Jinxia Zhao

The role of anti-mutated citrullinated vimentin antibodies in the diagnosis of early rheumatoid arthritis.

Objective. Anti-mutated citrullinated vimentin (MCV) antibodies have been reported as a fairly sensitive serological marker of rheumatoid arthritis (RA). We evaluated the diagnostic value of anti-MCV in a large cohort of Chinese patients with early RA. Methods. One hundred seventy patients with early RA (< 1 yr duration), 66 with other rheumatic diseases, 10 with infectious diseases, and 60 healthy individuals were included in our study. Serum anti-MCV and second-generation anti-cyclic citrullinated peptide antibodies (anti-CCP2) were measured by ELISA, and rheumatoid factor (RF) was measured by rate nephelometry. The associated clinical data of patients with early RA were also evaluated. Then disease activity was scored by the formula for Disease Activity Score (DAS)28, and the degree of radiological changes was assessed by Sharp score. Results. The prevalence of serum anti-MCV in patients with early RA (78.2%, 133/170) was significantly higher than that of other rheumatologic patients and patients with infectious diseases. It was 12% (3/25) in systemic lupus erythematosus, 9.5% (2/21) in primary Sjögren’s syndrome, 10% (1/10) in systemic sclerosis, 20% (2/10) in ankylosing spondylitis, 12.5% (1/8) in viral hepatitis type B, and 0% (0/2) in tuberculosis. Anti-MCV was not found in the serum of healthy subjects. The sensitivities of anti-MCV, anti-CCP2, and RF tests for early RA were 78.2%, 61.8%, and 72.4%, respectively, and the specificities were 93.4%, 96.3%, and 80.1%. The combination of anti-MCV and anti-CCP2 positivity showed a very high specificity (97.8%) and positive predictive value (97.1%), but a low sensitivity (58.8%). The sensitivity reached 81.2% when the union of anti-MCV and anti-CCP2 positivities was used as one combined criterion. Statistically, anti-MCV had significant correlation with anti-CCP2 (r = 0.587, p = 0.01, 2-tailed) and RF (r = 0.389, p = 0.01, 2-tailed). In addition, it had an interesting correlation with radiological assessment (r = 0.349, p = 0.05, 2-tailed). The anti-MCV had no significant correlation with other factors, such as erythrocyte sedimentation rate, C-reactive protein, antikeratin antibody, antiperinuclear factor, global visual analog scale score for joint pain, IgA, IgG, IgM, C3, C4, hidden rheumatoid factor for IgA (HRFIgA), HRFIgG, and DAS28. Conclusion. Anti-MCV is a novel diagnostic marker for early RA. It may be more useful if the anti-CCP2 assay is performed concomitantly to diagnose patients with early RA.

Prevalence and significance of antibodies to citrullinated human papilloma virus-47 E2345-362 in rheumatoid arthritis

It has been confirmed that antibodies to citrullinated profilaggrin306-324 may play important roles in RA. In this study, human papilloma virus (HPV)-47 E2345-362, homologous to profilaggrin306-324, was found using the NCBI BLAST program. Then, E2345-362 and citrullinated E2345-362, with arginine348 replaced by citrulline, were synthesized. The presence of antibodies against these peptides was examined by an enzyme-linked immunosorbent assay. Associations between these antibodies and the clinical and laboratory features of RA were evaluated. Although the prevalence and AU value of antibodies to the E2345-362 peptide were similar in RA and other rheumatic diseases, those of antibodies to the citrullinated E2345-362 peptide were significantly higher in RA than in other rheumatic diseases. Additionally, sera that were preincubated with cyclic citrullinated peptide (CCP) demonstrated lower AU values of anti-citrullinated E2345-362 peptide antibodies. Moreover, the prevalence of anti-CCP antibodies and that of anti-peptidylarginine deiminase (PADI4) antibodies in anti-citrullinated E2345-362-positive patients were all higher than those of anti-citrullinated E2345-362-negative patients. There were significant correlations between anti-citrullinated E2345-362 and anti-PADI4. RA patients with antibodies to citrullinated E2345-362 had higher DAS28 scores, erythrocyte sedimentation rates, and radiographic progression than those without the antibodies. These results suggest that HPV-47 E2 may act as an autoantigen in RA. The increase in PADI4 may make it easier to citrullinate the HPV-47 E2345-362 peptide, leading to the subsequent immune responses.

Successful treatment of SAPHO syndrome with severe spinal disorder using entercept: a case study.

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare disease. Presently, there is no treatment guideline for this illness. Several studies suggested entercept, a novel biological agent against tumor necrosis factor-alpha, is effective in treating SAPHO syndrome. We report a case in which the clinical conditions of a middle-aged female patient diagnosed with SAPHO syndrome, with noted spinal disorder, improved significantly after receiving entercept treatment. The patient remained stable after 3-month follow-up.

Mucosal administration of α-fodrin inhibits experimental Sjögren's syndrome autoimmunity

Introductionα-Fodrin is an autoantigen in Sjögrens syndrome. We hypothesized that mucosal administration of α-fodrin might prevent the disease.MethodsFour-week-old NOD mice were immunized (intranasal) with a 1 μg or 10 μg dose of α-fodrin every other day. PBS 10 μl/dose and Glutathione transferase (GST 10 μg/dose (control mice) were intranasally administrated by the same procedure. The salivary flow was maintained in immunized animals. The animals were analyzed for the presence of anti-Sjögrens syndrome A, anti-Sjögrens syndrome B, rheumatoid factor and antinuclear, anti-α-fodrin, and anti-type 3 muscarinic acetylcholine receptor polypeptide (anti-M3RP) by immunofluorescence or ELISA. The cytokines IFNγ and IL-10 were measured by ELISA. Salivary glands were examined by H&E staining and immunohistochemical analysis. The water-volume intake was calculated for each group. The induction of regulatory T cells was assessed by fluorescence-activated cell sorting analysis for the frequency of Foxp3+ cells among peripheral CD4+CD25+ T cells.ResultsThe appearance of anti-α-fodrin and anti-M3RP antibodies was delayed in mice immunized with α-fodrin. The titers of anti-α-fodrin and anti-M3RP antibodies were lower in immunized mice (P < 0.05), but there was no significant difference between the low-dose or high-dose immunization groups. Five out of eight mice in the GST group, five of eight mice in the PBS group, two of eight mice in the α-fodrin 1 μg/dose group, and three out of eight mice in the α-fodrin 10 μg/dose were positive for antinuclear antibodies. The levels of serum IFNγ in mice immunized with 1 μg/dose or 10 μg/dose α-fodrin, with PBS, and with GST were 41.9 ± 16.2 pg/ml, 37.1 ± 15.4 pg/ml, 86.8 ± 17.8 pg/ml and 71.6 ± 11.1 pg/ml, respectively, while we found no difference in the levels of serum IL-10 among the groups. The number of Foxp3+ CD4+CD25+ regulatory T cells was higher in the α-fodrin groups compared with the PBS and GST control groups (P < 0.05). Lymphocytic infiltration and expression of α-fodrin in the salivary glands was decreased in α-fodrin-treated groups. The fluid intake of mice in the 1 μg/dose α-fodrin, 10 μg/dose α-fodrin, PBS, and GST groups was 39.2 ± 2.1 ml, 40.4 ± 2.5 ml, 49.3 ± 3.1 ml and 51.6 ± 2.8 ml, respectively.ConclusionMucosal administration of α-fodrin effectively inhibited the progression of experimental Sjögrens syndrome autoimmunity.

Short-interval lower-dose intravenous cyclophosphamide as induction and maintenance therapy for lupus nephritis: a prospective observational study

Cyclophosphamide (CYC) has long been considered a gold standard in inducing renal remission and preventing renal flares for patients with systemic lupus erythematosus (SLE). However, the rational use of CYC has not reached a consensus, such as the timing and length of treatment, the route of administration, and the ideal dosage. The objective of this study was to assess the efficacy and safety of short-interval lower-dose (SILD) intravenous (IV) CYC in the treatment of SLE. A total of 225 patients with lupus nephritis were randomly assigned to a 1-year trial, either the SILD group (12 fortnightly pulses at a fixed dose of 400 mg followed by 6 monthly pulses) or high-dose (HD) group (6 monthly pulses followed by two quarterly pulses at a dose of 0.5~1.0 g/m2). At 6 months of treatment, 28 % (30/107) of patients in the SILD group reached a complete remission (CR), and 51.4 % (55/107) were in partial remission (PR), as compared with 32.7 % (35/107) and 45.8 % (49/107) in the HD group, respectively. Serum albumin, 24-h urinary protein, and the scores of disease activity were significantly improved in both groups at 6 months and maintained at the end of clinical trial. However, the SILD group showed much less menstrual disturbances (11.5 %), gastrointestinal adverse effects (5.3 %), and leukopenia (9.7 %) than the HD group (28.6, 26.8, and 19.8 %, respectively) at the end of clinical trial. The efficacy of the short-interval lower-dose (SILD) IV CYC regimen in the treatment of lupus nephritis is equivalent to that of the high-dose (HD) regimen, whereas the incidence of adverse events is much lower in the SILD group.

Is It Necessary to Combine Detection of Anticitrullinated Protein Antibodies in the Diagnosis of Rheumatoid Arthritis

Objective. Antibodies against citrulline-containing epitopes, such as antiperinuclear factor (APF), antikeratin antibodies (AKA), antifilaggrin antibodies, and anticyclic citrullinated peptide (anti-CCP) antibodies, are specific in rheumatoid arthritis (RA). Detection of APF, AKA, and anti-CCP has been widely used in clinical practice. However, studies on combined detection of these anti citrullinated protein antibodies (ACPA) in the significance of diagnosing RA have been limited. We aimed to detect APF, AKA, and anti-CCP antibodies and to evaluate the significance of combined detection of these ACPA in RA. Methods. A total of 551 patients with arthritic disorders, 304 with RA and 247 with other rheumatic diseases, were selected at the Department of Rheumatology and Immunology during the past 2 years. AKA and APF were tested by indirect immunofluorescence assay. Anti-CCP was detected using the second-generation ELISA kit. Results. The sensitivities of anti-CCP, AKA, and APF tests for RA were 76.2%, 43.4%, and 34.5%, respectively, while the specificities were 96.0%, 98.4%, and 99.6%. The combination of anti-CCP, AKA, and APF positivity had the highest specificity (100%), but it yielded a low sensitivity (28.3%). When 2 of the 3 ACPA were positive, the sensitivity and specificity were 48.4% and 99.2%, respectively. When either anti-CCP or AKA or APF was positive, sensitivity increased to 77.3%, but specificity decreased to 94.7%. Conclusion. Anti-CCP was the most valuable marker in the diagnosis of RA, among the 3 ACPA. Combined detection of anti-CCP, AKA, and APF did not increase the diagnostic capability for RA.

High remission and low relapse with prolonged intensive DMARD therapy in rheumatoid arthritis (PRINT): A multicenter randomized clinical trial.

Objectives: To determine whether prolonged intensive disease-modifying antirheumatic drug (DMARD) treatment (PRINT) leads to high remission and low relapse rates in patients with severe rheumatoid arthritis (RA). Methods: In this multicenter, randomized and parallel treatment trial, 346 patients with active RA (disease activity score (28 joints) [DAS28] (erythrocyte sedimentation rate [ESR]) > 5.1) were enrolled from 9 centers. In phase 1, patients received intensive treatment with methotrexate, leflunomide, and hydroxychloroquine, up to 36 weeks, until remission (DAS28 ⩽ 2.6) or a low disease activity (2.6 < DAS28 ⩽ 3.2) was achieved. In phase 2, patients achieving remission or low disease activity were followed up with randomization to 1 of 2 step-down protocols: leflunomide plus hydroxychloroquine combination or leflunomide monotherapy. The primary endpoints were good European League Against Rheumatism (EULAR) response (DAS28 (ESR) < 3.2 and a decrease of DAS28 by at least 1.2) during the intensive treatment and the disease state retention rate during step-down maintenance treatment. Predictors of a good EULAR response in the intensive treatment period and disease flare in the maintenance period were sought. Results: A good EULAR response was achieved in 18.7%, 36.9%, and 54.1% of patients at 12, 24, and 36 weeks, respectively. By 36 weeks, 75.4% of patients achieved good and moderate EULAR responses. Compared with those achieving low disease activity and a high health assessment questionnaire (HAQ > 0.5), patients achieving remission (DAS28 ⩽ 2.6) and low HAQ (⩽ 0.5) had a significantly higher retention rate when tapering the DMARDs treatment (P = 0.046 and P = 0.01, respectively). There was no advantage on tapering to combination rather than monotherapy. Conclusions: Remission was achieved in a proportion of patients with RA receiving prolonged intensive DMARD therapy. Low disease activity at the start of disease taper leads to less subsequent flares. Leflunomide is a good maintenance treatment as single treatment.

Efficacy and safety of weekly leflunomide for the treatment of early rheumatoid arthritis: a randomized, multi-center study.

The aim of this study was to determine the efficacy and safety of a weekly dose of leflunomide (50 mg/week) in early rheumatoid arthritis patients with mild or moderate disease activity.

The role of a proliferation-inducing ligand (APRIL) in the pathogenesis of rheumatoid arthritis

Objectives: To determine the differences in a proliferation-inducing ligand (APRIL) between seropositive and seronegative rheumatoid arthritis (RA) patients and further investigate the possible pathogenesis of the two subtypes of RA. Method:Concentrations of APRIL in sera (18 seropositive RA patients, 16 seronegative RA patients, and 10 healthy controls) and synovial fluid (SF) (eight seropositive RA patients, two seronegative RA patients, and 10 controls) were detected by enzyme-linked immunosorbent assay (ELISA). Infiltration of plasma cells, macrophages, and APRIL-positive cells in the synovium [14 seropositives, eight seronegatives, and 10 osteoarthritis (OA) controls] was detected by immunohistochemistry. Correlations between serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), 28-joint Disease Activity Score (DAS28), and sera/SF levels of APRIL and synovial cell infiltration were analysed. Results: The mean serum APRIL level of seropositive RA patients was significantly higher than that of seronegative patients (26.1 ± 31.2 vs. 8.0 ± 10.2 ng/mL, p = 0.03). The level of APRIL in the SF of seropositive RA patients was comparable to that of seronegative patients [47.9 ± 54.4 vs. 32.82 (6.52–59.12) ng/mL, p > 0.05]. The SF APRIL level of RA patients was higher than that of patients with other inflammatory arthritis. Dramatically increased infiltration of APRIL-positive cells in the RA synovium was observed compared with the OA group (seropositive RA vs. OA, p < 0.001; seronegative RA vs. OA, p = 0.001). The infiltration of both plasma cells and macrophages was more in seropositive RA than in OA (p = 0.013 and p = 0.003, respectively). Conclusions: The serum APRIL levels of seropositive RA patients are significantly higher than those of seronegative RA patients. APRIL may participate in the formation of seropositive RA.

Long-term outcomes and predictors of a large cohort of idiopathic retroperitoneal fibrosis patients: a retrospective study

Objectives: Idiopathic retroperitoneal fibrosis (iRPF) is an uncommon disease with inflammatory features. Most patients have good prognosis but some may relapse or even progress to chronic renal failure. The aims of the study were to investigate the prognosis of a large cohort of iRPF patients and explore the risk factors for poor outcomes. Methods: All patients with a definite diagnosis of iRPF in Peking University First Hospital between 1 January 2003 and 31 December 2016 were enrolled. Their clinical and laboratory data at diagnosis and subsequent follow-up visits were collected. The endpoint of follow-up was defined as disease relapse or the last follow-up. Results: In total, 155 iRPF patients (45 females, 110 males) with a mean ± sd age of 55.1 ± 12 years at diagnosis were enrolled. The median duration of follow-up was 45.3 (0.1–169.2) months. During the whole follow-up, 27/153 (17.6%) patients encountered at least one relapse. Higher baseline erythrocyte sedimentation rate (ESR) was associated with a higher risk of relapse [p = 0.021, odds ratio (OR) = 1.016, 95% confidence interval (CI) 1.002–1.029]. A longer course of glucocorticoid treatment was associated with a lower risk of relapse (p = 0.030, OR = 0.948, 95% CI 0.904–0.995). Patients with a permanent presence of hydronephrosis were more likely to develop renal atrophy (33/154 vs 19/51, χ2 = 5.069, p = 0.024). Conclusions: Higher baseline ESR and a shorter course of glucocorticoid treatment seemed to be predictors of relapse in iRPF patients. Prompt release of hydronephrosis to prevent kidney atrophy is very important for preserving renal function and improving the prognosis.