Construct validity of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) treatment target cut-offs in a BASDAI treat-to-target axial spondyloarthritis cohort: a cross-sectional study.

OBJECTIVE: In axial spondyloarthritis (axSpA), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) are recommended for use in treat-to-target (T2T) strategies. However, BASDAI disease states may be a less suitable T2T instrument than ASDAS, since BASDAI contains non-disease activity related items. The objective of our study was to investigate the construct validity of BASDAI and ASDAS disease states. METHOD: We performed a single-centre cross-sectional study on BASDAI and ASDAS construct validity in long-term BASDAI T2T-treated axSpA patients. Our hypothesis was that BASDAI is less representative of disease activity than ASDAS owing to the focus on pain and fatigue, and missing an objective item, e.g. C-reactive protein (CRP). This was operationalized using several subhypotheses. RESULTS: The study included 242 axSpA patients. BASDAI and ASDAS disease states showed a similar relation to Patient Acceptable Symptom State and T2T protocol adherence. The proportions of patients with high BASDAI and ASDAS disease activity fulfilling Central Sensitization Inventory and fibromyalgia syndrome criteria were similar. The correlation with fatigue was moderate for both BASDAI (Spearman's rho 0.64) and ASDAS (Spearman's rho 0.54) disease states. A high ASDAS was strongly correlated with increased CRP (relative risk 6.02, 95% CI 3.0-12.09), while this correlation was not seen for BASDAI (relative risk 1.13, 95% CI 0.74-1.74). CONCLUSION: Our study showed moderate and comparable construct validity for BASDAI- and ASDAS-based disease activity states, with the expected exception of association with CRP. Therefore, no strong preference can be given for either measure, although the ASDAS seems marginally more valid.

Immunoprofiling of early, untreated rheumatoid arthritis using mass cytometry reveals an activated basophil subset inversely linked to ACPA status.

BACKGROUND: Autoantibody production is a hallmark of rheumatoid arthritis (RA). Anti-citrullinated protein antibodies (ACPA) are highly disease-specific, and their presence is associated with more severe disease and poor prognosis compared to ACPA-negative patients. However, the immune cell composition associated with antibody-positive/negative disease is incompletely defined. Mass cytometry (MC) is a high-dimensional technique offering new possibilities in the determination of the immune cell composition in rheumatic diseases. Here, we set up a broad phenotyping panel to study the immune cell profile of early untreated RA to investigate if specific immune cell subsets are associated with ACPA+ versus ACPA- RA. METHODS: Freshly obtained PBMCs of early, untreated RA patients (8 ACPA+ and 7 ACPA-) were analysed using a 36-marker MC panel, including markers related to various immune lineages. Data were processed using Cytosplore for dimensional reduction (HSNE) and clustering. Groups were compared using Cytofast. A second validation cohort of cryopreserved PBMCs obtained from early RA patients (27 ACPA+ and 20 ACPA-) was used to confirm MC data by flow cytometry (FC). FC data were processed and analysed using both an unsupervised analysis pipeline and through manual gating. RESULTS: MC indicated no differences when comparing major immune lineages (i.e. monocytes, T and B cells), but highlighted two innate subsets: CD62L+ basophils (p = 0.33) and a subset of CD16- NK cells (p = 0.063). Although the NK cell subset did not replicate by FC, FC replication confirmed the difference in CD62L+ basophil frequency when comparing ACPA+ to ACPA- patients (mean 0.32% vs. 0.13%; p = 0.01). CONCLUSIONS: Although no differences in major lineages were found between early ACPA+ and ACPA- RA, this study identified the reduced presence of activated basophils in ACPA-negative disease as compared to ACPA-positive disease and thereby provides the first evidence for a connection between activated basophils and ACPA status.

Is it Useful to Repeat Magnetic Resonance Imaging of the Sacroiliac Joints After Three Months or One Year in the Diagnosis of Patients With Chronic Back Pain and Suspected Axial Spondyloarthritis?

OBJECTIVE: To investigate the value of repeated magnetic resonance imaging (MRI) of the sacroiliac (SI) joints in diagnosing chronic back pain patients in whom axial spondyloarthritis (SpA) is suspected and to examine determinants of positive MRI findings in SI joints. METHODS: Patients with chronic back pain (duration 3 months-2 years, age ≥16 years, age at onset <45 years) with ≥1 SpA feature who were included in the Spondyloarthritis Caught Early cohort underwent visits at baseline, at 3 months, and at 1 year. Visits included an evaluation of all SpA features and repeated MRI of SI joints. MRI-detected axial SpA positivity (according to the definition from the Assessment of SpondyloArthritis international Society) was evaluated by 2 or 3 well-trained readers who were blinded with regard to clinical information. The likelihood of a positive MRI finding at follow-up visits (taking into consideration contributing factors) was calculated by generalized estimating equation analysis. RESULTS: Of the 188 patients, 38.3% were male, the mean ± SD age was 31.0 ± 8.2 years, and the mean ± SD symptom duration was 13.2 ± 7.1 months. Thirty-one patients (16.5%) had positive MRI findings in the SI joints at baseline. After 3 months and after 1 year, the MRI results had changed from positive to negative in 3 of 27 patients (11.1%) and 11 of 29 patients (37.9%), respectively, which was attributable in part to the initiation of anti-tumor necrosis factor therapy. Status changes from negative to positive were seen in 5 of 116 patients (4.3%) after 3 months and in 10 of 138 patients (7.2%) after 1 year. HLA-B27 positivity and male sex were independent determinants of the likelihood of a positive MRI scan at any time point (42% in HLA-B27+ men and 6% in HLA-B27- women). If the baseline results were negative, the likelihood of a positive scan at follow-up was very low (≤7%). CONCLUSION: MRI-detected status changes in the SI joints were seen in a minority of the patients, and both male sex and HLA-B27 positivity were important predictors of MRI positivity. Our findings indicate that conducting MRI scans after 3 months or after 1 year in patients with suspected early axial SpA is not diagnostically useful.

Presence of multiple spondyloarthritis (SpA) features is important but not sufficient for a diagnosis of axial spondyloarthritis: data from the SPondyloArthritis Caught Early (SPACE) cohort.

OBJECTIVES: Concerns have been raised about overdiagnosis of axial spondyloarthritis (axSpA). We investigated whether patients with chronic back pain (CBP) of short duration and multiple SpA features are always diagnosed with axSpA by the rheumatologist, and to what extent fulfilment of the Assessment of SpondyloArthritis International Society (ASAS) axSpA criteria is associated with an axSpA diagnosis. METHODS: Baseline data from 500 patients from the SPondyloArthritis Caught Early cohort which includes patients with CBP (≥3 months, ≤2 years, onset <45 years) were analysed. All patients underwent full diagnostic workup including MRI of the sacroiliac joints (MRI-SI) and radiograph of sacroiliac joints (X-SI). For each patient, the total number of SpA features excluding sacroiliac imaging and human leucocyte antigen B27 (HLA-B27) status was calculated. RESULTS: Before sacroiliac imaging and HLA-B27 testing, 32% of patients had ≤1 SpA feature, 29% had 2 SpA features, 16% had 3 SpA features and 24% had ≥4 SpA features. A diagnosis of axSpA was made in 250 (50%) of the patients: 24% with ≤1 SpA feature, 43% with 2 SpA features, 62% with 3 SpA features and 85% with ≥4 SpA features. Of the 230 patients with a positive ASAS classification 40 (17.4%) did not have a diagnosis of axSpA. HLA-B27 positivity (OR 5.6; 95% CI 3.7 to 8.3) and any (MRI-SI and/or X-SI) positive imaging (OR 34.3; 95% CI 17.3 to 67.7) were strong determinants of an axSpA diagnosis. CONCLUSIONS: In this cohort of patients with CBP, neither the presence of numerous SpA features nor fulfilment of the ASAS classification criteria did automatically lead to a diagnosis axSpA. Positive imaging was considered particularly important in making a diagnosis of axSpA.

Are Additional Tests Needed to Rule Out Axial Spondyloarthritis in Patients Ages 16-45 Years With Short-Duration Chronic Back Pain and Maximally One Spondyloarthritis Feature?

OBJECTIVE: To investigate whether HLA-B27 testing and imaging of the sacroiliac joints are needed in patients with ≤1 spondyloarthritis (SpA) feature, referred to a secondary care setting, after medical history collection, clinical examination, and measurement of acute phase reactants. METHODS: Baseline data from patients in the Spondyloarthritis Caught Early (SPACE) cohort visiting the rheumatology outpatient clinic of 5 centers across Europe (with back pain ≥3 months, ≤2 years, onset at ages <45 years) were used. All patients underwent a full diagnostic work-up: magnetic resonance imaging (MRI) and radiographs of the sacroiliac joints, HLA-B27 testing, and assessment of all other SpA features. Patients were diagnosed according to the treating rheumatologist and classified according to the Assessment of SpondyloArthritis international Society (ASAS) axial SpA criteria. RESULTS: Of the 354 patients, 133 (37.5%) showed 0 or 1 SpA feature after medical history collection, physical examination, and measurement of acute phase reactants (38 without SpA features, 95 with 1 SpA feature). Of the patients with ≤1 SpA feature, 18.4% (with 0 SpA features) and 17.9% (with 1 SpA feature) were diagnosed with axial SpA according to the rheumatologist after additional investigations (HLA-B27 testing and sacroiliac joint imaging). Additionally, 4 of 38 patients (10.5%) without SpA features fulfilled the ASAS axial SpA criteria (all according to the imaging arm only: 2 as MRI+/modified New York criteria (mNY)+, 1 as MRI+/mNY-, and 1 as MRI-/mNY+). Of the 95 patients with 1 SpA feature, 22 (23.2%) fulfilled the ASAS axial SpA criteria (all according to the imaging arm only: 3 as MRI+/mNY+, 15 as MRI+/mNY-, and 4 as MRI-/mNY+). CONCLUSION: In these patients in a secondary care setting with ≤1 SpA feature, axial SpA could not be ruled out without sacroiliac joint imaging and/or HLA-B27 testing.

Classifying Back Pain and Peripheral Joint Complaints in Inflammatory Bowel Disease Patients: A Prospective Longitudinal Follow-up Study.

BACKGROUND AND AIMS: Peripheral joint complaints [pJTC] and chronic back pain [CBP] are the most common extra-intestinal manifestations in patients with inflammatory bowel disease [IBD]. This prospective study evaluates variables associated with joint/back pain, including IBD disease activity. METHODS: IBD patients with back pain ≥ 3 months and/or peripheral joint pain/swelling [n = 155], and IBD patients without joint complaints [n = 100; controls], were followed for a period of 1 year. Patients were classified as having SpondyloArthritis [SpA] according to several sets of criteria. Statistical analysis included logistic regression models and linear mixed model analysis. RESULTS: Of the 155 patients with joint/back pain, 13 had chronic back pain, 80 peripheral joint complaints, and 62 axial and peripheral joint complaints. Smoking, female gender, and IBD disease activity were independently associated with IBD joint/back pain. The Assessment in Spondyloarthritis International Society criteria for axial and peripheral SpA were fulfilled in 12.3% of patients, with 9.7% [n = 15] receiving a rheumatological diagnosis of arthritis. During the 12-month follow-up, the majority of the patients reporting joint/back pain remained stable. CONCLUSIONS: In our cohort, the majority of IBD patients reported joint/back pain and SpA was relatively common. To facilitate effective care, gastroenterologists should be aware of the various features of SpA to classify joint complaints and, by making use of an efficient referral algorithm, to refer CBP patients to the rheumatologist.

Magnetic resonance imaging of the hand joints in patients with inflammatory bowel disease and arthralgia: a pilot study.

OBJECTIVES: To assess whether subclinical inflammatory changes are present on magnetic resonance imaging (MRI) in patients with inflammatory bowel disease (IBD) and arthralgia. METHOD: In this pilot study, painful hand joints [metacarpophalangeal (MCP), proximal interphalangeal (PIP), and/or distal interphalangeal (DIP)] of 11 IBD patients (age 18-45 years) with continuous pain for > 6 weeks were scanned on a 1.5-T extremity MRI system. A control group of 11 IBD patients without joint pain who were matched for type and disease duration of IBD, gender, and age was included. All patients were clinically examined by a rheumatologist for the presence of pain and arthritis. Imaging was performed according to a standard arthritis protocol with intravenous contrast administration on the same day. Images (blinded for clinical information) were evaluated by two readers in consensus for the presence of joint fluid, synovitis, tenosynovitis, enthesitis, erosions, cartilage defects, and bone marrow oedema. RESULTS: Enthesitis was seen in three hand joints (MCP 2, MCP 3, PIP 3) of 2/11 (18%) arthralgia patients and in none of the control group (p = 0.48). A small amount of subchondral bone marrow oedema was seen in the metacarpal head of two controls. No other abnormalities were observed. CONCLUSIONS: Several young IBD patients with chronic hand pain had subclinical inflammation on MRI, which invites for further study in a larger group of patients.

Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles.

OBJECTIVES: To study the gene-environment interaction of tobacco exposure and shared epitope on autoantibodies in patients with rheumatoid arthritis and undifferentiated arthritis. METHODS: From incident cases of arthritis (n = 1305), patients who did not fulfil any classification criteria (undifferentiated arthritis (n = 486)) and those who fulfilled the American College of Rheumatology criteria for rheumatoid arthritis (n = 407) were identified. IgM rheumatoid factor (RF), anti-cyclic-citrullinated peptide (CCP) antibodies, and HLA-DRB1 alleles were determined. RESULTS: In rheumatoid arthritis, an interaction was found between tobacco exposure and shared epitope for the presence of anti-CCP antibodies, as the odds ratio for anti-CCP antibodies in patients having both tobacco exposure (TE) and shared epitope (SE) was higher than the summed odds ratios of patients having only tobacco exposure or shared epitope (odds ratios: TE+/SE-, 1.07; TE-/SE+, 2.49; and TE+/SE+, 5.27-all relative to TE-/SE-). A similar effect was found for RF, but stratification showed that the interaction primarily associated with the anti-CCP antibody response. In patients with undifferentiated arthritis at two weeks, or with persistent undifferentiated arthritis after one year, no interaction between tobacco exposure and shared epitope was observed for the presence of autoantibodies. CONCLUSIONS: Tobacco exposure increases the risk factor for anti-CCP antibodies only in shared epitope positive patients with rheumatoid arthritis. The gene-environment interaction between smoking and shared epitope leading to autoantibodies is specific for rheumatoid arthritis and is not observed in undifferentiated arthritis.

A comparison of the diagnostic accuracy and prognostic value of the first and second anti-cyclic citrullinated peptides (CCP1 and CCP2) autoantibody tests for rheumatoid arthritis.

OBJECTIVES: To compare the diagnostic performance and prognostic value of the anti-cyclic citrullinated peptide (CCP1) and anti-CCP2 autoantibody tests in a clinical setting. METHODS: Anti-CCP1 and anti-CCP2 antibody tests were performed on the same serum samples obtained from 467 patients with early arthritis from the Leiden Arthritis Cohort. The sensitivity, specificity, positive predictive value, and negative predictive value for discriminating between rheumatoid arthritis (RA) and non-RA at 1 year's follow up were calculated for both tests. Results were graphically presented using receiver operating characteristic curves. Progression of radiological joint damage was assessed over 4 years in patients with RA and used to assess the prognostics values of the CCP tests. RESULTS: At a similar specificity the CCP2 test had a higher sensitivity than the CCP1 test. Both tests identified a subgroup of patients with RA with an increased rate of joint damage progression. The anti-CCP2 test identified more patients with an increased rate of joint damage progression than the anti-CCP1 test, and in multiple regression analysis CCP2 was the better predictor of joint damage. CONCLUSIONS: The CCP2 test had better diagnostic and prognostic ability than the CCP1 test.

Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study.

OBJECTIVE: Rheumatoid arthritis (RA) is a common, severe, chronic inflammatory joint disease. Since the disease may initially be indistinguishable from other forms of arthritis, early diagnosis can be difficult. Autoantibodies seen in RA can be detected years before clinical symptoms develop. In an inception cohort of patients with recent-onset arthritis, we undertook this study to assess the predictive value of RA-specific autoantibodies to cyclic citrullinated peptides (CCPs) in patients with undifferentiated arthritis (UA). METHODS: Anti-CCP2 antibody tests were performed at baseline in 936 consecutive, newly referred patients with recent-onset arthritis. Patients who could not be properly classified 2 weeks after inclusion were categorized as having UA. Patients with UA were followed up for 3 years and evaluated for progression of their disease to RA as defined by the American College of Rheumatology (ACR) 1987 revised criteria. RESULTS: Three hundred eighteen of 936 patients with recent-onset arthritis were classified as having UA and were available for analysis. After 3 years of followup, 127 of 318 UA patients (40%) had been classified as having RA. RA had developed in 63 of 249 patients (25%) with a negative anti-CCP test and in 64 of 69 patients (93%) with a positive anti-CCP test (odds ratio 37.8 [95% confidence interval 13.8-111.9]). Multivariate analysis of the presence of anti-CCP antibodies and parameters from the ACR criteria identified polyarthritis, symmetric arthritis, erosions on radiographs, and anti-CCP antibodies as significant predictors of RA. CONCLUSION: Testing for anti-CCP antibodies in UA allows accurate prediction of a substantial number of patients who will fulfill the ACR criteria for RA.

Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis.

OBJECTIVE: To analyze the -2849 A/G interleukin-10 (IL-10) promoter polymorphism, which is associated with high (AG/GG) and low (AA) IL-10 production, in a cohort of rheumatoid arthritis (RA) patients and controls in order to gain a better understanding of its role in the incidence and progression of RA. METHODS: Allele frequencies of the promoter polymorphism -2849 A/G and carriage rates were compared in 283 RA patients, 413 patients with other rheumatic diseases, and 1,220 healthy controls. The rate of joint damage and baseline levels of IgG and IgM rheumatoid factors and anti-citrullinated peptide antibodies were measured and were correlated with the IL-10 gene polymorphism. Furthermore, the correlation between the invasiveness of fibroblast-like synoviocytes (FLS) and the -2849 IL-10 genotype was tested. RESULTS: The IL-10 genotype was not associated with the incidence of RA, but instead, correlated with disease progression, as determined by the extent of joint destruction. A higher rate of joint destruction was observed in patients with the genotype associated with high IL-10 production. Since FLS are thought to be involved in joint destruction, we analyzed IL-10 genotypes in conjunction with FLS invasiveness. Although adenoviral gene transfer of IL-10 to FLS inhibited their invasiveness, no differences were observed in vitro in the FLS from RA patients who were -2849 non-G carriers compared with those who were G carriers. Instead, patients with the -2849 AG/GG genotype, which is associated with high IL-10 production, had higher autoantibody titers at baseline. CONCLUSION: The -2849 IL-10 promoter polymorphism is associated with autoantibody production and subsequent joint damage in RA.

Discovery of distinctive gene expression profiles in rheumatoid synovium using cDNA microarray technology: evidence for the existence of multiple pathways of tissue destruction and repair.

Rheumatoid arthritis (RA) is a heterogeneous disease. We used cDNA microarray technology to subclassify RA patients and disclose disease pathways in rheumatoid synovium. Hierarchical clustering of gene expression data identified two main groups of tissues (RA-I and RA-II). A total of 121 genes were significantly higher expressed in the RA-I tissues, whereas 39 genes were overexpressed in the RA-II tissues. Among the 121 genes overexpressed in RA-I tissues, a relative majority of nine genes are located on chromosome 6p21.3. An interpretation of biological processes that take place revealed that the gene expression profile in RA-I tissues is indicative for an adaptive immune response. The RA-II group showed expression of genes suggestive for fibroblast dedifferentiation. Within the RA-I group, two subgroups could be distinguished; the RA-Ia group showed predominantly immune-related gene activity, while the RA-Ib group showed an additional higher activity of genes indicative for the classical pathway of complement activation. All tissues except the RA-Ia subgroup showed elevated expression of genes involved in tissue remodeling. These results confirm the heterogeneous nature of RA and suggest the existence of distinct pathogenic mechanisms that contribute to RA. The differences in expression profiles provide opportunities to stratify patients based on molecular criteria.

Regulation of CD 163 on human macrophages: cross-linking of CD163 induces signaling and activation.

CD163 is a member of the group B scavenger receptor cysteine-rich (SRCR) superfamily. This study describes aspects of the tissue distribution, the regulation of expression, and signal transduction after cross-linking of this receptor at the cell surface of macrophages. CD163 showed an exclusive expression on resident macrophages (e.g., red pulp macrophages, alveolar macrophages). The expression was inducible on monocyte-derived macrophages by glucocorticoids but not by interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma. The combination of IL-4 or GM-CSF with glucocorticoids resulted in a further increase. Subcellular analysis of alveolar macrophages by immunoelectron microscopy showed a plasma membrane localization of the antigen. Cross-linking of CD163 with monoclonal antibody induced a protein tyrosine kinase-dependent signal that resulted in (1) slow-type calcium mobilization, (2) inositol triphosphate production, and (3) secretion of IL-6 and GM-CSF. The data suggest a function for the SRCR-superfamily receptor CD163 in the regulation of inflammatory processes by macrophages.