Management of nonresponse to rituximab in rheumatoid arthritis: Predictors and outcome of re-treatment
E. M. Vital 1, S. Dass 1, A. C. Rawstron 2, M. H. Buch 1, V. Goëb 1, K. Henshaw 1, F. Ponchel 1, P. Emery 1 *
1University of Leeds, Chapel Allerton Hospital and Leeds Teaching Hospitals National Health Service Trust, Leeds, UK
2St. James’s Institute of Oncology, Leeds, UK
email: P. Emery (p.emery@leeds.ac.uk)
*Correspondence to P. Emery, Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK

Drs. Vital, Dass, and Buch have received honoraria from Roche (less than $10,000 each).
Dr. Emery has received consulting fees, speaking fees, and/or honoraria from UCB and Centocor (less than $10,000 each) and has served as a study investigator for Centocor.
Funded by:
National Institute of Health Research
French Society of Rheumatology

ABSTRACT

Objective
A proportion of patients with rheumatoid arthritis (RA) have disease that fails to respond to an initial cycle of rituximab. Using highly sensitive flow cytometry (HSFC), it has been shown that most patients who do not exhibit a response, as measured using the European League Against Rheumatism (EULAR) criteria, have persistent circulating B cell levels at week 2 after initial treatment with rituximab. This study was undertaken to examine whether an additional cycle of rituximab would improve B cell depletion and clinical response in patients whose disease did not respond to the initial cycle.

Methods
Patients with RA (n = 158) were treated with a first cycle of rituximab (2 infusions of 1 gm each). Clinical responses were assessed using EULAR criteria, and patients were categorized as either first-cycle responders or first-cycle nonresponders. Baseline characteristics of first-cycle nonresponders (n = 38) and first-cycle responders (n = 65) with complete data were compared. First-cycle nonresponders (n = 25) were treated with a second cycle of rituximab at least 6 months after the first cycle. HSFC was performed at baseline, immediately prior to the second infusion (week 2), 1 month after the second infusion (week 6), and then every 3 months for each cycle of rituximab. Complete B cell depletion was defined as being <0.0001 × 109 cells/liter.

Results
At baseline, the number of preplasma cells was significantly higher in first-cycle nonresponders than in first-cycle responders (P = 0.003). Following the first infusion of the first cycle of rituximab, only 9% of first-cycle nonresponders (3 of 34) exhibited complete depletion of B-lineage cells, compared with 37% of first-cycle responders (22 of 59) (P = 0.007). Following the first infusion of the second cycle of rituximab, 38% of first-cycle nonresponders exhibited complete depletion. Twenty-six weeks after the second cycle, there was a significant improvement in the Disease Activity Score in 28 joints, with 72% of patients exhibiting a EULAR response.

Conclusion
RA patients whose disease did not respond to an initial cycle of rituximab have higher circulating preplasma cell numbers at baseline and incomplete depletion. Our findings indicate that an additional cycle of rituximab administered prior to total B cell repopulation enhances B cell depletion and clinical responses.
Received: 6 July 2009; Accepted: 11 January 2010

A 76 year old lady presented with a 8 month history of progressive proximal muscle weakness. There were no skin lesions. A peak Creatine Kinase is 900. A muscle biopsy was performed.

Discussion - There was clear perifascicular muscle fibre atrophy on hemotoxylin-eosin staining. Some regenerating fibres were seen. Although there was occasional inflammatory infiltration of the muscle fibres, something commonly seen in polymyositis, the diagnosis was more consistent with that of dermatomyositis.

There was a suggestion that muscle tissue should be stained for complements in particular C5a in individuals that display proximal muscle weakness without evidence of perifascicular atrophy on biopsy. Many patients with dermatomyositis do not have skin manifestations, and a sample bias can delay the diagnosis.

Left ventricular structure and function in patients with rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging
Jon T. Giles 1, Ashkan A. Malayeri 1, Veronica Fernandes 1, Wendy Post 1, Roger S. Blumenthal 1, David Bluemke 2, Jens Vogel-Claussen 1, Moyses Szklo 1, Michelle Petri 1, Allan C. Gelber 1, Lyndia Brumback 3, João Lima 1, Joan M. Bathon 1 *
1Johns Hopkins University, Baltimore, Maryland
2National Institutes of Health Clinical Center, NIH, Bethesda, Maryland
3University of Washington, Seattle
email: Joan M. Bathon (jbathon@jhmi.edu)
*Correspondence to Joan M. Bathon, Division of Rheumatology, Johns Hopkins University, 5200 Eastern Avenue, Suite 4100, Baltimore, MD 21224

Funded by:
NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases); Grant Number: AR-050026
National Heart, Lung, and Blood Institute; Grant Number: N01-HC-95159, N01-HC-95166, N01-HC-95169
Arthritis National Research Foundation

ABSTRACT

Objective
Heart failure is a major contributor to cardiovascular morbidity and mortality in patients with rheumatoid arthritis (RA), but little is known about myocardial structure and function in this population. This study was undertaken to assess the factors associated with progression to heart failure in patients with RA.

Methods
With the use of cardiac magnetic resonance imaging, measures of myocardial structure and function were assessed in men and women with RA enrolled in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis study, a cohort study of subclinical cardiovascular disease in patients with RA, in comparison with non-RA control subjects from a cohort enrolled in the Baltimore Multi-Ethnic Study of Atherosclerosis.

Results
Measures of myocardial structure and function were compared between 75 patients with RA and 225 frequency-matched controls. After adjustment for confounders, the mean left ventricular mass was found to be 26 gm lower in patients with RA compared with controls (P < 0.001), an 18% difference. In addition, the mean left ventricular ejection fraction, cardiac output, and stroke volume were modestly lower in the RA group compared with controls. The mean left ventricular end systolic and end diastolic volumes did not differ between the groups. In patients with RA, higher levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and current use of biologic agents, but not other measures of disease activity or severity, were associated with significantly lower adjusted mean values for the left ventricular mass, end diastolic volume, and stroke volume, but not with ejection fraction. The combined associations of anti-CCP antibody level and biologic agent use with myocardial measures were additive, without evidence of interaction.

Conclusion
These findings suggest that the progression to heart failure in RA may occur through reduced myocardial mass rather than hypertrophy. Both modifiable and nonmodifiable factors may contribute to lower levels of left ventricular mass and volume.

Source here

“Recently a 45 year old lady with a 10 year history of rheumatoid arthritis, presented to us in congestive cardiac failure. She had no prior cardiac events and was well until a few weeks ago. There was also no other identifiable cardiac risk factors. An echocardiogram showed an ejection fraction of 15%. Her rheumatoid arthritis disease activity was otherwise relatively controlled. ”

The above case scenario is probably not unique and underlines the increasing association between rheumatoid arthritis and cardiac diseases. However, what is interesting about this article is the fact that the use of biologic agents has been implicated in lowering ventricular mass. There was no mention about whether there were differences between the various biologic agents. Should we now be measuring ventricular mass before instituting biologics? Or should the patients receiving biologic agents be maintained on a close follow up with echocardiograms?

It is undeniable that the increasing use of biologics may reveal widening chinks in the biologic armour.

Ankle Click here
Elbow Click here
Shoulder Click here
Knees Click here

Knee Click here
Foot and Ankle Click here
Hip Click here
Elbow Click Here
Hand and wrist Click here
Shoulder Click here

A short lecture on approaches to rheumatological problems was given by myself. It covers common complaints, approach to joint pain, the role of primary care physicians and the significance of immunological tests like the Antinuclear Antibody test.

We thanks the primary care team for the opportunity of being part of their CME activity.

TE Cheah

By Nancy Walsh, Contributing Writer, MedPage Today
Published: March 22, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

A halo sign detected on ultrasound, indicating edema of the temporal artery, is both sensitive and specific for giant cell arteritis, a meta-analysis suggests.
The presence of a unilateral halo sign had an overall sensitivity of 68% (95% CI 0.61 to 0.74) and specificity of 91% (95% CI 0.88 to 0.94), according to Aikaterini Arida, MD, and colleagues from Athens University Medical School in Greece.

With a bilateral halo sign, the sensitivity and specificity were 43% and 100%, respectively, the investigators reported online in BMC Musculoskeletal Disorders.

The American College of Rheumatology 1990 criteria for the diagnosis of giant cell arteritis require the presence of three of the following:

Age 50 years or older
New onset of localized headache
Temporal artery tenderness on palpation or decreased pulsation
Erythrocyte sedimentation rate of 50 mm/hour or higher
Abnormal temporal artery biopsy

Rapid diagnosis and initiation of treatment are mandatory in this condition because of the potential for irreversible vision loss, the most feared outcome associated with this most common of adult vasculitidies.

However, certainty about the correct diagnosis also is imperative, because of the potential for serious adverse effects with the necessary long-term corticosteroid treatment.

While biopsy has traditionally been recommended, there is a high probability of false-negative results because of the segmental nature of giant cell arteritis.

Other studies have found that almost 20% of patients with negative biopsy findings are eventually diagnosed with the disease, particularly if the biopsy is done only unilaterally.

In recent years, therefore, researchers have investigated the use of ultrasonography as a noninvasive means to evaluate the inflamed temporal arteries.

In an earlier meta-analysis of studies done before 2004, ultrasonographic findings suggestive of giant cell arteritis included edema, represented by a dark, hypoechoic circumferential wall thickening around the artery lumen, as well as stenoses and occlusions.

However, Arida and colleagues determined in a controlled study that stenoses and occlusions were not diagnostically useful, because these findings are common among the elderly or patients with macrovascular disease.

To further explore the utility of ultrasound for clinically suspected giant cell arteritis, they conducted a meta-analysis of prospective studies published through 2009 using the ACR criteria as the reference standard.

Eight studies with 575 patients were included in the analysis.

Based on the ACR criteria, 204 had a final diagnosis of giant cell arteritis.

In terms of sensitivity and specificity, there was considerable heterogeneity among the studies.

Therefore, the investigators also calculated diagnostic odds ratios, which express how much greater the odds of having the disease are for a patient with a positive test result than a negative result.

The pooled diagnostic odds ratio with a unilateral halo sign was 33.69 (95% CI 8.21 to 138.23), the investigators reported.

This rose to 65.03 (95% CI 17.86 to 236.82) with bilateral findings, which indicates “considerable diagnostic accuracy” for ultrasonography.

The diagnostic odds ratio also was constant across the studies included in the meta-analysis.

The sensitivity and specificity of 68% and 91% for the unilateral halo sign are comparable to estimates for these other diagnostic tests widely used in rheumatology:

Rheumatoid factor in rheumatoid arthritis, 69% and 85%
Anti-cyclic citrullinated peptide in rheumatoid arthritis, 67% and 95%
Anti-dsDNA antibodies for systemic lupus erythematosus, 61% and 95%
The investigators suggested that in the presence of unilateral halos, a directed biopsy could be done, while bilateral halos might prompt corticosteroid treatment without a biopsy.

“Compared with temporal artery biopsy, ultrasonography is very well tolerated, more accessible, less costly and a more rapid and easier to perform procedure, with high reproducibility,” the investigators said.

It also permits examination of the entire superficial temporal and other cranial arteries, which can increase the diagnostic yield.

The investigators pointed out that their analysis was unable to show direct superiority for ultrasound compared with microscopic examination of a biopsy specimen.

An advantage of biopsy, they noted, is that the presence of giant cells has been found to be strongly associated with vision loss.

Important technical requirements for accurate ultrasound include a need for high-quality Doppler ultrasound equipment and a linear probe with a frequency higher than 8 MHz. The sonographer should be experienced in vascular ultrasound.

“The findings of this meta-analysis suggest that validation of a revised set of classification criteria for [giant cell arteritis] which will include the halo sign is warranted,” they concluded.