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.

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.

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.

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.

The effectiveness of early treatment with "second-line" antirheumatic drugs. A randomized, controlled trial.

OBJECTIVE: To compare two therapeutic strategies for patients with recent-onset rheumatoid arthritis. DESIGN: Open, randomized clinical trial. SETTING: Outpatient clinics of six clinical centers. PATIENTS: 238 consecutive patients with recently diagnosed rheumatoid arthritis. INTERVENTIONS: Delayed or immediate introduction of treatment with slow-acting antirheumatic drugs (SAARDs). MEASUREMENTS: Primary end points were functional disability, pain, joint score, and erythrocyte sedimentation rate at 6 and 12 months and progression of radiologic abnormalities at 12 months. RESULTS: Statistically significant advantages at 12 months for patients receiving the SAARD strategy (immediate treatment with SAARDs) with regard to all primary end points that may be clinically important are indicated by the differences in improvements from baseline and their 95% CIs. These differences were 0.3 (95% CI, 0.2 to 0.6) for disability (range, 0 to 3), 10 mm (CI, 1 to 19 mm) for pain (range, 0 to 100 mm), 39 (CI, 4 to 74) for joint score (range, 0 to 534), and 11 mm/h (CI, 3 to 19 mm/h) for erythrocyte sedimentation rate (range, 1 to 140 mm/h), all in favor of SAARD treatment. The SAARD strategy also appears to be advantageous at 6 months. Radiologic abnormalities progressed at an equal rate in the SAARD and the non-SAARD groups; the difference in progression (range, 0 to 448) was 1 (CI, -3 to 5). Analyses were based on the intention-to-treat principle and thus included 29% of patients in the non-SAARD group who discontinued the non-SAARD treatment strategy; treatment was usually discontinued because of insufficient effectiveness. The SAARD strategy including two alternative SAARDs could not be continued by 8% of patients, usually because of adverse reactions. CONCLUSIONS: Early introduction of SAARDs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis.

Comparison of cystic rheumatoid arthritis and erosive rheumatoid arthritis.

OBJECTIVE: To test the hypothesis that cystic rheumatoid arthritis (RA), characterized as subchondral cysts as the only radiographic abnormality in hands and feet for 2 years after first abnormal radiograph, is a mild subset of RA. METHODS: Fifty-four patients with cystic RA were compared with 144 RA controls matched for age, sex, disease duration, and year of first visit. All patients were randomly selected from a database of 1580 patients with RA attending the clinic 1982-88. In 1994, data of 90% of the patients were collected by one investigator, blinded to the study groups. All available radiographs were scored for erosions and cysts by one radiologist. RESULTS: During 17 years of followup (range 2-48 yrs), the cystic RA group had less severe disease. There were fewer disease modifying antirheumatic drug prescriptions and fewer orthopedic operations in the group with cystic RA. The proportion of Rose-Waaler seropositives and the proportion of patients with extraarticular manifestations were the same for both groups. At final assessment, the median Health Assessment Questionnaire score was significantly lower for the group with cystic RA (0,88 vs 1,56; p <0.01). The final radiographic score was significantly lower for the cystic RA group (0,22 vs 0,58; p <0.01). The outcome differences remained after correcting for early radiographic score, rheumatoid factor, early erythrocyte sedimentation rate (ESR), and presence of comorbidity in a multiple regression model. Mortality was the same for both groups. CONCLUSION: Cystic RA is a relatively mild subset of RA.

Methotrexate osteopathy in long-term, low-dose methotrexate treatment for psoriasis and rheumatoid arthritis.

BACKGROUND: In dermatology and rheumatology, methotrexate is frequently prescribed in low dosages per week; in oncology, high dosages per week are prescribed. Methotrexate osteopathy was first reported in children with leukemia treated with high doses of methotrexate. In animal studies, low doses of methotrexate proved to have an adverse effect on bone metabolism, especially on osteoblast activity. OBSERVATIONS: Methotrexate osteopathy is a relatively unknown complication of low-dose methotrexate treatment. We describe three patients treated with low-dose oral methotrexate in whom signs and symptoms were present that were similar to those found in children treated with high doses of methotrexate. All three patients had a triad of severe pain localized in the distal tibiae, osteoporosis, and compression fractures of the distal tibia, which could be identified with radiographs, technetium Tc 99m scanning, and magnetic resonance imaging. CONCLUSIONS: Methotrexate osteopathy can occur in patients treated with low doses of methotrexate, even over a short period of time. As pain is localized in the distal tibia, it is easily misdiagnosed as psoriatic arthritis of the ankle, but the diagnosis can be correctly made by careful investigation and use of imaging techniques. The only therapy is withdrawal of methotrexate. It is important that more physicians become aware of this side effect of methotrexate therapy, which can occur along with arthritic symptoms.

Fatal pulmonary fibrosis complicating low dose methotrexate therapy for rheumatoid arthritis.

We report the fatal disease course of 2 aged patients with rheumatoid arthritis (RA). Both had respiratory complaints after 10-15 weeks of treatment with methotrexate (MTX). After withdrawal of MTX, and despite the use of corticosteroids and ventilatory support, both died of respiratory failure. Post mortem examination showed extensive pulmonary fibrosis, bronchiolitis obliterans, and hyperplasia of type II pneumocytes. To our knowledge, this is the first report of fatal pulmonary fibrosis following short courses of low dose MTX therapy for RA.

The impact of endpoint measures in rheumatoid arthritis clinical trials.

In clinical trials on the effectiveness of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA), it is common to apply a large number of endpoint measures. This practice has several disadvantages. To determine which endpoint measures are most valuable, reports of 32 clinical trials on six DMARDs were reviewed. The frequency with which each endpoint measure was used is described and discussed, as well as the frequency with which the values of each endpoint were significantly different in statistical comparisons within or between groups, thus showing ability to discriminate between drugs not equally effective. The results of this review are discussed and compared with other reports in the literature on the choice of endpoint measures in RA clinical trials. The authors conclude that it is still common practice to evaluate multiple outcome measures. The number of measures could be reduced by using only those that are generally considered important, are sensitive to change, and are able to differentiate between drugs in clinical trials. A joint count, assessment of pain, a questionnaire on functional status, and measurement of erythrocyte sedimentation rate are sufficient.