Early radiological progression remains associated with long-term joint damage in real-world rheumatoid arthritis patients treated to the target of remission.

OBJECTIVE: To evaluate radiological damage and to explore characteristics associated with radiological progression in rheumatoid arthritis (RA) treated to the target of remission in a real-world setting. METHODS: Baseline to 6 year follow-up data were used from an observational early RA cohort. Radiographs of hands and feet at baseline, 6 months, and 1, 3, and 6 years were scored using the modified Sharp/van der Heijde score (SHS). The threshold for rapid radiological progression (RRP) after 6 months was based on the calculated smallest detectable change of 3.95. Negative binomial generalized linear mixed model and logistic regression analyses were performed to examine which variables were associated with RRP and 6 year radiological progression. RESULTS: Most radiological damage occurred in the first year of treatment [median 2.0 interquartile range (IQR) 1.0-4.0 SHS points] compared to the subsequent 5 years of follow-up (median 3.0 IQR 1.0-5.0 SHS points). While low disease activity was achieved within 6 months on average, 18.8% of the patients developed RRP. Anti-cyclic citrullinated peptide (anti-CCP) positivity [incidence rate ratio (IRR) 1.42, p = 0.03], baseline erosive disease (IRR 1.60, p = 0.02), and RRP (IRR 3.28, p < 0.001) were associated with 6 year radiological progression. Erosive disease was the strongest predictor of RRP (odds ratio 8.8, p < 0.001). CONCLUSION: Long-term radiological outcome is limited in most real-world RA patients treated to the target of remission, but RRP still occurs. Anti-CCP positivity, baseline erosive disease, and RRP remain associated with long-term radiological outcome.

Long-term disease and patient-reported outcomes of a continuous treat-to-target approach in patients with early rheumatoid arthritis in daily clinical practice.

Patients in real life may differ from those in clinical trials. The aim of this study is to report 5-year outcomes of a continuous treat-to-target (T2T) approach in patients with rheumatoid arthritis (RA) in daily clinical practice. In the Dutch RhEumatoid Arthritis Monitoring cohort, all patients with a clinical diagnosis of RA were treated according to a protocolled T2T strategy, aimed at 28-joint Disease Activity Score (DAS28) < 2.6. Outcomes were percentages of patients in distinct levels of disease activity, mean course of DAS28 and prevalence of sustained (drug-free) remission. Also, data on functional disability (Health Assessment Questionnaire) and health-related quality of life (Short-Form 36) were examined. Mean DAS28 improved from 4.93 (95% CI 4.81-5.05) at baseline to 2.49 (95% CI 2.35-2.63) after 12 months and remained stable thereafter. Percentages of patients at 12 months with DAS28 < 2.6 (remission), DAS28 ≥ 2.6 and ≤ 3.2 (low disease activity), DAS28 > 3.2 and ≤ 5.1 (moderate disease activity) and DAS28 > 5.1 (high disease activity) were 63, 16, 18 and 3%, respectively. Sustained remission (DAS28 < 2.6 during ≥ 6 months) was observed at least once in 84% of the patients and drug-free remission (DAS28 < 2.6 during ≥ 6 months after withdrawal of all disease-modifying anti-rheumatic drugs) in 36% of the patients. Functional disability and health-related quality of life significantly improved during the first 24 weeks. Continuous application of T2T in real-life RA patients leads to favourable disease- and patient-related outcomes.

[Amyloidosis despite normal ESR]. / Niet-verhoogde BSE, maar toch amyloïdose.

BACKGROUND: Amyloidosis is a clinical picture brought on by extracellular deposits of insoluble, non-degradable proteins. The clinical presentation of amyloidosis depends upon the type of protein and the organ afflicted. CASE DESCRIPTION: A 65-year-old woman had stiffness of the locomotor apparatus, recurrent carpal tunnel syndrome and problems with swallowing. Laboratory and urine investigations initially showed no abnormalities, but histopathological investigation of a synovial biopsy revealed amyloidosis with light-chain deposits. This turned out to be due to multiple myeloma. CONCLUSION: Amyloidosis can present with atypical symptoms, such as stiffness. Normal erythrocyte sedimentation rate (ESR) and normal urine analysis do not exclude this diagnosis. When there are clinical indications of amyloidosis further analysis for free-light chains should be performed, even when ESR is normal.

Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three-year results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort.

OBJECTIVE: Treat-to-target (T2T) leads to improved clinical outcomes in early rheumatoid arthritis (RA). The question is whether these results sustain in the long term. Our objective was to investigate the 3-year results of a protocolized T2T strategy in daily clinical practice. METHODS: In the Dutch Rheumatoid Arthritis Monitoring remission induction cohort, patients newly diagnosed with RA were treated according to a T2T strategy aimed at remission (Disease Activity Score in 28 joints [DAS28] <2.6). Patients were treated with methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with anti-tumor necrosis factor α agents in case of failure. Primary outcomes were disease activity, Health Assessment Questionnaire (HAQ) score, Short Form 36 physical component summary (PCS) and mental component summary (MCS) scores, and the Sharp/van der Heijde score (SHS) after 3 years. Secondary outcomes were sustained DAS28 remission (≥6 months) and remission according to the provisional American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition. RESULTS: After 3 years (n = 342), 61.7% of patients were in DAS28 remission and 25.3% met the provisional ACR/EULAR definition of remission. Sustained remission was experienced by 70.5%, which in the majority was achieved with conventional disease-modifying antirheumatic drugs only. The median scores were 0.4 (interquartile range [IQR] 0.0-1.0) for the HAQ, 45.0 (IQR 38.4-53.2) for the PCS, 53.1 (IQR 43.2-60.8) for the MCS, and 6.0 (IQR 3.0-13.0) for the total SHS. CONCLUSION: In very early RA, T2T leads to high (sustained) remission rates, improved physical function and health-related quality of life, and limited radiographic damage after 3 years in daily clinical practice.

Efficacy of intraarticular infliximab in patients with chronic or recurrent gonarthritis: a clinical randomized trial.

OBJECTIVE: To evaluate the efficacy and safety of intraarticular infliximab compared with intraarticular methylprednisolone in patients with gonarthritis. METHODS: In 23 patients with recurrent gonarthritis despite previous intraarticular corticosteroid therapy, a total of 41 intraarticular injections (20 infliximab and 21 methylprednisolone) were performed in 28 knees. Initial therapy was randomly assigned, and crossover therapy was eligible within 3 months. The clinical effect was assessed during 6 months of followup. The primary outcome was event-free survival, defined as the time after treatment until local retreatment was performed and/or nonimprovement of the knee joint score. Adverse effects were recorded during followup. RESULTS: All patients treated with intraarticular infliximab had an insufficient response. In contrast, 8 of the 21 intraarticular methylprednisolone injections were effective (P = 0.004). Between groups, no differences in the patients' age, disease duration, number of disease-modifying antirheumatic drugs, or previous intraarticular methylprednisolone were observed. Reported adverse effects were not related to therapy. CONCLUSION: Treatment with intraarticular infliximab injection was not effective in patients with a chronically inflamed knee joint. Intraarticular injection with methylprednisolone was superior despite previous intraarticular corticosteroid therapy. Further investigation is needed to provide these patients with a better alternative.

Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible.

BACKGROUND: Many strategies, including intradermal vaccination, have been tested to augment antibody responses upon vaccination. This strategy has not been evaluated in different groups of immunocompromized patients. We conducted a prospective, randomized study to compare the humoral response upon standard intramuscular influenza vaccination with the response upon reduced-dose intradermal vaccination in patients treated with anti-tumor necrosis factor (TNF)-alpha, human immunodeficiency virus (HIV)-infected patients, hematologic stem cell transplantation (HSCT) patients, and healthy controls. METHODS: In total 156 immunocompromized patients and 41 healthy controls were randomized to receive either 0.5mL of the 2005/2006 trivalent influenza vaccine intramuscular or 0.1mL intradermal. Humoral responses, determined by hemagglutination inhibition assay, were measured before and 28 days postvaccination. Geometric mean titers (GMTs) and protection rates (PRs) are reported as primary outcomes, adverse events as a secondary outcome. RESULTS: Reduced-dose intradermal vaccination leads to similar GMTs and PRs, within all tested groups, compared to the standard intramuscular vaccination. Healthy controls yielded significantly better GMTs and PRs than immunocompromized patients. Local skin reactions after intradermal vaccination occurred less frequent and were milder in immunocompromized patients than in healthy subjects and were predictive for a positive vaccination outcome for individual subjects. CONCLUSIONS: Intradermal influenza vaccination is a feasible alternative for standard intramuscular vaccination in several groups of immunocompromized patients, including those treated with anti-TNF, HIV-infected patients and HSCT patients. The occurrence of a local skin reaction after intradermal vaccination is predictive of a response to at least one of the vaccine antigens.

[Three patients with a fracture during methotrexate use, possibly due to methotrexate osteopathy]. / Drie patiënten met een botfractuur tijdens het gebruik van methotrexaat, mogelijk door methotrexaatosteopathie.

Three female patients, aged 76, 64 and 74 years old, who were treated with low-dose methotrexate due to an inflammatory joint disorder, developed severe pain in a lower extremity. The pain increased on weight bearing and could not be explained by arthritis. Conventional x-ray investigation showed a fracture in the second patient. In the other two patients insufficiency fractures were visualized by MRI and bone scan. Because methotrexate osteopathy was suspected, treatment with methotrexate was stopped. All three patients made a rapid recovery after discontinuation. Methotrexate osteopathy is characterized by pain, osteoporosis and microfractures, and was first reported in children treated with high-dose methotrexate for a malignancy. Similar clinical features are reported in the literature in patients with chronic joint inflammation treated with low-dose methotrexate. The causal relationship between the insufficiency fractures and the use of methotrexate is still under debate. Although the clinical picture fits with methotrexate osteopathy, these patients often also have other risk factors for osteoporotic insufficiency fractures.

Synergistic immunosuppressive effect of anti-TNF combined with methotrexate on antibody responses to the 23 valent pneumococcal polysaccharide vaccine.

INTRODUCTION: The efficacy of the immune response upon vaccination in patients treated with anti-tumor necrosis factor-alpha (anti-TNF) with or without methotrexate is the subject of debate. We studied the effect of immunosuppressive treatment, including anti-TNF and methotrexate, on the response to pneumococcal polysaccharide (PPS) vaccine. METHODS: Fifty-two patients treated with immunosuppressives including anti-TNF (anti-TNF group), 41 patients given a similar immunosuppressive regimen without anti-TNF (no anti-TNF group), and 18 healthy controls were vaccinated with a 23 valent PPS vaccine. The percentage of patients treated with methotrexate in the anti-TNF and no anti-TNF group was 65% and 76%, respectively. Antibodies against four of the vaccine antigens (PPS 6B, 9V, 19F and 23F) were measured before and 4 weeks after vaccination. The primary outcome was the response rate, defined as the percentage with a postvaccination titer 0.35 microg/ml in combination with at least a twofold increase in antibody titer. The protection rate was defined as a postvaccination titer > or = 0.35 microg/ml. RESULTS: The use of methotrexate was the strongest predictor of impaired vaccination outcome. Anti-TNF caused an additional immunosuppressive effect in the presence of methotrexate, leading to the lowest response percentages in patients using the combination of these two drugs. The underlying disease, other immunosuppressives such as prednisone or type of anti-TNF agent used did not influence vaccination outcome. CONCLUSIONS: Patients who were treated with the combination of methotrexate and anti-TNF demonstrated a significantly impaired immune response following pneumococcal polysaccharide vaccination as compared to patients treated with either methotrexate or anti-TNF only or immunosuppressives excluding these two compounds.

The effect of anti-tumour necrosis factor alpha treatment on the antibody response to influenza vaccination.

OBJECTIVES: The effect of anti-tumour necrosis factor (TNF) therapy on the antibody responses to vaccines is the subject of ongoing debate. Therefore, we investigated the effect of the three currently available anti-TNF agents on influenza vaccination outcomes in a patient population with long-standing disease. METHODS: In a prospective cohort study, we assessed the antibody response upon influenza vaccination in 112 patients with long-standing autoimmune disease treated with immunosuppressive medication either with anti-TNF (etanercept, adalimumab or infliximab; n = 64) or without anti-TNF (n = 48) and a control group of 18 healthy individuals. Antibody responses were determined by haemagglutination inhibition assay, before and 4 weeks after vaccination. RESULTS: The proportion of individuals with a protective titre (>or=40) after vaccination was large (80-94%) and did not significantly differ between the three groups. Post-vaccination geometric mean antibody titres against influenza (A/H3N2 and B) were significantly lower in the 64 patients treated with anti-TNF compared with the 48 patients not receiving anti-TNF, and the healthy controls. CONCLUSIONS: The antibody response to influenza vaccination in patients treated with anti-TNF is only modestly impaired. The proportion of patients that achieves a protective titre is not significantly diminished by the use of TNF blocking therapies.

Infliximab and methotrexate as induction therapy in patients with early rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy of infliximab plus methotrexate (MTX) as induction therapy in patients with early rheumatoid arthritis (RA). METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with active, early RA who were included as group 4 of the BeSt study were initially treated with infliximab (3 mg/kg) in combination with MTX (25 mg/week). The Disease Activity Score (DAS) was measured every 3 months. In patients with persistent low disease activity (DAS 2.4, the infliximab dosage was increased (maximum 10 mg/kg), and they were subsequently switched to another DMARD. Except for intraarticular administration, corticosteroids were not permitted. Functional ability and the modified Sharp/van der Heijde score were determined after 2 years of therapy. RESULTS: Of the 120 patients, 67 responders (56%) had persistent low disease activity and discontinued infliximab after a median of 9.9 months, with a median MTX dosage of 10 mg/week after 2 years. Ten other patients experienced a disease flare after discontinuation and resumed infliximab after a median of 3.7 months. Thirteen patients did not achieve persistent low disease activity and received infliximab at various dosages. Treatment was unsuccessful in 30 patients. In the 67 responders, the progression of joint damage was lower than in the 30 patients in whom treatment failed. CONCLUSION: Fifty-six percent of patients with active early RA, initially treated with infliximab plus MTX, could discontinue infliximab after achieving a DAS of

Advanced magnetic resonance imaging of the brain in patients treated with TNF-alpha blocking agents.

OBJECTIVE: Neurological symptoms have been reported in patients treated with anti-TNF-alpha. In a pilot study we evaluated the effect of anti-TNF-alpha on cerebral parenchyma using advanced Magnetic Resonance (MR) techniques. METHODS: Seven patients with a systemic inflammatory disease (5 rheumatoid arthritis, 2 psoriatic arthritis) had Magnetization Transfer Imaging, Diffusion Weighted Imaging (DWI) and Magnetic Resonance Spectroscopy (MRS) of the brain before and after administration of anti-TNF-alpha. Four patients were neuropsychologically evaluated. RESULTS: After treatment with TNF-alpha blocking agents the Magnetization Transfer Ratio histogram Peak-heights (MTR-Pht) of the white and gray matter decreased (p < 0.01 and p < 0.05 respectively). The Apparent Diffusion Coefficient for the white and gray matter and the metabolite ratios in the centrum semiovale did not significantly change after therapy. Neuropsychological assessment showed no difference before and after anti-TNF-alpha. CONCLUSION: The decrease of the MTR-Pht after anti-TNF-alpha therapy suggests loss of parenchyma integrity; however, these changes could not be attributed to inflammation or demyelination based on our complementary DWI and MRS data. The decrease of the MTR-Pht did not result in decreased cognitive function.

A nasal squamous cell carcinoma complicated by a paraneoplastic syndrome consisting of a myositis and anti-Jo-1 autoantibodies.

We report a female patient with the clinical features of a Jo-1-syndrome as a paraneoplastic phenomenon secondary to a nasal squamous cell carcinoma.

Accuracy of the Jamshidi trocar biopsy in the diagnosis of bone tumors.

Obtaining a histologic diagnosis is crucial in patients presenting with a tumor or a tumorous condition of the bone. The incisional surgical and the closed trocar biopsy are the most frequently used techniques for obtaining a representative tissue sample for histologic evaluation. This study reports on the reliability of 270 Jamshidi trocar biopsies performed on 258 patients with osseous tumors and tumorlike lesions. All patients were evaluated clinically and radiographically by a team consisting of an orthopaedic surgeon, a radiologist, and a surgical pathologist. In nearly all cases the biopsy and the resection were performed by the same orthopaedic surgeon. The biopsy site was determined in accordance with the planned subsequent resection surgery. Overall, an accurate diagnosis could be reached in 90.7% of the total number of 270 Jamshidi biopsies and in 95% of the 258 patients. The failure rate of the 270 biopsies was 9.3%. No specific contraindications with regard to the kind of lesion were found. Except for the pelvis, the localization of the lesion did not influence the rate of success. The high accuracy of the trocar biopsy, combined with the advantages of this technique over the incisional surgical biopsy, makes it a safe, fast, and adequate technique for obtaining a histologic sample of a bone tumor.

Unique combination of an ovarian gonadoblastoma, dysgerminoma, and mucinous cystadenoma in a patient with Turner's syndrome: a cytogenetic and molecular analysis.

Phenotypically female patients with a (mosaic) XY karyotype are at high risk to develop gonadoblastoma with potential progression to dysgerminoma. We studied a Turner's syndrome patient with a composite ovarian neoplasm of a gonadoblastoma, a dysgerminoma, and a mucinous cystadenoma. Nonradioactive in situ hybridization showed that the patient had a XO/XY genotype with deletion of part of Yq. Molecular analysis located the chromosomal breakpoint in deletion interval 6, indicating that potential genes responsible for the development of gonadoblastoma may be located on the short arm of the Y chromosome or on the long arm, centromeric of deletion interval 6. Moreover, using the XO/XY mosaicism as a clonal marker, the dysgerminoma and the mucinous cystadenoma were shown to be of independent origin. Therefore, in this case, we find support for the hypothesis that mucinous cysts with gastrointestinal epithelium can be of ovarian surface epithelial cell origin. This case also demonstrated that the occurrence of a composite tumor does not unequivocally imply that both components are of the same origin. Clonal analysis is required to determine the relation of the tumor constituents.