The pharmacokinetics of ¹²4I-rituximab in patients with rheumatoid arthritis.

Rheumatoid arthritis is a destructive inflammatory joint disorder. Pre- and mature B-cells, characterized by CD20 antigen expression, play an important role in the inflammatory process. Rituximab, a chimeric monoclonal antibody against the CD20 antigen, has been approved since 2006 for the treatment of patients with rheumatoid arthritis. However, not all patients benefit from this treatment. Persistent activity of the disease has been reported despite treatment with rituximab. Imaging of radiolabeled rituximab can be used to monitor the biodistribution of rituximab, and potentially to predict the efficacy of the treatment. In this study, rituximab was radiolabeled with ¹²4Iodine for positron emission tomography (PET) imaging. The aim of this study was to investigate the pharmacokinetics and biodistribution of ¹²4I-rituximab in patients with rheumatoid arthritis, to establish the optimal procedure for PET imaging. Eligible patients received 50 MBq ¹²4I-rituximab, corresponding to approximately 1.5 mg rituximab. Wholebody PET/CT imaging was performed at 10 min, 24 hrs, and 48 hrs post injection. The total body activity, radioactivity in whole blood, and rituximab serum levels were determined. ¹²4I-rituximab has favorable pharmacokinetics for targeting of (pathological) B cells and imaging over several days, but only after pre-treatment with unlabeled rituximab. In addition, protection of the thyroid is recommended to prevent uptake of released ¹²4I.

CD20 antigen imaging with ¹²4I-rituximab PET/CT in patients with rheumatoid arthritis.

INTRODUCTION: Visualization of the CD20-antigen expression could provide a tool to localize sites of inflammation and could be of additive value in the diagnosis, and subsequently, in the treatment follow-up of patients with rheumatoid arthritis. In this study, an anti-CD20 monoclonal antibody, rituximab (Mabthera®), was radiolabeled with ¹²4Iodine. We report the first results of I¹²4-rituximab PET/CT in patients with rheumatoid arthritis. METHODS: Eligible patients received 50 MBq ¹²4I-rituximab. Wholebody PET/CT imaging was performed at 10 min, 24 h, 48 h and 72-96 h post injection. Images were evaluated primarily on a visual basis and were correlated with disease activity as determined by physical examination and clinical measures. RESULTS: Joints with visually detectable targeting of ¹²4I-rituximab were observed in 4 out of 5 evaluable patients. Only the images at 24 h and later showed accumulation in joints, indicating that the visualized signal represented active targeting of rituximab to the CD20 antigen. Several images showed CD20 positive B-cell infiltration in joints which were clinically normal, while a few clinically diagnosed arthritis localizations were not visualized. This discrepancy suggests that infiltration of CD20 positive B-cells in synovium is a phenomenon that is at least partially independent of clinical inflammation. The level of uptake in joints was generally low, representing less than 0.5% of the injected dose. CONCLUSION: We have shown the feasibility of CD20 antigen imaging using ¹²4I-rituximab in patients with rheumatoid arthritis. Further research is needed to elucidate the clinical significance of demonstrated B-cell infiltration in rheumatic joints.

The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor alpha expression in the synovium.

OBJECTIVE: To determine whether the heterogeneous clinical response to tumour necrosis factor (TNF)alpha blocking therapy in rheumatoid arthritis (RA) can be predicted by TNFalpha expression in the synovium before initiation of treatment. METHODS: Prior to initiation of infliximab treatment, arthroscopic synovial tissue biopsies were obtained from 143 patients with active RA. At week 16, clinical response was evaluated using the 28-joint Disease Activity Score (DAS28). Immunohistochemistry was used to analyse the cell infiltrate as well as the expression of various cytokines, adhesion molecules and growth factors. Stained sections were evaluated by digital image analysis. Student t tests were used to compare responders (decrease in DAS28 > or =1.2) with non-responders (decrease in DAS28 <1.2) and multivariable regression was used to identify the independent predictors of clinical response. RESULTS: Synovial tissue analysis confirmed our hypothesis that the baseline level of TNFalpha expression is a significant predictor of response to TNFalpha blocking therapy. TNFalpha expression in the intimal lining layer and synovial sublining were significantly higher in responders than in non-responders (p = 0.047 and p = 0.008, respectively). The numbers of macrophages, macrophage subsets and T cells (all able to produce TNFalpha) were also significantly higher in responders than in non-responders. The expression of interleukin (IL)1beta, IL6, IL18, IL10, E-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was not associated with response to anti-TNFalpha treatment. CONCLUSION: The effects of TNFalpha blockade are in part dependent on synovial TNFalpha expression and infiltration by TNFalpha producing inflammatory cells. Clinical response cannot be predicted completely, indicating involvement of other as yet unknown mechanisms.

Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation.

OBJECTIVES: All complement pathways lead to the formation of C5a, which is believed to contribute to the influx and activation of C5a-receptor (C5aR) bearing cells into the joints of patients with rheumatoid arthritis (RA). Studies in animal models of RA have suggested therapeutic potential of C5aR blockade. In this study, we examined the effects of the C5aR blockade on synovial inflammation in RA patients. METHODS: We performed a double-blind, placebo-controlled study using an orally administered C5aR-antagonist. Twenty-one patients with active RA were randomized 2:1 to treatment with a C5aR-antagonist AcF- (OpdChaWR) (PMX53) vs placebo for 28 days. Serum concentrations of PMX53 were determined. Synovial tissue was obtained at baseline and after 28 days of treatment for pharmacodynamic analysis using immunohistochemistry and digital image analysis. RESULTS: All patients completed the study. Areas under the curve (AUCs) of PMX53 in patients' blood samples showed a mean of 40.8 nmol h/l. There was neither decrease in cell infiltration, nor changes in key biomarkers associated with clinical efficacy after active treatment. In addition, there was no trend towards clinical improvement in the C5aR-antagonist-treated group compared with placebo nor was there a correlation between the AUC and clinical response. CONCLUSIONS: Treatment with PMX53 did not result in a reduction of synovial inflammation despite reaching serum levels of PMX53 that block C5aR-mediated cell activation in vitro. The data suggest that C5aR blockade does not result in reduced synovial inflammation in RA patients.

Joint laxity and the relationship between muscle strength and functional ability in patients with osteoarthritis of the knee.

OBJECTIVE: To establish the impact of knee joint laxity on the relationship between muscle strength and functional ability in osteoarthritis (OA) of the knee. METHODS: A cross-sectional study of 86 patients with OA of the knee was conducted. Tests were performed to determine varus-valgus laxity, muscle strength, and functional ability. Laxity was assessed using a device that measures the angular deviation of the knee in the frontal plane. Muscle strength was measured using a computer-driven isokinetic dynamometer. Functional ability was assessed by observation (100-meter walking test) and self report (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]). Regression analyses were performed to assess the impact of joint laxity on the relationship between muscle strength and functional ability. RESULTS: In regression analyses, the interaction between muscle strength and joint laxity contributed to the variance in both walking time (P = 0.002) and WOMAC score (P = 0.080). The slope of the regression lines indicated that the relationship between muscle strength and functional ability (walking time, WOMAC) was stronger in patients with high knee joint laxity. CONCLUSION: Patients with knee OA and high knee joint laxity show a stronger relationship between muscle strength and functional ability than patients with OA and low knee joint laxity. Patients with OA, high knee joint laxity, and low muscle strength are most at risk of being disabled.

Disability and health-related quality of life among patients with rheumatoid arthritis: association with radiographic joint damage, disease activity, pain, and depressive symptoms.

OBJECTIVE: To study the associations between disability and health-related quality of life (HRQoL), respectively, and radiographic joint damage, disease activity, pain, and depressive symptoms among patients with rheumatoid arthritis (RA). METHODS: Data were collected through questionnaires and clinical examinations at baseline (1997) and at 2 years' follow-up among patients with RA (n = 307). Disability was measured with a validated Dutch questionnaire, derived from the Health Assessment Questionnaire (HAQ), and HRQoL with a validated Dutch version of the RAND-36, using physical (PCS) and mental (MCS) component summary scales. Multivariate linear regression analyses were performed to assess the relationship between disability or HRQoL and radiographic damage, disease activity, pain, and depressive symptoms. RESULTS: Pain, with respect to disability and PCS, and depressive symptoms, with respect to MCS, were more important predictors than radiographic damage and disease activity. CONCLUSIONS: Daily RA practice needs to be broadened by regular assessment of disease burden from the patients' perspectives. Patient-reported measures, such as disability or HRQoL, should be incorporated for monitoring health outcomes of individual patients and for initiating and evaluating therapy.

Quantification of the response to miltefosine treatment for visceral leishmaniasis by QT-NASBA.

A male patient with psoriatic arthritis and visceral Leishmania infantum infection was treated with oral miltefosine 50 mg three times a day for 4 weeks at the Academic Medical Center, Amsterdam, The Netherlands. Miltefosine plasma concentrations were measured with liquid chromatography/mass spectrometry. The parasite load was followed by quantitative nucleic acid sequence-based amplification (QT-NASBA) assay in blood. Miltefosine elicited a prompt therapeutic effect. After an initial worsening of symptoms and an increase of QT-NASBA values during the first week, recovery was rapidly achieved. QT-NASBA values declined exponentially and were negative after 6 weeks. Miltefosine plasma concentrations continued to accumulate during the 4 weeks of treatment. The terminal elimination half-life was 14.8 days.

Long-term outcome in polymyositis and dermatomyositis.

BACKGROUND: Although polymyositis and dermatomyositis are regarded as treatable disorders, prognosis is not well known, as in the literature long-term outcome and prognostic factors vary widely. AIM: To analyse the prognostic outcome factors in polymyositis and adult dermatomyositis. METHODS: We determined mortality, clinical outcome (muscle strength, disability, persistent use of drugs and quality of life) and disease course and analysed prognostic outcome factors. RESULTS: Disease-related death occurred in at least 10% of the patients, mainly because of associated cancer and pulmonary complications. Re-examination of 110 patients after a median follow-up of 5 years showed that 20% remained in remission and were off drugs, whereas 80% had a polycyclic or chronic continuous course. The cumulative risk of incident connective tissue disorder in patients with myositis was significantly increased. 65% of the patients had normal strength at follow-up, 34% had no or slight disability, and 16% had normal physical sickness impact profile scores. Muscle weakness was associated with higher age (odds ratio (OR) 3.6; 95% confidence interval (CI) 1.3 to 10.3). Disability was associated with male sex (OR 3.1; 95% CI 1.2 to 7.9). 41% of the patients with a favourable clinical outcome were still using drugs. Jo-1 antibodies predicted the persistent use of drugs (OR 4.4, 95% CI 1.3 to 15.0). CONCLUSIONS: Dermatomyositis and polymyositis are serious diseases with a disease-related mortality of at least 10%. In the long term, myositis has a major effect on perceived disability and quality of life, despite the regained muscle strength.

Structural joint changes, malalignment, and laxity in osteoarthritis of the knee.

OBJECTIVE: To assess the relationship between (i) structural joint changes (i.e. joint space narrowing and osteophyte formation) and laxity and (ii) joint malalignment and laxity in osteoarthritis (OA) of the knee. METHODS: A cross-sectional study was carried out on 35 outpatients with osteoarthritis of the knee. Weight-bearing radiographs of the knees were used to assess joint space narrowing (JSN) and osteophyte formation. Knee joint laxity was assessed using a device that measures the angular deviation of the knee in the frontal plane (varus-valgus laxity). Malalignment was assessed using a goniometer. All analyses were performed using knees as units of analysis (i.e. 70 knees). RESULTS: The mean laxity of 70 knees was 8.0+/-4.1 degrees. Knees with minute JSN were significantly more lax than knees with no JSN. There was no significant relationship between osteophyte formation and laxity. Malaligned knees were significantly more lax than aligned knees. CONCLUSION: Both joint space narrowing and malalignment are related to laxity. These results support the premise that biomechanical factors play a role in the degeneration of the osteoarthritic knee joint.

Polymyositis: an overdiagnosed entity.

BACKGROUND: According to widely used criteria (Bohan and Peter criteria, 1975), dermatomyositis (DM) is differentiated from polymyositis (PM) only by skin changes. More recent criteria also include histopathologic characteristics enabling the distinction between PM and DM and the differentiation of sporadic inclusion body myositis (s-IBM) from PM. The authors investigated the applicability of diagnostic features for diagnosing PM and DM. METHODS: The authors performed a retrospective follow-up study of 165 patients with 1) a previous diagnosis of myositis; 2) subacute onset of symmetric, proximal weakness; and 3) an evaluation between 1977 and 1998 excluding other neuromuscular disorders. RESULTS: The diagnoses at initial evaluation based on clinical, laboratory, and histopathologic criteria were PM, 9 (5%); DM, 59 (36%; 54 isolated, 3 with associated connective tissue disease [CTD], 2 with associated malignancy); unspecified myositis (perimysial/perivascular infiltrates, no PM or DM), 65 (39%; 38 isolated myositis, 26 with associated CTD, 1 with malignancy); and possible myositis (necrotizing myopathy, no inflammatory infiltrates), 32 (19%; 29 isolated myositis, 3 with associated CTD). At follow-up evaluation, five of the nine patients with PM had typical s-IBM features. None of the remaining four patients complied with the assumed typical signs of PM. Ten of the 38 patients with isolated unspecified myositis had been diagnosed with a CTD. CONCLUSIONS: Polymyositis is an overdiagnosed entity. At evaluation, more than half the patients with autoimmune myositis cannot be specifically diagnosed with polymyositis or dermatomyositis. A quarter of patients with isolated unspecified myositis subsequently developed connective tissue disease.

Dimension-specific burden of caregiving among partners of rheumatoid arthritis patients.

OBJECTIVES: To assess subjective caregiver burden among partners of rheumatoid arthritis (RA) patients and to identify partner and patient variables and objective caregiver burden related to subjective caregiver burden. METHODS: In 2001, 134 patients diagnosed with RA and their caregiving partners participated in a postal questionnaire survey. Information was gathered on age, gender and health problems of patient and partner, disease duration of the patient, objective caregiver burden and subjective caregiver burden of the partner (using the multidimensional Caregiver Reaction Assessment). Correlation coefficients were computed between the subjective caregiver burden dimensions. Multivariate analyses were performed to identify variables that explained the variation in subjective burden. RESULTS: Partners of RA patients derived, on average, a high level of self-esteem from giving care. Negative subjective caregiver burden was to a large degree caused by a disrupted schedule and to a smaller degree by a lack of family support, financial problems and loss of physical strength. Problems of the partner with mobility or with pain/discomfort and problems of the patient with self-care activities and activities of daily life had the largest impact on negative levels of subjective caregiver burden. CONCLUSIONS: Health parameters of the patient and partner have a considerable predictive value for the development of high levels of subjective burden in partners of RA patients. Support strategies should be developed for partners of RA patients, and should focus especially on reducing the burden caused by a disrupted schedule, and simultaneously on increasing the focus of caregivers on the positive aspects of caregiving.

Health care utilization among rheumatoid arthritis patients referred to a rheumatology center: unequal needs, unequal care?

OBJECTIVE: To quantify the utilization of health care by rheumatoid arthritis (RA) patients and to estimate the contribution of patient characteristics to the explanation of the use of care, in order to evaluate whether those in need of care actually receive care. METHODS: A questionnaire survey and a clinical examination were conducted among patients with RA referred to a rheumatology center. Health care utilization was assessed for medical care, allied health care, psychosocial care, and home care. The influence of sociodemographic variables and clinical and health characteristics on health care utilization was assessed by means of logistic regression. RESULTS: Multivariate analyses showed that, for all types of services, disease-related factors explained most of the utilization. However, some sociodemographic variables (age, sex, and living situation) were also related to the utilization of care. CONCLUSION: Most patients received the care they needed. However, for the elderly with RA, problems in access to allied health care and psychosocial care exist.

Rhemulatologists' performance in dailiy practice.

OBJECTIVE: To assess rheumatologists' performance for 8 rheumatologic conditions and to explore possible explanatory factors. METHODS: After written informed consent was obtained, 27 rheumatologists (21% of all Dutch rheumatologists) practicing in 16 outpatient departments were each visited by 8 incognito "standardized patients" (SPs). The diagnoses of these 8 cases account for about 23% of all new referred patients in the Netherlands. Results for ordered lab tests as well as real radiographs with corresponding results from a radiologist were simulated. Information from the visits was obtained from the SPs, who completed predefined case-specific checklists, and by collecting data on resource utilization. Feedback was provided. RESULTS: Altogether 254 encounters took place, of which 201 were first visits and 53 were followup visits. SPs were unmasked twice during a visit. There was considerable variation in resource utilization (lab tests and imaging) between cases and between rheumatologists. Mean costs per rheumatologist ranged from US $ 4.67 to $ 65.36 per visit for lab tests and from US $ 33.15 to $ 226.84 per visit for imaging tests. No significant correlations were seen between resource utilization costs and number of years of clinical experience or performance on checklist scores. Rheumatologists with longer experience had lower total item checklist scores (r = -0.47; P < 0.05). CONCLUSION: A considerable variation in resource utilization was found among 27 Dutch rheumatologists. The information obtained is an excellent source for discussion on the appropriateness of care.

New therapeutic targets for rheumatoid arthritis.

New insights into the pathogenesis of rheumatoid arthritis (RA) and consequently new targets of therapy are covered in a broad overview fashion. Short-term significant beneficial effect on RA disease activity has been established in a small but rapidly growing number of double-blind placebo-controlled trials now including recombinant human IL-1 receptor antagonist, chimeric (mouse/human) monoclonal antibodies (mAb) against TNF alpha (cA2), humanised (human/mouse) anti-TNF alpha mAb (CDP571) and recombinant human TNF-receptor-Fc fusion protein (TNFR:Fc). Placebo-controlled trials of anti-T cells agents such as chimeric anti-CD4 mAb (cM-T412) and anti-CD5 immunoconjugate, did not demonstrate clinical benefit. A placebo-controlled study of the anti-T cell derived cytokine IL-2 (DAB486IL-2) showed only modes clinical improvement. Other anti-T cell approaches such as autologous T cell vaccination and induction of tolerance by oral type II collagen have been unsuccessful. The one controlled trial with an anti-inflammatory cytokine, recombinant human IFN-gamma, showed modest clinical benefits. Controlled trials with IL-4 and IL-10 and with anti-adhesion molecules are awaited.

Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells.

The production of IgG rheumatoid factors in the inflamed synovium of many patients with rheumatoid arthritis (RA) implies that local sites exist where plasma cell precursors undergo isotype switching and affinity maturation by somatic mutation and selection. Lymphonodular infiltrates of the synovium-containing germinal centers (GCs), are candidates to fulfill such function in the rheumatoid patient. It has been suggested that these GCs are organized around, obviously ectopic, follicular dendritic cells (FDCs). The present study attempts to find out whether these putative FDCs 1) are specific for RA, 2) have the same phenotype and functional capacity as FDCs in lymphoid organs, and 3) may locally differentiate from fibroblast-like synoviocytes (FLS). Synovial biopsies from patients with RA versus non-RA, yet arthritic backgrounds, were compared. Cells with the FDC phenotype were found in both RA and non-RA tissues as well as in single cell suspensions thereof. When FLS were cultured in vitro, part of these cell lines could be induced with IL-1beta and TNF-alpha to express the FDC phenotype, irrespective of their RA or non-RA background. By contrast, the FDC function, i.e., stable binding of GC B cells and switching off the apoptotic machinery in B cells, appeared to be the prerogative of RA-derived FLS only. The present data indicate that FDC function of FLS in RA patients is intrinsic and support the idea that synovial fibroblast-like cells have undergone some differentiation process that is unique for this disease.

Incidence and sources of native and prosthetic joint infection: a community based prospective survey.

OBJECTIVES: To determine the incidence and sources of bacterial arthritis in the Amsterdam health district and the maximum percentage of cases that theoretically would be preventable. METHODS: Patients with bacterial arthritis diagnosed between 1 October 1990 and 1 October 1993 were prospectively reported to the study centre by all 12 hospitals serving the district. Data were gathered on previous health status, source of infection, and microorganisms involved. RESULTS: 188 episodes of bacterial arthritis were found in 186 patients. Most of the 38 children were previously healthy. Fifty per cent of the adults were 65 years or older. Of the adults 84% had an underlying disease, in 59% a joint disorder. Joint surgery constituted the largest part of direct infections (33%) and skin defects were the most important source of haematogenous infections (67%). Infection of joints containing prosthetic or osteosynthetic material by a known haematogenous source occurred 15 times (8%). Staphylococcus aureus was the causative organism in 44% of all positive cultures. CONCLUSION: The incidence of bacterial arthritis was 5.7 per 100,000 inhabitants per year. Preventive measures directed to patients with prosthetic joints or osteosynthetic material, and a known haematogenous source would have prevented at most 8% of all cases.

[Sore throat in rheumatoid arthritis: 2 patients with cricoarytenoid arthritis]. / Keelpijn bij reumatoïde artritis: twee patiënten met cricoarytenoïd-artritis.

In two patients with chronic rheumatoid arthritis, a woman aged 65 and a man aged 56 years, cricoarytenoid arthritis was diagnosed. The symptoms were hoarseness, sore throat and stridor. In both patients a narrowed glottic fissure was found. In one patient tracheostomy was necessary to guarantee a free airway; in the other, therapy with local corticosteroid injections (triamcinolone), combined with immunosuppressive therapy (prednisone), was effective. Early detection through anamnesis and laryngoscopy allows early therapy with a good prognosis.

Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis?

OBJECTIVE: To investigate whether methotrexate (MTX) has a steroid sparing effect in the treatment of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). METHODS: We carried out a randomised double blind, placebo controlled study in 40 patients with PMR, six of whom also had clinical symptoms of GCA. A temporal artery biopsy specimen was available from 37 patients; GCA was found in six of the specimens. Among the six patients with clinical signs of GCA, three had a positive biopsy specimen. All patients were started on prednisone 20 mg/day, irrespective of clinical signs and biopsy result, supplemented with a weekly, blinded capsule containing either MTX 7.5 mg or placebo. The prednisone dose was decreased as soon as clinical symptoms disappeared and erythrocyte sedimentation rate, C reactive protein level, or both, had normalised. RESULTS: Twenty one patients were followed for two years, or at least one year after discontinuing medication. No differences were found between the MTX group and the placebo group concerning time to achieve remission, duration of remission, number of relapses, or cumulative prednisone doses. After 21 weeks the mean daily prednisone dose was reduced by 50%. Forty percent of all patients were able to discontinue prednisone within two years. Median duration of steroid treatment was 47.5 weeks (range 3-104). No serious complications from GCA were encountered. CONCLUSIONS: With a (rapid) steroid tapering regimen, it was possible to reduce the mean daily prednisone dose by 50% in 21 weeks and to cease prednisone in 40% of the patients within two years. With this regimen, no steroid sparing effect of MTX in a dosage of 7.5 mg/week was found.