood eosinophilia. Internal organs are generally not affected. Initiation of systemic glucocorticoid therapy at an early stage results in a good response and remission of symptoms. This is illustrated in 3 cases of EF to demonstrate the importance of early detection in this disease.

Prevalence of vertebral deformities and symptomatic vertebral fractures in corticosteroid treated patients with rheumatoid arthritis.

OBJECTIVE: This study was designed to determine whether the prevalence of vertebral deformities in patients with rheumatoid arthritis (RA) treated with corticosteroids (Cs) is higher than in RA patients not receiving Cs therapy. PATIENTS AND METHODS: This multicentre cross-sectional study included 205 patients with RA who were receiving Cs orally on a daily basis and 205 patients with RA who did not receive Cs, matched for sex and age. Vertebral deformities were scored according to the Kleerekoper method. RESULTS: Vertebral deformities were found in 52 (25%) patients on Cs and in 26 (13%) patients not on Cs. Sixteen (8%) patients in the group on Cs had experienced clinical manifestations of an acute vertebral fracture in the past vs only three patients (1.5%) among those not on Cs. The use of Cs tended to increase the risk of developing a vertebral deformity [adjusted odds ratio (OR) 1.56, 95% confidence interval (CI) 0.81-2.99] and symptomatic vertebral fracture (adjusted OR 1.42, 95% CI 0.24-8.32). Each 1-mg increase in the current daily Cs dose increased the risk of a vertebral deformity (adjusted OR 1.05, 95% CI 0.98-1.13) and of a symptomatic vertebral fracture (adjusted OR 1.05, 95% CI 0.89-1.24). CONCLUSION: There is a higher prevalence of vertebral deformities and clinical manifestations of vertebral fractures in patients on Cs than in those not on Cs. Our data indicate that the use of Cs and each 1-mg increase in the current daily Cs dose may increase the risk of development of a vertebral deformity and symptomatic vertebral fracture in patients with RA.

Immunogenetic heterogeneity of seronegative rheumatoid arthritis and the antiperinuclear factor.

HLA typing was carried out in 132 patients with rheumatoid arthritis (RA) with long term follow up, and special attention was focused on rheumatoid factor negative patients. The patients were divided into four groups: 55 patients with a seropositive RA and a positive antiperinuclear factor (group A); 39 seropositive patients but a negative antiperinuclear factor (group B); 14 patients consistently seronegative for 3-28 years (mean 11.8 years) but positive for antiperinuclear factor (group C); patients consistently negative for 3-28 years (mean 11.8) and also negative for antiperinuclear factor (group D). The prevalence of HLA-DR4 was 31/55 (56%), 29/39 (74%), 10/14 (71%), and 9/24 (37%) for groups A, B, C, and D respectively, and in all groups was significantly higher than in 277 healthy controls (55/277, 20%). No significant difference was found between seropositive (groups A and B) and seronegative (groups C and D) patients, but groups A, B, and C had higher prevalences than group D. It is concluded that in seronegative RA HLA-DR4 is preferentially associated with the antiperinuclear factor positive group.

Antiperinuclear factor, a rheumatoid arthritis specific autoantibody: its relation to Epstein-Barr virus.

We studied the prevalence of antiperinuclear factor (APF), an antibody frequently (50-80%) present in sera of patients with rheumatoid arthritis (RA), in different groups of patients. Sera from 123 patients with RA and 28 patients with recent Epstein-Barr virus (EBV) infection showed APF in 63 and 51% of the patients, respectively. These frequencies were significantly increased (p0.001) when compared with 123 healthy blood donors (12%) and in 58 patients with herpes virus infections other than EBV (18%). Relations with other EBV elicited antibodies in RA and the relevance of EBV in RA are discussed. Our data suggest that EBV might be the immunogen for APF, an antibody, until now considered to be an autoantibody.

Methotrexate in refractory rheumatoid arthritis.

Fourteen patients with severe rheumatoid arthritis refractory to hydroxychloroquine, gold-thioglucose, D-penicillamine and azathioprine completed a 6-month open study with oral methotrexate (2.5 to 5 mg every 12 hours, three doses weekly). Twelve of them were followed up for 12 months. Compared with pretreatment values, there was a significant reduction in duration of morning stiffness (p less than 0.01), in the number of tender or painful joints (p less than 0.02), number of swollen joints (p less than 0.01), visual analog scale, patient's assessment of joint discomfort and overall well-being (p less than 0.01) after 2, 6 and 12 months. Likewise there was an improvement in the erythrocyte sedimentation rate (p less than 0.001) C-reactive protein (p less than 0.01) and the levels of IgG, IgM and IgA (p less than 0.01). Two patients were withdrawn from the study, one for severe diarrhoea and one because of a depression. Adverse reactions during methotrexate therapy included nausea (5/16) and transaminase elevation (4/16). We conclude that this pilot study provides evidence that a weekly low dose of methotrexate is effective in the short-term treatment for patients with rheumatoid arthritis, refractory to hydroxychloroquine, auriothioglucose, D-penicillamine and azathioprine.

Reaction patterns of monoclonal antibodies to DNA.

Starting with spleen cells from MRL/lpr, NZB/W, and graft-vs-host-diseased mice, we prepared a total of 57 hybridomas that produce antibodies to DNA. Using various approaches, we studied the avidity of these monoclonals in relation to their behavior in four anti-DNA assays. From the results obtained, we postulate that on the basis of anti-DNA avidity the anti-DNA ELISA, the polyethylene glycol assay, the indirect immunofluorescence test on Crithidia luciliae, and the Farr assay (in this order) detect a decreasing amount of anti-dsDNA, the Farr assay being strictly selective for high avidity anti-dsDNA. mAb selected by the anti-DNA ELISA generally were of a low avidity toward DNA. Using cardiolipin and dextran sulfate, a polyanion that bears a resemblance in charge to DNA, we studied the cross-reactivity of the monoclonals. A total of 6 of the 57 monoclonals were found to cross-react with cardiolipin, and 26 with dextran sulfate. We observed an inverse relationship between anti-DNA avidity and cross-reactivity: the lower the avidity of the antibody, the more cross-reactive it is. Based on these findings, we postulate that it is at least questionable whether low avidity, cross-reactive (monoclonal) anti-DNA is representative for the anti-DNA found in patients with SLE.

Routine testing for antinuclear antibodies: a comparison of immunofluorescence, counterimmunoelectrophoresis and immunoblotting.

We compared the classical immunofluorescence test (IFT) and counterimmunoelectrophoresis method (CIE) with the new immunoblotting technique (IBT) for the detection of antinuclear antibodies (ANA). Sera from 200 patients were tested in all three assays. Patients were classified as having either rheumatic disease including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), primary Raynaud's phenomenon or nonrheumatic disease. Within these broad categories, we observed that IFT and IBT showed a more or less comparable sensitivity and specificity (IFT: 0.54 and 0.82, respectively; IBT: 0.39 and 0.79, respectively). The CIE method combines a high specificity (0.99) with an extremely low sensitivity (0.08). By combining positive results obtained by IFT and IBT, a higher specificity (0.97) but a diminished sensitivity (0.24) is obtained. As IBT allows simultaneous discrimination between ANA of different specificities, we also tested for a correlation between the presence of anti-Sm, anti-RNP and anti-SS-B and the disease category. Only anti-SS-B discriminated significantly between rheumatic- and nonrheumatic disease. Anti-RNP was found in 50% of the SLE patients and in 50% of the MCTD patients; anti-Sm in 17% of the SLE patients and 25% of the MCTD patients. Anti-SS-B was found in 33% of the SLE patients. However, predictive rates of these ANA were low: 0.37 (anti-RNP), 0.67 (anti-Sm) and 0.43 (anti-SS-B). We conclude that from a practical point of view IFT is the preferable assay to screen for the presence of ANA. To characterize ANA specificities, however, the IBT is far superior to the CIE technique.

Antiperinuclear factor: indicator of more severe disease in seronegative rheumatoid arthritis.

The specificity of antiperinuclear factor (APF) for patients with rheumatoid arthritis (RA) is well documented. It is unknown whether detection of these antibodies adds information to the detection of rheumatoid factor (RF). In a group of 132 patients with RA, 94 were RF positive. Of the 38 patients persistently negative for RF, 14 (37%) were positive for APF. These 14 proved to have a disease course similar to that of RF positive patients. This similarity was shown most impressively by radiological progression of the disease, and to a lesser extent, by the medication needed to control the disease and the number of extraarticular manifestations. No significant correlation was shown between APF and antinuclear antibodies. Among the RF positive patients with their generally poorer prognosis, APF identified the worst affected. Our study suggests that APF in serum of patients with RA is associated with a poor disease outcome, especially in RF negative patients.

Antinuclear antibodies in patients with systemic lupus erythematosus: a comparison of counterimmunoelectrophoresis and immunoblotting.

Traditionally, the method used mostly to identify antinuclear antibody (ANA) specificities is the counterimmunoelectrophoresis technique (CIE), in which a salt extract of rabbit thymus powder (so-called extractable nuclear antigen or ENA) serves as the source of antigen. Recently, the immunoblotting technique (IBT) has been introduced in the serology of antinuclear antibodies. A nuclear extract of HeLa cells is generally used as antigen in this method. In this paper, we compared both methods using sera of patients with active systemic lupus erythematosus (SLE). Only anti-Sm, anti-RNP, and Anti-SSB were taken into consideration, as the former technique only allowed the identification of these specificities. Within these restrictions, we found that, of 77 patients with SLE, 21 had CIE-detectable antibodies in their circulation and 29 IBT-detectable antibodies. Anti-RNP and anti-SSB were detected more frequently with the CIE than with the IBT; anti-Sm, on the other hand, was detected more frequently with the IBT than with the CIE. Several significant correlations were found between incidences of measured antibody specificities and disease features. The presence of anti-RNP (both if measured with the IBT or with the CIE) was found to be negatively correlated with nephritis. If measured with the IBT, the presence of anti-Sm correlated negatively with hematological disorders, and the presence of anti-SSB correlated positively with renal involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

An improved incubation apparatus for Western blots used for the detection of antinuclear antibodies.

To facilitate the use of Western blots for the detection of antibodies, we have developed an incubation apparatus. The use of this apparatus simplifies the incubation of blots with antisera, permits the testing of large numbers of sera and eliminates artefacts caused by the use of loose strips. The introduction of a pressure bag in the lower lid of the apparatus secures a steady pressure over the entire blot, a feature lacking in currently available commercial equipment. The detection of antinuclear antibodies is presented as an example of the use of this incubator.

The effect of glucocorticosteroids on bone marrow mononuclear phagocytes in culture.

The effect of hydrocortisone and dexamethasone both in vivo and in vitro was studied in mouse bone marrow cultures in methylcellulose and in two liquid culture systems, one using Leighton tubes with a flying coverslip to grow adherent colonies and the other using Teflon culture bags to obtain suspension cultures. Although the total number of nucleated bone marrow cells was not greatly influenced by glucocorticosteroid treatment of the mice, a marked decrease in the number of colony-forming units and of mononuclear phagocytes was observed. Inhibition of colony growth in methylcellulose and of growth of mononuclear phagocytes in Teflon culture bags also occurred when glucocorticosteroids were added to in vitro cultures. Both drugs caused an almost complete inhibition of the growth of adherent colonies, and 3H-thymidine labeling of the cells was correspondingly low. When the glucocorticosteroids were added to cultures pre-incubated for 5 days in the presence of conditioned medium, the 3H-thymidine labeling of macrophages and promonocytes was markedly reduced, whereas there was no change in the labeling of monoblasts.