USC Rheumatology Fellowship

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2007-05-25T08:49:00.000-07:00

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Arhtitis and Rheumatism (May 2007)

2007-05-14T09:20:00.000-07:00

Cultivation of Tropheryma whipplei from the synovial fluid in Whipple's arthritis

This report describes a patient who presented with fever, weight loss, diarrhea, and adenopathy. At the time of presentation he had a 28-year history of unusually severe destructive polyarthritis. Duodenal biopsy revealed periodic acid-Schiff-positive macrophages. Polymerase chain reaction studies showed positivity for Tropheryma whipplei in synovial fluid, synovial tissue, and lymph node specimens, and Whipple's disease was diagnosed. T whipplei was successfully cultivated from the synovial fluid by both cell culture and axenic culture. This strain (named ART1) was subcultured and subsequently established and genotyped. Antibiotic treatment was instituted in the patient, after which his symptoms remitted. These findings show for the first time that Whipple's arthritis may be, at least in some cases, a septic arthritis.

Arthritis and Rheumatism (May 2007)

2007-05-14T09:19:00.000-07:00

B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents

Patients with rheumatoid arthritis (RA) in whom the response to anti-tumor necrosis factor (anti-TNF) therapy is inadequate have several therapeutic options, such as switching to an alternative anti-TNF agent or initiating B cell-depleting therapy with rituximab (RTX). Although both therapeutic options have been proven effective in trials, no head-to-head comparisons are available. The aim of this study was to compare the effectiveness of RTX with that of an alternative anti-TNF agent in the management of patients with RA who had an inadequate response to anti-TNF therapy.This prospective cohort study was nested within the Swiss Clinical Quality Management RA cohort and included all patients who had an inadequate response to at least 1 anti-TNF agent and subsequently received either 1 cycle of RTX or an alternative anti-TNF agent. The primary outcome was the evolution of RA disease activity (as measured on the Disease Activity Score in 28 joints [DAS28]), which was analyzed using multivariate regression models for longitudinal data.One hundred sixteen patients with RA were included; 50 patients received 1 cycle of RTX, and 66 patients were treated with a second or a third alternative anti-TNF agent. At baseline, there were no significant differences between the 2 groups in age, sex, disease duration, and disease activity. Evolution of the DAS28 was more favorable in the group that received RTX compared with the group that received an alternative anti-TNF agent (P = 0.01). At 6 months, the mean decrease in the DAS28 was -1.61 (95% confidence interval [95% CI] -1.97, -1.25) among patients receiving RTX and -0.98 (95% CI -1.33, -0.62) among those receiving subsequent anti-TNF therapy.The results of this observational study suggest that treatment with RTX may be more effective than switching to an alternative anti-TNF agent in patients with RA in whom active disease persists despite anti-TNF therapy.

Arthritis and Rheumatism (May 2007)

2007-05-14T09:18:00.000-07:00

The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 PERSON-YEARS of observation

To ascertain the relationship between anti-tumor necrosis factor (anti-TNF) therapy, methotrexate (MTX), and the risk of lymphoma in patients with rheumatoid arthritis (RA). This report updates our previous report during 29,314 person-years of followup.Participants in the National Data Bank for Rheumatic Diseases (NDB) longitudinal study of long-term outcomes of RA completed semiannual questionnaires from 1998 through 2005, during 89,710 person-years of followup. Lymphoma reports were validated by medical records. The association between lymphoma and treatment was investigated using conditional logistic regression, adjusted for severity and demographic covariates.Of the 19,591 participants, 55.3% received biologic agents and 68.0% received MTX while enrolled in the NDB. The lymphoma incidence rate was 105.9 (95% confidence interval [95% CI] 86.6-129.5) per 100,000 person-years of exposure. Compared with the SEER (Surveillance, Epidemiology, and End-Results) lymphoma database, the standardized incidence ratio was 1.8 (95% CI 1.5-2.2). The odds ratio (OR) for lymphoma in patients who received anti-TNF therapy compared with patients who did not receive anti-TNF therapy was 1.0 (95% CI 0.6-1.8 [P = 0.875]). The OR for lymphoma in patients who received anti-TNF plus MTX therapy compared with patients who received MTX treatment alone was 1.1 (95% CI 0.6-2.0 [P = 0.710]). Infliximab and etanercept considered individually also were not associated with a risk of lymphoma.In a study of lymphoma in 19,591 RA patients over 89,710 person-years of followup, which included exposure to anti-TNF therapy in 10,815 patients, we did not observe evidence for an increase in the incidence of lymphoma among patients who received anti-TNF therapy.

Arthritis and Rheumatism (May 2007)

2007-05-14T09:15:00.000-07:00

The antiinflammatory mechanism of methotrexate depends on extracellular conversion of adenine nucleotides to adenosine by ecto-5[prime]-nucleotidase: Findings in a study of ecto-5[prime]-nucleotidase gene-deficient mice

Evidence from in vitro, in vivo, and clinical studies indicates that adenosine mediates, at least in part, the antiinflammatory effects of methotrexate (MTX), although the biochemical events involved have not been fully elucidated. This study was undertaken to investigate whether MTX exerts antiinflammatory effects in mice that lack ecto-5[prime]-nucleotidase (ecto-5[prime]-NT) (CD73) and are unable to convert AMP to adenosine extracellularly, in order to determine whether adenosine is generated intracellularly and transported into the extracellular space or is generated from the extracellular dephosphorylation of AMP to adenosine.Male CD73 gene-deficient mice and age-matched wild-type mice received intraperitoneal injections of saline or MTX (1 mg/kg/week) for 5 weeks. Air pouches were induced on the back by subcutaneous injection of air; 6 days later, inflammation was induced by injection of carrageenan.Fewer leukocytes, but higher levels of tumor necrosis factor [alpha] (TNF[alpha]), accumulated in the air pouches of vehicle-treated CD73-deficient mice compared with those of wild-type mice. As expected, MTX treatment reduced the number of leukocytes and TNF[alpha] levels in the exudates and increased exudate adenosine concentrations in wild-type mice. In contrast, MTX did not reduce exudate leukocyte counts or TNF[alpha] levels or increase exudate adenosine levels in CD73-deficient mice.These results demonstrate that the antiinflammatory actions of MTX are mediated, at least in part, by increased release of adenine nucleotides that are hydrolyzed extracellularly to adenosine via an ecto-5[prime]-NT-dependent pathway.

!This is Dr. Horwitz's favorite question!

Arthritis and Rheumatism (May 2007)

2007-05-14T09:14:00.000-07:00

Association of Anti-Cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis

Anti-cyclic citrullinated peptide (anti-CCP) antibodies are rheumatoid arthritis (RA)-specific serologic markers. RA susceptibility has been associated with HLA-DRB1 shared epitope (SE) alleles and single-nucleotide polymorphism (SNP) haplotypes in the peptidyl arginine deiminase 4 gene (PADI4). This study was undertaken to determine whether anti-CCP levels are associated with PADI4 haplotypes and/or SE alleles in Korean patients with RA.Three nonsynonymous SNPs in PADI4 (padi4_89, padi4_90, and padi4_92) and SE alleles were genotyped, and serum anti-CCP levels were measured, in 311 patients with nonerosive or erosive RA. The relationships between anti-CCP levels and PADI4 haplotypes and/or SE alleles were analyzed statistically.Anti-CCP levels were significantly higher in patients carrying the PADI4 RA risk haplotype than in patients who did not have the risk haplotype, among anti-CCP-positive patients with RA with a disease duration of [le]34 months (P = 0.041), but not among patients with a longer disease duration or among those who had erosive RA versus nonerosive RA. In contrast, the levels were significantly higher in SE carriers than in noncarriers among patients with RA with a disease duration of [ge]141 months (P = 0.0037) and among those who had erosive RA (P = 0.000098), but not among patients who had a shorter disease duration or those who had nonerosive RA.The PADI4 RA risk haplotype is associated with increased anti-CCP levels in RA patients with disease of short duration, and PADI4 may play a role in early RA. In contrast, SE alleles are associated with increased anti-CCP levels in RA patients with very longstanding disease and in patients with erosive RA, suggesting that SE alleles play a role in very late RA.

Arthritis Research & Therapy (May 2007)

2007-05-14T09:10:00.000-07:00

Association of cerebrospinal fluid anti-ribosomal P protein antibodies with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus

We explored the relationship of antibodies to the whole ribosomal P proteins (P0, P1, P2) in cerebrospinal fluid (CSF) with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus (SLE). CSF were obtained from 71 SLE patients (52 patients with diffuse psychiatric/neuropsychological syndromes [diffuse NP-SLE] and 19 patients with neurologic syndromes or peripheral neuropathy [focal NP-SLE]) as well as from 24 patients with non-inflammatory neurological disease. IgG antibodies to the C-terminal 22 amino acids ribosomal P synthetic peptide (anti-PC22) and those to purified bovine ribosomal P proteins (P0, P1, P2) (anti-whole P) were determined by enzyme-linked immunosorbent assay, using affinity purified IgG anti-PC22 as standard. The concentrations of antibodies to epitopes other than the C-terminal 22 amino acids of ribosomal P proteins were calculated by subtracting anti-PC22 from anti-whole P (anti-PEX.C22). CSF anti-whole P were significantly elevated in diffuse NP-SLE compared with focal NP-SLE or control patients. By contrast, there were no significant differences in CSF anti-PC22 levels among the 3 groups. Of note, CSF anti-PEX.C22 were significantly elevated in diffuse NP-SLE compared with the other 2 groups. CSF anti-PEX.C22 were not significantly correlated with CSF anti-PC22, but with CSF antibodies against the recombinant ribosomal P0 protein lacking the C-terminal 22 amino acids (C22-depleted rP0). Moreover, CSF anti-PEX.C22 or CSF anti- C22-depleted rP0, but not CSF anti-PC22, were significantly correlated with CSF anti-neuronal cell antibodies (anti-N). These results indicate that CSF IgG antibodies to the epitopes other than the C-terminal 22 amino acids of ribosomal P proteins, which might contain one of the major targets of CSF anti-N, are associated with the development of diffuse NP-SLE.

Arthritis Research & Therapy

2007-05-14T09:06:00.000-07:00

Treatment of posttraumatic and focal osteoarthritic cartilage defects of the knee with autologous polymer-based three-dimensional chondrocyte grafts: 2-year clinical results

Autologous chondrocyte implantation (ACI) is a clinical effective procedure for the regeneration of articular cartilage defects. BioSeed(R)-C is a second generation ACI tissue engineering cartilage graft that is based on autologous chondrocytes embedded in a three-dimensional bioresorbable two component gel-polymer-scaffold. In the present prospective study, we have evaluated the short-to-mid-term efficacy of BioSeed(R)-C for the arthrotomic and arthroscopic treatment of posttraumatic and degenerative cartilage defects in a group of patients suffering from chronic posttraumatic and/or degenerative cartilage lesions of the knee. Clinical outcome was assessed in 40 patients with a two-year clinical follow-up before and at 3, 6, 12 and 24 months after implantation using the modified Cincinnati Score, the Lysholm Score, the Knee injury and Osteoarthritis Outcome Score (KOOS), and the current health assessment form (SF-36) of the International Knee Documentation Committee as well as histological analysis of second-look biopsies. Significant improvement (p <>

Annals of Rheumatic Disease (May 2007)

2007-05-14T09:04:00.000-07:00

Effect of chondroitin sulphate in symptomatic knee osteoarthritis: a multicentre, randomised, double-blind, placebo-controlled study

Objective: To evaluate the efficacy and tolerability of chondroitin sulphate (chondroitin sulphate) in knee osteoarthritis.
Patients and methods: A 24-week, randomised placebo-controlled trial of chondroitin sulphate (1 g/day) in patients with symptomatic knee osteoarthritis as measured on a visual analgue scale. Pain on daily activities and Lequesne’s Index were the primary efficacy criteria. Secondary outcomes included the rate of responders according to the outcome measures in rheumatoid arthritis clinical trials of the Osteoarthritis Research Society International (OMERACT-OARSI) criteria, quality of life, patient’s/physician’s global assessments and carry-over effect after treatment. Biochemical markers of bone (CTX-I), cartilage (CTX-II) and synovium (hyaluronic acid) metabolism were also measured. Safety was assessed by recording adverse events (AEs). Statistical analysis was performed on the inter-group differences in the intention-to-treat population.
Results: 307 patients were included in the study. 28 (9%) patients discontinued the study because of lack of efficacy or AEs. At the end of treatment, the decrease in pain was –26.2 (24.9) and –19.9 (23.5) mm and improved function was –2.4 (3.4) (–25%) and –1.7 (3.3) (–17%) in the chondroitin sulphate and placebo groups, respectively (p = 0.029 and 0.109). The OMERACT-OARSI responder rate was 68% in the chondroitin sulphate and 56% in the placebo group (p = 0.03). The investigator’s assessments and short form 12 (SF-12) physical component reported improvement more frequently in the chondroitin sulphate than in the placebo group (p = 0.044 and 0.021, respectively). No significant difference was observed between treatment groups for changes in biomarkers over 24 weeks. However, there was a significant difference between non-responders and responders according to the OARSI criteria for 24-week changes of CTX-I (p = 0.018) and CTX-II (p = 0.014). Tolerance was considered to be satisfactory.
Conclusion: This study failed to show an efficacy of chondroitin sulphate on the two primary criteria considered together, although chondroitin sulphate was slightly more effective than placebo on pain, OMERACT-OARSI response rate, investigator’s assessment and quality of life.

Annals of Rheumatic Disease (May 2007)

2007-05-14T09:03:00.000-07:00

Cognitive-behavioural therapies and exercise programmes for patients with fibromyalgia: state of the art and future directions

This review provides an overview of the effects of non-pharmacological treatments for patients with fibromyalgia (FM), including cognitive–behavioural therapy, exercise training programmes, or a combination of the two. After summarising and discussing preliminary evidence of the rationale of non-pharmacological treatment in patients with FM, we reviewed randomised, controlled trials for possible predictors of the success of treatment such as patient and treatment characteristics. In spite of support for their suitability in FM, the effects of non-pharmacological interventions are limited and positive outcomes largely disappear in the long term. However, within the various populations with FM, treatment outcomes showed considerable individual variations. In particular, specific subgroups of patients characterised by relatively high levels of psychological distress seem to benefit most from non-pharmacological interventions. Preliminary evidence of retrospective treatment analyses suggests that the efficacy may be enhanced by offering tailored treatment approaches at an early stage to patients who are at risk of developing chronic physical and psychological impairments.

Annals of Rheumatic Disease (May 2007)

2007-05-14T09:02:00.000-07:00

Clinical trial of a leucotriene B4 receptor antagonist, BIIL 284, in patients with rheumatoid arthritis

Background: Several clinical and experimental lines of evidence suggest that leucotriene B4 (LTB4), an arachidonic acid derivative with potent proinflammatory properties, plays a key role in the pathophysiology of rheumatoid arthritis (RA).
Objective: To evaluate the efficacy and safety of BIIL 284, an oral long-acting LTB4 receptor antagonist, as monotherapy for the treatment of patients with active RA.
Methods: This was a multi-centre, randomised, double-blind, placebo-controlled trial of patients with active RA of 3 months’ duration. A total of 342 patients were randomised to receive 5 mg, 25 mg or 75 mg of BIIL 284 or placebo. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR) 20.
Results: Although a higher percentage of ACR 20 responders was observed in the groups treated with 25 mg and 75 mg of BIIL 284 compared with those treated with placebo, no statistically significant differences were found between any of the three active treatment groups compared with the placebo group with regard to the primary or secondary end points. All trial treatments were safe and well tolerated.
Conclusions: This clinical trial demonstrates that treatment of patients with active RA with a potent oral long-acting LTB4 receptor antagonist produced only modest improvements in disease activity. The results of this trial support the conclusion that LTB4 is not a major contributor to the inflammatory process in RA.

Arthritis and Rheumatism (April 2007)

2007-04-09T10:25:00.000-07:00

Gabapentin in the treatment of fibromyalgia: A randomized, double-blind, placebo-controlled, multicenter trial

Objective

To assess the efficacy and safety of gabapentin in patients with fibromyalgia.

Methods

A 12-week, randomized, double-blind study was designed to compare gabapentin (1,200-2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0-10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of 30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the measure of effect.

Results

Gabapentin-treated patients displayed a significantly greater improvement in the BPI average pain severity score (P = 0.015; estimated difference between groups at week 12 = -0.92 [95% confidence interval -1.75, -0.71]). A significantly greater proportion of gabapentin-treated patients compared with placebo-treated patients achieved response at end point (51% versus 31%; P = 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated.

Conclusion

Gabapentin (1,200-2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia.

Arthritis and Rheumatism (April 2007)

2007-04-09T09:59:00.000-07:00

Association between valgus and varus alignment and the development and progression of radiographic osteoarthritis of the knee

Objective

Although knee malalignment is assumed to correlate with knee osteoarthritis (OA), it is still unknown whether malalignment precedes the development of OA or whether it is a result of OA. The aim of this study was to assess the relationship between malalignment and the development of knee OA as well as progression of knee OA.

Methods

A total of 1,501 participants in the Rotterdam study were randomly selected. Knee OA at baseline and at followup (mean followup 6.6 years) was scored according to the Kellgren/Lawrence (K/L) grading system. Alignment was measured by the femorotibial angle on radiographs at baseline. Multivariable logistic regression for repeated measurements was used to analyze the association of malalignment with the development and progression of OA.

Results

Of 2,664 knees, 1,012 (38%) were considered to have normal alignment, 693 (26%) had varus alignment, and 959 (36%) had valgus alignment. A comparison of valgus alignment and normal alignment showed that valgus alignment was associated with a borderline significant increase in development of knee OA (odds ratio [OR] 1.54, 95% confidence interval [95% CI] 0.97-2.44), and varus alignment was associated with a 2-fold increased risk (OR 2.06, 95% CI 1.28-3.32). Stratification for body mass index showed that this increased risk was especially seen in overweight and obese individuals but not in non-overweight persons. The risk of OA progression was also significantly increased in the group with varus alignment compared with the group with normal alignment (OR 2.90, 95% CI 1.07-7.88).

Conclusion

An increasing degree of varus alignment is associated not only with progression of knee OA but also with development of knee OA. However, this association seems particularly applicable to overweight and obese persons.

Annal of Rheumatic Diseases (April 2007)

2007-04-09T09:44:00.000-07:00

Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system

Aim: Neuropsychiatric systemic lupus erythematosus (NPSLE) isa serious treatment-resistant phenotype of systemic lupus erythematosus.A standard treatment for NPSLE is not available. This reportdescribes the clinical and laboratory tests of 10 patients withNPSLE before and after rituximab treatment, including changesin lymphocyte phenotypes.

Methods: Rituximab was administered at different doses in 10patients with refractory NPSLE, despite intensive treatment.

Results: Treatment with rituximab resulted in rapid improvementof central nervous system-related manifestations, particularlyacute confusional state. Rituximab also improved cognitive dysfunction,psychosis and seizure, and reduced the SLE Disease ActivityIndex Score at day 28 in all 10 patients. These effects lastedfor >1 year in five patients. Flow cytometric analysis showedthat rituximab down regulated CD40 and CD80 on B cells and CD40L,CD69 and inducible costimulator on CD4+ T cells.

Conclusions: Rituximab rapidly improved refractory NPSLE, asevident by resolution of various clinical signs and symptomsand improvement of radiographic findings. The down regulationof functional molecules on B and T cells suggests that rituximabmodulates the interaction of activated B and T cells throughcostimulatory molecules. These results warrant further analysisof rituximab as treatment for NPSLE.

Rheumatology Oxford (April 2007)

2007-04-09T09:32:00.000-07:00

Pregnancy in rheumatology patients exposed to anti-tumour necrosis factor (TNF)- therapy

Objectives. Anti-tumour necrosis factor (TNF)- therapies areconsidered category B drugs for pregnancy. Although sometimesprescribed to women of reproductive age, data in humans arelimited with regard to safety for a developing fetus. The objectivesof the present article are to report experience of anti-TNF-use in pregnancy, and review the international literature.

Methods. Since 1999 the present authors have used anti-TNF-(infliximab, etanercept, adalimumab) to treat patients withvarious chronic rheumatic conditions. All patients were prospectivelyfollowed during their treatment time and data were systematicallycollected.

Results. In a group of 442 patients treated with anti-TNF, threewomen with RA unexpectedly became pregnant One treated withetanercept chose a therapeutic termination at two and a halfmonths, despite of any ultrasound anomaly, and satisfactoryfetal growth. The other two patients (one with adalimumab exposureand one with etanercept exposure) delivered healthy infants.The following perinatal complications were observed: prematurity,neonatal jaundice, neonatal urinary Escherichia coli infectionand adrenal congenital hyperplasia of probable hereditary origin.

Conclusions. To date, there is no evidence that TNF- antagonistsare associated with embryo toxicity, teratogenicity or increasedpregnancy loss. However, caution should be taken when anti-TNFagents are used during pregnancy, as human experience is stillextremely limited, particularly in patients with rheumatic diseasesamong whom there are several alarming reports. The potentialrisk should be balanced against the known risks associated withDMARDs and steroid therapy. Large registries will be necessarybefore firm conclusions can be drawn.

Rheumatology Oxford (April 2007)

2007-04-09T09:28:00.000-07:00

Urine protein-to-creatinine ratio in an untimed urine collection is a reliable measure of proteinuria in lupus nephritis

Objective. To evaluate the accuracy of urine protein-to-creatinine(P/C) ratio in an untimed urine specimen as compared with 24h total protein excretion for measurement of proteinuria inpatients with lupus nephritis.

Methods. Proteinuria in patients with lupus nephritis was assessedby 24 h total protein excretion and spot urine P/C ratio. Correlationand limits of agreement between the two methods were evaluated.The discriminant cutoff values for spot urine P/C ratio in predicting24 h protein ‘threshold’ excretion of 0.3, 0.5,1.0 and 3.5 g/day were determined using receiver operating characteristiccurves.

Results. A total of 165 samples were available for assessmentwith 21.8% excluded due to inadequate collection. A strong correlation(r = 0.91, P <> and 24 h urine protein excretion. Bland–Altman plot showedthe two tests had acceptable limits of agreement in low levelof protein excretion (–0.86 to +0.92 g/day when proteinexcretion was <2.0> protein excretion increased. The spot urine P/C ratios of 0.45(sensitivity 0.92; specificity 0.88), 0.7 (0.92; 0.89) and 1.84(1.0; 0.86) mg/mg reliably predicted 24 h urine total proteinequivalent ‘thresholds’ at 0.5, 1.0 and 3.5 g/day.

Conclusion. This study supports the recommendation of usingspot urine P/C ratio in screening and monitoring proteinuriain patients with lupus nephritis. However, in assessing theexact amount of proteinuria, the urine P/C ratio may have unacceptablywide limits of agreement in high protein excretion range.

Rheumatology Oxford (April 2007)

2007-04-09T09:22:00.000-07:00

Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs

Objective. To assess safety and efficacy of repeated B-celldepletion with rituximab in patients with rheumatoid arthritis(RA).

Methods. Thirty-seven patients with refractory RA entered intoa programme of repeated B-lymphocyte depletion (up to 5 cycles,89 cycles in total) with protocols based on the anti-CD20 monoclonalantibody, rituximab, have been observed over periods of >5yrs (n = 22) or 3–5 yrs (n = 14).

Results. Twenty two subjects have been followed up for >5yrs. Average duration of benefit per cycle was 15 months (maximum43 months), and time to re-treatment 20 months. Nineteen patientsremain on the programme. Patients were withdrawn for lack ofefficacy (n = 5), hypersensitivity infusion reaction (n = 1),brevity of response (n = 8), or occurrence of adverse respiratoryevents (n = 1). Sixteen major lower respiratory events occurredduring the 180 patient-yrs of follow-up. Of these only one hadlow IgG. In patients receiving rituximab ± cyclophosphamide(cy) carcinomata have developed as follows: breast (3, +cy),ovary (1, +cy), transitional cell (1, +cy), and renal cell (1,–cy). Falls in total immunoglobulin levels to below thenormal range occurred in 12 patients for IgM (undetectable levelsin three after repeated cycles), seven for IgG and one for IgA,not taking into account patients who started off with low immunoglobulinlevels before the first cycle.

Conclusion. Repeated B-lymphocyte depletion over a 5-yr periodappears to be an acceptable and relatively well-tolerated therapyin RA with a relatively high rate of continuation. Long-termeffects on immunoglobulin levels require surveillance.

Current and Experimental Rheumatology (March 2007)

2007-04-09T09:05:00.000-07:00

Fibromyalgia treatment update.

Current Opinion in Rheumatology. 19(2):111-117, March 2007.
Rooks, Daniel S

Abstract:
Purpose of review: Fibromyalgia is a common chronic pain disorder characterized by complex symptomatology and few consistently effective treatments. The purpose of this review is to highlight the recent literature from April 2005 through September 2006 involving treatment options.

Recent findings: Prior evidence suggests that medication and self-management approaches to care can improve symptoms, function and well-being in this patient population. Recent studies examining the efficacy of two serotonin and norepinephrine-reuptake inhibitors - duloxetine and milnacipran - and the anticonvulsant pregabalin are encouraging. Studies evaluating different forms of exercise continue to support the belief that increased physical activity is an essential component of any treatment plan for the patient with fibromyalgia. Three studies added to the understanding of treatment adherence. Finally, three studies evaluating the efficacy of acupuncture in the treatment of fibromyalgia showed conflicting results, but added to the knowledge needed for clinicians to have substantive conversations with patients.

Summary: Recent studies support the recommendation of a multimodal approach to treatment involving individualized, evidence-based pharmacotherapy and self-management. Treatment goals should include the improvement of symptoms, primarily pain and sleep, and the promotion of positive health behaviors with the aim of improving physical function and emotional well-being.

Arthritis Reasearch and Therapy (Issue 2 - March 2007)

2007-04-09T08:43:00.000-07:00

A pilot study of IL-1 inhibition by anakinra in acute gout

Monosodium urate crystals stimulate monocytes and macrophages to release IL-1β through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study.

Rheumatology - Oxford

2007-03-23T11:48:00.000-07:00

A comparison of clinical vs ultrasound determined synovitis in rheumatoid arthritis utilizing gray-scale, power Doppler and the intravenous microbubble contrast agent ‘Sono-Vue’

Objectives. Synovitis in rheumatoid arthritis (RA) is assessedclinically by the presence of joint tenderness and swelling.Synovial thickening and increased vascularity may also be detectedby high-resolution ultrasonography (US) and power Doppler (PD).This study investigated the relationship between clinical andsonographic features of synovial disease utilizing US, PD andthe contrast agent Sono-Vue®.

Methods. Forty RA patients were recruited. One proximal inter-phalangealor metacarpophalangeal joint was selected per patient, as beingunambiguously either: swollen and tender, just swollen, justtender or neither swollen nor tender (Nil). Ten joints wereselected per clinical group. On US, the mean synovial thicknesswas measured and synovial hypertrophy and erosions were gradedsubjectively. Synovial vascularity demonstrated by PD was scoredsubjectively pre- and post-contrast.

Results. All grades of synovial vascularity were found in eachclinical group including the Nil group. There were significantdifferences between the four clinical groups for both synovialhypertrophy (P = 0.024) and PD scores pre- (P = 0.022) and post-(P = 0.039) contrast. Tender-only joints showed significantlyless vascularity than other groups. Post-contrast, the medianPD scores increased in all but the Nil group, in some casesfrom the normal to abnormal range.
Conclusion.
Synovitis demonstrated by US and PD is not predictedby patterns of disease as described by joint swelling and tendernessdespite unambiguous selection of joints. Synovial vascularitywas the least in tender-only joints and was heterogeneous inall other groups, including Nil joints. These findings questionthe reliability of traditional clinical signs in RA synovitisassessment.

Annals of Rheumatic Disease - March 2007

2007-03-23T11:01:00.001-07:00

Comparison of Disease Activity Score (DAS)28- erythrocyte sedimentation rate and DAS28- C-reactive protein threshold values
Objective: To estimate the disease activity score (DAS)28-C-reactiveprotein (CRP) threshold values that correspond to DAS28-erythrocytesedimentation rate (ESR) values for remission, low disease activityand high disease activity in patients with rheumatoid arthritis.

Methods: DAS28 data were analysed using a large observationalstudy (Institute of Rheumatology Rheumatoid Arthritis) databaseof 6729 patients with rheumatoid arthritis. Firstly, the relationshipbetween the DAS28-ESR and the DAS28-CRP values was analysed.Secondly, the best DAS28-CRP trade-off values for each thresholdwere calculated using receiver operating characteristic (ROC)curves.

Results: The correlation coefficient of ESR versus CRP was 0.686,whereas that of DAS28-ESR versus DAS28-CRP was 0.946, showingthe strong linear relationship between DAS28-ESR and DAS28-CRPvalues. DAS28-CRP threshold values corresponding to remission,low disease activity and high disease activity were 2.3, 2.7and 4.1, respectively. The sensitivity and specificity fromthe ROC curves were gradually reduced as DAS28 values becamelower.

Conclusions: This study showed that DAS28-CRP and DAS28-ESRwere well correlated, but the threshold values should be reconsidered.As the results were derived from only Japanese patients, itis essential to compare DAS28-CRP threshold values in peopleof other ethnic groups.

Annals of Rheumatic Disease - March 2007

2007-03-23T10:46:00.000-07:00

Prediction models for rheumatoid arthritis during diagnostic investigation: evaluation of combinations of rheumatoid factor, anti-citrullinated protein/peptide antibodies and the human leucocyte antigen-shared epitope

Objectives: To calculate the probabilities for rheumatoid arthritisin a consecutive cohort of patients during diagnostic investigation.Different logistic regression models evaluating the value ofhuman leucocyte antigen (HLA)-shared epitope determination andtesting for rheumatoid factor and anti-citrullinated protein/peptideantibodies (ACPA) were fitted.

Methods: 1003 consecutive patients were included in the study,presenting a new diagnostic problem for which rheumatoid arthritiswas included in the differential diagnosis. All patients weretested for ACPA, rheumatoid factor and HLA-shared epitope.

Results: After 1 year, diagnoses were established: 153 patientshad definite rheumatoid arthritis and 629 patients had rheumatoidarthritis excluded. Rheumatoid factor, used as a continuousmarker, is useful in evaluating the probability for rheumatoidarthritis. Combined rheumatoid factor and shared epitope testingmay provide additional predictive information, but combinedACPA and rheumatoid factor testing is superior. The redundancyof shared epitope testing in a model that includes ACPA testingcan be explained by the high association between ACPA and sharedepitope both in patients with rheumatoid arthritis and in thosewith non-rheumatoid arthritis. The value of rheumatoid factortesting increased if patients presented with at least one swollenjoint at baseline.

Conclusion: Valid probabilities for rheumatoid arthritis duringroutine diagnostic investigation were calculated, and showedthat the potential additional value of shared epitope testingdisappears when ACPA testing is available. Combined rheumatoidfactor and ACPA testing is useful, especially when rheumatoidfactor is considered as a continuous parameter reflecting anincreasing probability for rheumatoid arthritis at higher rheumatoidfactor titres. The value of (continuous) rheumatoid factor testingincreases when the a priori chance is higher.

Arthritis and Rheumatism - March 2007

2007-03-23T10:33:00.000-07:00

Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout

Objective
To evaluate the efficacy, immunogenicity, and tolerability of intravenous (IV) PEGylated recombinant mammalian urate oxidase (PEG-uricase) for the treatment of severe gout.
Methods
Single infusions of PEG-uricase (at doses ranging from 0.5 mg to 12 mg) were administered to 24 patients (6 cohorts of 4 patients each) in a phase I clinical trial. Plasma uricase activity (pUox), the plasma urate concentration (pUAc), and the uric acid-to-creatinine ratio (UAc:Cr) in urine were monitored for 21 days after dosing. Adverse events and the IgG antibody response to PEG-uricase were followed up for 35 days.
Results
All patients completed the trial. Maximum pUox was linearly related to the IV dose of PEG-uricase, the area under the curve (AUC) value increased linearly (up to a dose of 8 mg), and the pUox half-life was 6.4-13.8 days. After doses of 4-12 mg, the pUAc fell within 24-72 hours, from a mean ± SD value of 11.1 ± 0.6 mg/dl to 1.0 ± 0.5 mg/dl; the AUC value for the pUAc was equivalent to maintaining the pUAc at 1.2-4.7 mg/dl for 21 days postinfusion. The UAc:Cr ratio in urine fell in parallel with the pUAc. IgG antibodies to PEG-uricase, mostly IgG2 and specific for PEG, developed in 9 patients, who had more rapid enzyme clearance but no allergic reactions. All adverse events were mild to moderate, with gout flares being most common.
Conclusion
The bioavailability, efficacy, and tolerability of IV PEG-uricase were greater than the bioavailability, efficacy, and tolerability observed in a previous phase I trial of subcutaneous PEG-uricase. Infusing 4-12 mg of PEG-uricase every 2-4 weeks should maintain the pUAc well below the therapeutic target of 6 mg/dl and greatly reduce renal uric acid excretion. This treatment could be effective in depleting expanded tissue urate stores in patients with chronic or tophaceous gout.

Arthritis and Rheumatism - March 2007

2007-03-23T10:24:00.000-07:00

Glucocorticoids and cardiovascular events in rheumatoid arthritis: A population-based cohort study
Abstract
Objective
To determine the relationship between glucocorticoid exposure and cardiovascular (CV) events in patients with rheumatoid arthritis (RA).
Methods
A total of 603 adult residents of Rochester, Minnesota with incident RA between 1955 and 1995 were followed up through their medical records for a median of 13 years (total of 9,066 person-years). Glucocorticoid exposure was defined 3 ways: tertiles of cumulative exposure; recent use ( more than 3 months) versus past use ( more than 3 months); and average daily dosage ( more 7.5 mg/day or more 7.5 mg/day). CV events, including myocardial infarction, heart failure, and death from CV causes, were defined according to validated criteria. Cox regression models were adjusted for demographic features, CV risk factors, and RA characteristics.
Results
Rheumatoid factor (RF)-negative patients with exposure to glucocorticoids were not at increased risk of CV events, irrespective of the glucocorticoid dosage or timing of use, as compared with the reference group of RF-negative patients who had never been exposed to glucocorticoids. In contrast, RF-positive patients were at increased risk of CV events, particularly with higher cumulative exposure, higher average daily dosage, and recent use of glucocorticoids. RF-positive patients with high cumulative exposure to glucocorticoids had a 3-fold increased risk of CV events (hazard ratio 3.06 [95% confidence interval 1.81-5.18]), whereas RF-negative patients with high cumulative exposure were not at increased risk (hazard ratio 0.85 [95% confidence interval 0.39-1.87]).
Conclusion
RF-positive but not RF-negative patients were at increased risk of CV events following exposure to glucocorticoids. These findings suggest that glucocorticoids interact with RF status to modulate the occurrence of CV events in patients with RA. The mechanisms underlying this interaction are unknown and should be the subject of further research.

Arthritis and Rheumatism - March 2007

2007-03-23T10:15:00.000-07:00

Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than does treatment with azathioprine plus methylprednisolone in patients with proliferative lupus nephritis
Abstract
Objective
To analyze the effect of treatment with either pulse cyclophosphamide (CYC) or azathioprine (AZA) combined with methylprednisolone (MP), on serial biopsy results in patients with proliferative lupus nephritis, and to evaluate the predictive value of various histopathologic and clinical parameters with regard to disease outcome.
Methods
Biopsy specimens from patients with proliferative lupus nephritis, obtained at study entry and after 2 years of therapy, were scored according to a standardized method, and results assessed in relation to disease outcome.
Results
Of the 87 patients originally enrolled, 39 underwent repeat biopsy. These patients were representative of the overall group, both at entry and at 2-year followup. The median activity index changed from 8.0 to 2.7 (no differences between the treatment groups). In the group treated with AZA plus MP (AZA group), the increase in the median chronicity index (from 2.7 to 3.8) was larger than that in the CYC group (from 2.7 to 3.0) (P = 0.050). In multivariate analyses, renal function at enrollment and after 2 years was the best predictor of renal function at the last visit, while none of the histopathologic variables (either at entry or at 2 years) added to this prediction. Comparing patients whose disease transitioned to class II with those who had persistent proliferative lupus nephritis revealed no differences between the treatment groups at either time point, and no clinical differences at 2 years. However, a higher serum creatinine level at entry and greater proteinuria at last visit were characteristic of patients who still had proliferative lupus nephritis at 2 years.
Conclusion
These results indicate that, although both CYC and AZA are effective in reducing active lesions in lupus nephritis, progression of chronic lesions is more effectively halted by CYC. Variables assessed by repeat biopsy do not predict clinical outcome.

Arthritis and Rheumatism - March 2007

2007-03-23T10:01:00.000-07:00

The United States rheumatology workforce: Supply and demand, 2005-2025
Abstract
ObjectiveTo develop and apply a model that allows prediction of current and future supply and demand for rheumatology services in the US.
MethodsA supply model was developed using the age and sex distribution of current physicians, retirement and mortality rates, the number of fellowship slots and fill rates, and practice patterns of rheumatologists. A Markov projection model was used to project needs in 5-year increments from 2005 to 2025.
ResultsThe number of rheumatologists for adult patients in the US in 2005 is 4,946. Male and female rheumatologists are equally distributed up to age 44; above age 44, men predominate. The percent of women in adult rheumatology is projected to increase from 30.2% in 2005 to 43.6% in 2025. The mean number of visits per rheumatologist per year is 3,758 for male rheumatologists and 2,800 for female rheumatologists. Assuming rheumatology supply and demand are in equilibrium in 2005, the demand for rheumatologists in 2025 is projected to exceed supply by 2,576 adult and 33 pediatric rheumatologists. The primary factors in the excess demand are an aging population which will increase the number of people with rheumatic disorders, growth in the Gross Domestic Product, and flat rheumatology supply due to fixed numbers entering the workforce and to retirements. The productivity of younger rheumatologists and women, who will make up a greater percentage of the future workforce, may also have important effects on supply. Unknown effects that could influence these projections include technology advances, more efficient practice methods, changes in insurance reimbursements, and shifting lifestyles. Current data suggest that the pediatric rheumatology workforce is experiencing a substantial excess of demand versus supply.
ConclusionBased on assessment of supply and demand under current scenarios, the demand for rheumatologists is expected to exceed supply in the coming decades. Strategies for the profession to adapt to this changing health care landscape include increasing the number of fellows each year, utilizing physician assistants and nurse practitioners in greater numbers, and improving practice efficiency.

NEJM - March 22nd 2007

2007-03-23T09:59:00.000-07:00

NALP1 in Vitiligo-Associated Multiple Autoimmune Disease

ABSTRACT

Background Autoimmune and autoinflammatory diseases involveinteractions between genetic risk factors and environmentaltriggers. We searched for a gene on chromosome 17p13 that contributesto a group of epidemiologically associated autoimmune and autoinflammatorydiseases. The group includes various combinations of generalizedvitiligo, autoimmune thyroid disease, latent autoimmune diabetesin adults, rheumatoid arthritis, psoriasis, pernicious anemia,systemic lupus erythematosus, and Addison's disease.

Methods We tested 177 single-nucleotide polymorphisms (SNPs)spanning the 17p13 linkage peak for association with diseaseand identified a strong candidate gene. We then sequenced DNAin and around the gene to identify additional SNPs. We carriedout a second round of tests of association using some of theseadditional SNPs, thus elucidating the association with diseasein the gene and its extended promoter region in fine detail.

Results Association analyses resulted in our identifying asa candidate gene NALP1, which encodes NACHT leucine-rich-repeatprotein 1, a regulator of the innate immune system. Fine-scaleassociation mapping with the use of DNA from affected familiesand additional SNPs in and around NALP1 showed an associationof specific variants with vitiligo alone, with an extended autoimmuneand autoinflammatory disease phenotype, or with both. Conditionallogistic-regression analysis of NALP1 SNPs indicated that atleast two variants contribute independently to the risk of disease.

Conclusions DNA sequence variants in the NALP1 region are associatedwith the risk of several epidemiologically associated autoimmuneand autoinflammatory diseases, implicating the innate immunesystem in the pathogenesis of these disorders.

Annals of Internal Medicine - March 2007

2007-03-23T09:52:00.000-07:00

Comparison of Treatment Strategies in Early Rheumatoid Arthritis

Objective: To evaluate whether the initial clinical and radiographicefficacy of combination therapies could be maintained duringthe second year of follow-up in patients with early rheumatoidarthritis.

Design: Randomized, controlled clinical trial with blindedassessors.

Setting: 18 peripheral and 2 university medical centers inthe Netherlands.

Patients: 508 patients with early active rheumatoid arthritis.

Intervention: Sequential monotherapy (group 1), step-up combinationtherapy (group 2), initial combination therapy with taperedhigh-dose prednisone (group 3), or initial combination therapywith infliximab (group 4). Trimonthly treatment adjustmentswere made to achieve low disease activity.

Measurements: Primary end points were functional ability (HealthAssessment Questionnaire) and Sharp–van der Heijde scorefor radiographic joint damage.

Results: Groups 3 and 4 had more rapid clinical improvementduring the first year; all groups improved further to a meanfunctional ability score of 0.6 (overall, P = 0.257) and42% were in remission (overall, P = 0.690) during the secondyear. Progression of joint damage remained better suppressedin groups 3 and 4 (median scores of 2.0, 2.0, 1.0, and 1.0 ingroups 1, 2, 3, and 4, respectively [P = 0.004]). After2 years, 33%, 31%, 36%, and 53% of patients in groups 1 through4, respectively, were receiving single-drug therapy for initialtreatment. There were no significant differences in toxicity.

Limitations: Patients and physicians were aware of the allocatedgroup, and the assessors were blinded.

Conclusions: Currently available antirheumatic drugs can behighly effective in patients with early rheumatoid arthritisin a setting of tight disease control. Initial combination therapiesseem to provide earlier clinical improvement and less progressionof joint damage, but all treatment strategies eventually showedsimilar clinical improvements. In addition, combination therapycan be withdrawn successfully and less treatment adjustmentsare needed than with initial monotherapies.

Rheumatology (January 2007 issue)

2007-01-27T21:06:00.000-08:00

Hospitalization for gastrointestinal bleeding associated with non-steroidal anti-inflammatory drugs among elderly patients using low-dose aspirin: a retrospective cohort study

E. Rahme1, M. Bardou2, K. Dasgupta1, Y. Toubouti1, J. Ghosn1 and A. N. Barkun1,3

Objectives.
Many elderly patients are prescribed both low-dose aspirin (ASA), for cardiovascular protection and non-steroidal anti-inflammatory drugs (NSAIDs) for pain control. Compared with non-selective NSAIDs (NS-NSAIDs), celecoxib has a superior gastrointestinal (GI) safety profile in general. It is unclear, however, whether this fact holds good among patients taking ASA.
We compared GI hospitalization rates among elderly patients taking celecoxib, NS-NSAIDs, celecoxib and ASA or NS-NSAIDs and ASA.
Methods.
This was a retrospective cohort study using Quebec government databases. All patients 65 yrs of age or older who filled a prescription for celecoxib or an NS-NSAID between April 1999 and December 2002 were included. Cox regression models were used to compare the GI hospitalization rates between the four exposure categories adjusting for potential confounders.
Results.
A total of 332 491 patients were included. Among 1 522 307 celecoxib prescriptions, 430 214 were filled by patients concurrently receiving ASA (celecoxib and ASA); 195 369 of 863 646 NS-NSAID prescriptions were filled by patients receiving ASA (NS-NSAID and ASA). Celecoxib without ASA was less likely than NS-NSAID without ASA to be associated with GI hospitalization [hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.33–0.50]; celecoxib and ASA was also less likely to be associated with GI hospitalization than NS-NSAID and ASA (HR 0.62, 95% CI 0.48–0.80); GI hospitalization rates were similar for celecoxib and ASA and NS-NSAID without ASA (HR 1.01, 95% CI 0.81–1.25).
Conclusion.
Among elderly patients receiving cardiovascular protection with ASA and pain control with anti-inflammatory drugs, celecoxib may be safer with regards to GI toxicity than NS-NSAIDs.

Annals of the Rheumatic Diseases (January 2007 issue)

2007-01-27T20:33:00.000-08:00

Body mass index associated with onset and progression of osteoarthritis of the knee but not of the hip: The Rotterdam Study

M Reijman1, H A P Pols3, A P Bergink2,3, J M W Hazes4, J N Belo5, A M Lievense5 and S M A Bierma-Zeinstra5

Objective: To investigate the relationship between body mass index (BMI) and the incidence and progression of radiological knee as well as of radiological hip osteoarthritis.
Design: Cohort study.
Setting: Population based.
Participants: 3585 people aged >=55 years were selected from the Rotterdam Study, on the basis of the availability of radiographs of baseline and follow-up.
Main outcome measures: Incidence of knee or hip osteoarthritis was defined as minimally grade 2 at follow-up and grade 0 or 1 at baseline. The progression of osteoarthritis was defined as a decrease in joint space width.
Methods: x Rays of the knee and hip at baseline and follow-up (mean follow-up of 6.6 years) were evaluated. BMI was measured at baseline.
Results: A high BMI (>27 kg/m2) at baseline was associated with incident knee osteoarthritis (odds ratio (OR) 3.3), but not with incident hip osteoarthritis. A high BMI was also associated with progression of knee osteoarthritis (OR 3.2). For the hip, a significant association between progression of osteoarthritis and BMI was not found.
Conclusion: On the basis of these results, we conclude that BMI is associated with the incidence and progression of knee osteoarthritis. Furthermore, it seems that BMI is not associated with the incidence and progression of hip osteoarthritis.

Annals of the Rheumatic Diseases (January 2007 issue)

2007-01-27T20:03:00.000-08:00

Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis

By van der Laken, C J, Voskuyl, A E, Roos, J C, Stigter van Walsum, M, de Groot, E R, Wolbink, G, Dijkmans, B A C, Aarden, L A

Background:
Many patients with rheumatoid arthritis are currently successfully treated with infliximab (anti-tumour necrosis factor); however, about 30% of the patients do not respond to infliximab. One of the postulated hypotheses of not responding is the fast clearance of infliximab due to the development of infliximab–anti-infliximab complexes.
Objective:
To investigate the in vivo mechanism of not responding and the role of human anti-chimeric antibodies (HACAs) by using radiolabelled infliximab.
Methods:
Two responding and two non-responding patients with rheumatoid arthritis, infused with radiolabelled infliximab, were investigated by both imaging and serum analysis.
Results:
Images showed predominant presence of infliximab in blood up to 24 h, with a trend of faster blood clearance and of higher liver/spleen uptake in a non-responding patient. Clinically inflamed joints showed uptake of the drug. The HACA level in the non-responders was high (1641 and 1008 U/ml), but low or not detectable in responders. Sucrose gradients of serum showed antibody complexes in both non-responders. Various sizes of antibody complexes, including very large ones, were observed in a non-responder who developed a serious infusion reaction.
Conclusion:
Formation of infliximab–anti-infliximab complexes were found in non-responders due to the presence of large amounts of HACA. This finding, supported by both imaging and serum analysis data, may explain failure of infliximab treatment.

Arthritis & Rheumatism (January 2007 issue)

2007-01-27T19:49:00.000-08:00

Outcomes after switching from one anti-tumor necrosis factor agent to a second anti-tumor necrosis factor agent in patients with rheumatoid arthritis

Kimme L. Hyrich, Mark Lunt, Kath D. Watson, Deborah P. M. Symmons, Alan J. Silman *, British Society for Rheumatology Biologics Register
University of Manchester, Manchester, UK

Abstract
Objective
Patients with rheumatoid arthritis (RA) who experience treatment failure with one anti-tumor necrosis factor (anti-TNF) agent, due to either inefficacy or toxicity, are frequently switched to a second anti-TNF agent, although the benefits of switching are unknown. The present study was undertaken to compare drug continuation rates between the first course and second course of anti-TNF therapy.
Methods
The study involved a prospective cohort of RA patients from a UK national register of new anti-TNF treatment starts (n = 6,739; 876 starting adalimumab, 2,826 starting etanercept, and starting 3,037 infliximab). Over a mean 15 months of followup, 841 patients stopped taking the first drug due to inefficacy and 1,023 stopped the first drug due to toxicity, of whom 503 and 353, respectively, were switched to a second anti-TNF agent. Kaplan-Meier survival curves were plotted to determine continuation rates for each course, and Cox regression was used to compare each course for the risk of stopping and the reason for stopping (inefficacy or toxicity).
Results
Overall, 73% of patients who switched to a second anti-TNF agent remained on the new therapy by the end of followup. First drug discontinuation due to inefficacy was associated with an increased rate of second drug discontinuation due to inefficacy (hazard ratio [HR] 2.7, 95% confidence interval [95% CI] 2.1-3.4) but not toxicity (HR 1.1, 95% CI 0.9-1.5). Similarly, first drug discontinuation due to toxicity was associated with an increased rate of second drug discontinuation due to toxicity (HR 2.3, 95% CI 1.9-2.9) but not inefficacy (HR 1.2, 95% CI 0.8-1.6).
Conclusion
RA patients who are switched to a second anti-TNF drug have high rates of continuation, although among those who must discontinue treatment, the reasons for stopping a second drug are related to the reasons for stopping the first drug. This large data set from the UK provides the first estimates of the magnitude of these effects in patients with long-standing severe RA.

Arthritis & Rheumatism (January 2007 issue)

2007-01-27T19:43:00.000-08:00

Effects of short-term infliximab therapy on autoantibodies in systemic lupus erythematosus

By Martin Aringer, Günter Steiner, Winfried B. Graninger, Elisabeth Höfler, Carl W. Steiner, Josef S. Smolen

Abstract
Objective
To analyze changes in autoantibodies occurring in patients with systemic lupus erythematosus (SLE) treated with 4 infusions of the chimeric anti-tumor necrosis factor (TNF) antibody infliximab.
Methods
In an open-label safety study, 7 patients with SLE were treated with infliximab at weeks 0, 2, 6, and 10 in combination with azathioprine or methotrexate. Antibodies to double-stranded DNA (dsDNA) were determined by radioimmunoassay and the Crithidia luciliae indirect immunofluorescence assay; anticardiolipin antibodies (aCL) and antibodies to histone and chromatin were measured by enzyme-linked immunosorbent assay. Antihistone antibodies were also analyzed by immunoblotting. Peripheral blood mononuclear cells from healthy individuals and SLE patients were incubated for 2 weeks with or without TNF. TNF was removed by washing and by the addition of infliximab. Apoptotic cells were stained with annexin V and analyzed by flow cytometry.
Results
Autoantibodies to dsDNA increased in 5 of 7 patients. Histone, chromatin, and IgM aCL levels were increased in 4 of 7, 6 of 7, and 4 of 7 patients, respectively, peaking 4-10 weeks after the last infliximab infusion, but falling to baseline levels or lower thereafter. In the in vitro experiments, TNF withdrawal after long-term incubation with recombinant human TNF led to increased percentages of apoptotic cells.
Conclusion
While TNF blockade was clinically effective, the majority of SLE patients treated with infliximab showed an increase in autoantibodies to nuclear antigens and phospholipids. These increases were transient and were not associated with disease flares. Increased availability of apoptotic antigens after TNF blockade may play a role in the autoantibody formation induced by TNF blockade.