We are interested in the risk of sepsis in prosthetic joints after the use of biologic purposes for RA. We were therefore interested to read the study by 'Galloway et al (1). Galloway and colleagues have used data from the BSR biologics registry to examine the frequency of septic arthritis in anti - TNF treated patients and have found that both anti TNF therapy and previous prosthetic joints increase the...
We are interested in the risk of sepsis in prosthetic joints after the use of biologic purposes for RA. We were therefore interested to read the study by 'Galloway et al (1). Galloway and colleagues have used data from the BSR biologics registry to examine the frequency of septic arthritis in anti - TNF treated patients and have found that both anti TNF therapy and previous prosthetic joints increase the risk of septic
arthritis in RA subjects. The authors conclude that there is an increased risk of sepsis in prosthetic joints and those patients require careful follow up for septic arthritis after treatment with anti-TNF drugs. This
advice is emphasised by a series of patients which we have recently described (2) in which three rheumatoid arthritis patients with prosthetic joints developed sepsis after treatment with anti-TNF drugs between 3 and 20 years post surgery. Thus even patients many years after joint
replacements require regular follow up by an appropriately trained health
professional if treated with anti-TNF therapies.
References
1. Galloway J. Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70;1810-1814, doc 101136/and 2011,152769.
2. Abbas M, Grennan DM, Chelliah EG. A case series of sepsis in prosthetic joints after commencement of anti-TNF therapy in patients with RA, Northwest Rheumatology Club Meeting; 20.5.11.
We thank Poubelle et al for their interest in our publication "Cytokine mRNA profiling identifies B cells as a major source of RANKL in rheumatoid arthritis "[1]
We share an enthusiasm with Professor Poubelle for the role of neutrophils in the pathophysiology of rheumatoid arthritis and agree that neutrophils are often the dominant cell population in rheumatoid synovial fluid.
We thank Poubelle et al for their interest in our publication "Cytokine mRNA profiling identifies B cells as a major source of RANKL in rheumatoid arthritis "[1]
We share an enthusiasm with Professor Poubelle for the role of neutrophils in the pathophysiology of rheumatoid arthritis and agree that neutrophils are often the dominant cell population in rheumatoid synovial fluid.
However, we disagree with a number of comments made in their letter. They state that we did not mention the possibility that other cell types beside B cells produce RANKL in the joint; however, this is not the case as we stated in the discussion that "previous studies have reported the expression of RANKL by RA synovial fibroblasts, T cells and chondrocytes".
We regret that due to space restrictions we did not cite their interesting work. In their studies [2, 3] which are largely based on in vitro differentiation of a myeloid cell line towards neutrophil-like cells and on in vitro culture of peripheral blood neutrophils, they have shown
increased mRNA expression and surface expression of RANKL upon stimulation. However, in their experiments on ex vivo isolated synovial fluid neutrophils, protein expression of RANKL was not significantly increased, and there was no induction of RANKL mRNA expression above that
found in peripheral blood neutrophils. Our data are consistent with this - that there is no mRNA over-expression of RANKL in neutrophils isolated from synovial fluid of RA patients ex vivo when compared to peripheral
blood cells. For us, it was a key objective to get as close as possible to the in vivo situation in the RA patient, without allowing the effects of cell culture to confound results. Hence we restricted our studies to
freshly obtained, unstimulated, ex vivo samples.
Furthermore, Poubelle et al. suggested that we should use more than one anti-RANKL antibody. Indeed, this is what we did. As mentioned in our Methods section [1] we used two different antibodies, a mouse monoclonal
anti-RANKL as well as a polyclonal rabbit anti-RANKL (Figure 5 Yeo et al.).
A further suggestion was that we should use more than one method to confirm our data, and indeed we three methods: used real-time PCR and flow cytometry to analyze synovial fluid cells, and immunofluorescence staining
for synovial tissue (Figure 5 Yeo et al).
Our data are clear that, among the synovial fluid cell populations isolated ex vivo, B cells are the cell type that expressed the highest level of RANKL mRNA.
References
[1] Yeo L, Toellner KM, Salmon M et al. Cytokine mRNA profiling identifies B cells as a major source of RANKL in rheumatoid arthritis. Ann Rheum Dis Jul 8. epub ahead of print.
[2] Poubelle PE, Chakravarti A, Fernandes MJ et al. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from patients with rheumatoid arthritis and by healthy human
blood neutrophils. Arthritis Res Ther 2007;9:R25.
[3] Chakravarti A, Raquil MA, Tessier P et al. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood 2009;114:1633-44.
Merrill, et al. [1] reported that sifalimumab with safety profile and clinical activity was used in the phase I, multicentre, double-blind randomised study as an anti-IFN alpha monoclonal antibody in systemic lupus erythematosus (SLE), in which sifalimumab neutralized overexpression of the type I IFN signature in SLE patients in a dose-dependent manner as well as USP18/ESI-1 were inhibited, providing furthe...
Merrill, et al. [1] reported that sifalimumab with safety profile and clinical activity was used in the phase I, multicentre, double-blind randomised study as an anti-IFN alpha monoclonal antibody in systemic lupus erythematosus (SLE), in which sifalimumab neutralized overexpression of the type I IFN signature in SLE patients in a dose-dependent manner as well as USP18/ESI-1 were inhibited, providing further evidence of a correlation between decreased IFN-inducible protein/gene expression and
skin lesion improvement after a dose of sifalimumab. That indicated type I IFN may play an important role in the pathogenesis of SLE and blockade of IFN alpha may be a useful strategy for reducing disease activity.
In fact, therapy of anti-IFN alpha in SLE has been studied in other investigations. Yao, et al. [2] also revealed sifalimumab could neutralize overexpressed type I IFN signature in SLE patients in a dose-dependent manner. Dermal inflammation and certain proteins associated with IFN alpha/beta inducible gene expression (IP10, HERC5, ISG15) were decreased in the skin of sifalimumab-treated patients within two weeks of dosing.
Moreover, Yao, et al. [3] indicated that sifalimumab led to inhibition of excessively expressed type I IFN signature in WB (whole bolld) of patients. Meanwhile, downregulated CD4+ T cells, dendritic cells (DCs),
plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) were detected, along with suppressed expression of both type I IFN-inducible mRNAs and protein occurred in skin lesions of SLE patients in another study. Similarly, McBride, et al. [4] showed out another humanized IgG1 monoclonal antibody, rontalizumab, which might inhibit human IFN alpha also in dose-dependent inhibition of the type I IFN signature. In addition, two effective therapeutic agents in SLE, glucocorticoids and
chloroquine, can downregulate the IFN signature or inhibit IFN alpha production by NIPC/pDC40; type I IFNAR-knockout experimental murine lupus models have a significantly reduced SLE disease [5].
Therefore, these results might suggest a potential role of anti-IFN alpha therapy for SLE, especially with sifalimumab. Although SLE is a chronic systemic autoimmune
disease characterized by kinds of autoantibody production, complement activation and immune-complex deposition, since IFN alpha has been found to play an important role in the pathogenesis of SLE, researches are arising [6]. Some studies suggest that the decreased number of circulating
pDCs may attribute to a migration of these cells to tissues, owing to an increased number of pDCs readily detected in renal tissue, skin and lymph nodes from lupus patients. These pDCs are activated in vivo and synthesize
IFN alpha, indicating that these cells are responsible for the continuous IFN alpha production in lupus [7].
In conclusion, evidences suggest a posssible role of sifalimumab in the treatment of SLE, however, further studies are need to give comprehensive research.
References
1. Merrill JT, Wallace DJ, Petri M, et al. Safety pro?le and clinical activity of sifalimumab, a fully human anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-
blind randomised study. Ann Rheum Dis 2011 Jul 27.
2. Yao Y, Richman L, Higgs BW, et al. Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus.
Arthritis Rheum 2009;60:1785-1796.
3. Yao Y, Higgs BW, Richman L, et al. Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFN alpha antibody, in systemic lupuserythematosus. Arthritis Res Ther 2010;12 (Suppl 1):S6.
4. McBride JM, Wallace DJ, Yao Z, et al. Dose-dependent modulation of interferon regulated genes with administration of single and repeat doses of Rontalizumab in a phase I, placebo controlled, double blind, dose
escalation study in SLE [abstract 2072]. Arthritis Rheum 2009;60:S775-S776.
5. Ronnblom L, Pascual V. The innate immune system in SLE: type I interferons and dendritic cells. Lupus 2008;17:394-399.
6. Crow MK. Interferon-alpha: a therapeutic target in systemic lupus erythematosus. Rheum Dis Clin North Am 2010;36:173-186.
7. Ronnblom L, Alm GV, Eloranta ML. The type I interferon system in the development of lupus. Semin Immunol 2011;23:113-121.
We read with interest the study by Petri et al. (1), which showed absence of effect of atorvastatin on the change in coronary artery calcium and carotideal intima media thickness in lupus patients treated for 2 years. Lupus was been considered a coronary heart disease (CHD) equivalent by some authors given the major increase of cardiovascular risk in this disease (2).
We read with interest the study by Petri et al. (1), which showed absence of effect of atorvastatin on the change in coronary artery calcium and carotideal intima media thickness in lupus patients treated for 2 years. Lupus was been considered a coronary heart disease (CHD) equivalent by some authors given the major increase of cardiovascular risk in this disease (2).
The authors reported that patients with atherosclerotic disease or LDL > 190 mg/dl were excluded from the sample. Observing the baseline
characteristics of the patients, more than 50% had from the start LDL cholesterol <= 100 mg/dl, which is considered the desirable level for patients with CHD and equivalents (3). HDL cholesterol >= 60 mg/dl, which has protective effect for atherosclerotic disease, was present in 44% percent of the sample. On the other hand, patients with diabetes mellitus (DM) were allowed, but these patients should have been excluded given that DM is a CHD equivalent. However, the number of these patients was small.
Considering the evidence, it is possible that the broad criteria used for selection of patients and the inclusion of many patients with low cardiovascular risk profile may have precluded a positive effect of
atorvastatin on the reduction of progression of atherosclerosis in this study.
References
1. Petri MA, Kiani AN, Post W, et al. Lupus
Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis 2011;70:760-5.
2. Bruce IN. Cardiovascular disease in lupus patients: should all patients be treated with statins and aspirin? Best Pract Res Clin Rheumatol 2005;19:823-38.
3. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39.
We read with interest the recent article by Davies et al. [1] reporting on venous thrombotic events (VTEs) in patients with rheumatoid arthritis (RA) treated with antitumour necrosis factor (anti-TNF). They suggest that anti-TNF therapy is not associated with an increased risk of VTEs in RA patients, although, until the present time, retrospective studies looking at VTEs in anti-TNF-treated RA patients have...
We read with interest the recent article by Davies et al. [1] reporting on venous thrombotic events (VTEs) in patients with rheumatoid arthritis (RA) treated with antitumour necrosis factor (anti-TNF). They suggest that anti-TNF therapy is not associated with an increased risk of VTEs in RA patients, although, until the present time, retrospective studies looking at VTEs in anti-TNF-treated RA patients have produced conflicting results.[2] We previously reported that anti-TNF drugs were a likely cause of VTE development in RA patients following major orthopaedic surgery.[3] Because of these contradictory results, the effects of anti-TNF therapy on the risk of VTEs after orthopaedic intervention remain unclear.
Orthopedic procedures, including total joint arthroplasties (TJAs) such as total knee arthroplasty (TKA) and total hip arthroplasty (THA), have substantially improved overall patient function and quality of life.
However, complications after surgery, especially postoperative VTEs, can pose serious functional and psychological challenges. Therefore, more data are needed on the effects of non-biological and biological disease-
modifying antirheumatic drugs (DMARDs) after surgical intervention. The aim of this study was to identify risk factors for acute VTEs after TJAs.
This was a retrospective study of 500 consecutive patients undergoing TJAs during a 5-year period from January 2005 to December 2009. All RA patients fulfilled the 1987 revised American College of Rheumatology criteria for RA and/or the 2010 RA classification criteria.[4, 5] The timing of surgical intervention for patients treated with biological DMARDs was based on guidelines from the British Society for Rheumatology and the Japan College of Rheumatology.[6, 7] VTEs of the lower extremities were diagnosed using venous ultrasonography by three experienced medical technologists who were blinded to which patients were taking biological DMARD therapy. Twenty-three patients with preoperative VTEs were excluded.
Multivariate logistic regression analysis was performed to determine the risk factors for postoperative VTEs. A p-value of <0.05 was considered statistically significant. All analyses were performed using R-2.9.1 statistical software.
There were 130 patients who developed postoperative VTE. Multivariate logistic regression analysis showed that age (p=0.0012, odds ratio [OR]=1.04 [1.01-1.06]), use of biological DMARDs (p=0.0048, OR=2.72 [1.36-5.45]), past history of VTEs (p=0.033, OR=2.48 [1.07-5.70]), and TKA (vs. THA) (p=0.000083, OR=4.32 [2.09-8.96]) were risk factors for VTE.
Case reports [8] and basic research have shown that TNF-alpha decreases platelet activation and inhibits thrombus formation, and that TNF-alpha blocking by a biological DMARD may lead to thrombus formation.[9] The results of our study also suggest that biological DMARDs
may cause the occurrence of VTE in RA patients after TJA. However, this study had several limitations. Among RA-related surgeries, TJA was designated high risk surgery for the development of VTEs by the American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines.[10] Moreover, VTEs of the lower extremities were identified using venous ultrasonography, and the sample size was not large enough to investigate complications after joint surgery in RA patients treated with biological DMARDs.
Therefore, to confirm the risks for VTEs after TJA in RA patients
treated with anti-TNF, additional prospective studies are necessary.
References
1. Davies R, Galloway JB, Watson KD, et al.
Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. (Online first)
2. Petitpain N, Gambier N, Wahl D, et al. Arterial and venous thromboembolic events during anti-TNF therapy: a study of 85 spontaneous reports in the period 2000-2006. Biomed Mater Eng 2009;19(4-5):355-64.
3. Kawakami K, Ikari K, Kawamura K, et al. Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factor-alpha blockers: perioperative interruption of tumour necrosis factor-alpha blockers decreases complications? Rheumatology (Oxford) 2010;49(2):341-7.
4. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31(3):315-24.
5. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American
College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69(9):1580-8.
6. Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001).
Rheumatology (Oxford) 2005;44(2):157-63.
7. Koike R, Takeuchi T, Eguchi K, et al. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod Rheumatol 2007;17(6):451-8.
9. Cambien B, Bergmeier W, Saffaripour S, et al.
Antithrombotic activity of TNF-alpha. J Clin Invest 2003;112(10):1589-96.
10. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):381S-453S.
In a paper recently published online (Ann Rheum Dis, doi: 10.1136/ard.2011.153312), the authors found that B lymphocytes from rheumatoid arthritis (RA) synovial fluids and tissues expressed RANKL.
They stated that B cells were a major source of this cytokine in RA without considering that certain other synovial fluid cells and tissular cells have been reported to express RANKL in RA. In fact, they did...
In a paper recently published online (Ann Rheum Dis, doi: 10.1136/ard.2011.153312), the authors found that B lymphocytes from rheumatoid arthritis (RA) synovial fluids and tissues expressed RANKL.
They stated that B cells were a major source of this cytokine in RA without considering that certain other synovial fluid cells and tissular cells have been reported to express RANKL in RA. In fact, they did not introduce nor discuss previous studies that demonstrated RANKL expression by macrophages in synovial tissue from RA,1 and by neutrophils in RA synovial fluids.2, 3 In addition, among RA patients the authors showed in figure 2, 4/9 and 2/8 had synovial fluid RANKL-expressing macrophages and
neutrophils, respectively. Considering the high number of neutrophils in synovial fluids of active RA and their presence in synovium of early and late RA,4 it is impossible to neglect RANKL expressed by these inflammatory cells (Figure 1A, B, C). Moreover, neutrophils present in RA synovial tissues also express RANKL (Figure 1D, E). It is also important to stress that, although multiple antibodies against RANKL are presently
available, much attention must be paid to their efficiency in recognizing RANKL depending on the types of experiments, as recently reported by Vandooren et al.5 As a corollary, convincing data based on anti-RANKL
evaluation require the demonstration of similar results by using different antibodies in similar experiments with or without appropriate competition data if needed. In addition, these data will be comforted by showing
converging results of the presence of RANKL using different methodologies, i.e PCR, cytofluorometry, histochemistry, western blotting (whole cell lysates, cell membranes, or specific organelles). We showed, by using
these various methods, the presence of RANKL in neutrophils from RA synovial fluids, in neutrophils (from healthy donors) incubated in cell-free RA synovial fluids, and in murine neutrophils from air pouches.2, 3 Interestingly, most of the non-inflammatory cells do not express RANKL (or have a very low RANKL expression); they require a pathological condition and the presence of inflammatory stimuli to become RANKL-expressing cells.
In conclusion, several cell types like cells of myeloid origin (i.e. T and B lymphocytes, NK cells,6 monocytes/macrophages, neutrophils), cells of mesenchymal origin (i.e. osteoblasts, fibroblasts, synoviocytes...) and tumor cells can acquire the capacity to express large amounts of RANKL, and thus be implicated in disease pathogenesis and be efficiently targeted by an anti-RANKL therapy.
References
1. Crotti TN, Smith MD, Weedon H, et al. Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 2002;61:1047-54.
2. Poubelle PE, Chakravarti A, Fernandes MJ, et al. Differential expression of RANK, RANK-L, and osteoprotegerin by synovial fluid neutrophils from
patients with rheumatoid arthritis and by healthy human blood neutrophils. Arthritis Res Ther 2007;9:R25.
3. Chakravarti A, Raquil MA, Tessier P, et al. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption. Blood 2009;114:1633-44.
4. Tak PP, Smeets TJ, Daha MR, et al. Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 1997;40:217-25.
5. Vandooren B, Cantaert T, Noordenbos T, et al. The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral
spondylarthritis is partially disconnected from inflammation. Arthritis Rheum 2008;58:718-29.
6. Soderstrom K, Stein E, Colmenero P, et al. Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci U
S A 2010;107:13028-33.
Figure 1 Expression of RANKL by rheumatoid synovial fluid (SF) and
tissue neutrophils. (A) Purified SF neutrophils from a patient with active
RA were stained with a mouse anti-human CD66b monoclonal antibody followed
by a goat anti-mouse Alexa 488 antibody (Invitrogen; A11001). (B) Purified
SF neutrophils were stained for human RANKL by a polyclonal goat anti-
human RANKL (santa cruz; sc-7627) antibody followed by a rabbit anti-goat
Alexa 568 (Invitrogen; A11079) antibody. (C) Merge of neutrophil staining
with both anti-CD66b (green) and anti-RANKL (red) that shows SF
neutrophils expressing RANKL. (D-F) Paraffin-embedded RA synovial tissue
was deparaffinized, rehydrated and serial 3 ?m sections were stained for
human RANKL using a polyclonal rabbit anti-human RANKL (Peprotech; 500-
P133) antibody followed by an HRP-conjugated anti-rabbit antibody and
diaminobenzidine; sections were counterstained with haematoxylin. (D)
magnification: x100. (E) RA synovial tissue neutrophils (segmented
nucleus) express RANKL (brown); magnification: x600. (F) Negative control
with isotype (rabbit IgG)-matched staining; magnification: x600.
Image
Kollias et al. [1] presented an eloquent discussion of animal models of arthritis, remarking on their imperfect modeling of rheumatoid arthritis.
Among the models discussed was the human tumor necrosis factor (TNF) transgenic mice model. Examination of images of bone damage2 in this model3 suggested a previously unrecognized, intriguing effect/role of TNF.
We use the phrase bone damage, as the most imp...
Kollias et al. [1] presented an eloquent discussion of animal models of arthritis, remarking on their imperfect modeling of rheumatoid arthritis.
Among the models discussed was the human tumor necrosis factor (TNF) transgenic mice model. Examination of images of bone damage2 in this model3 suggested a previously unrecognized, intriguing effect/role of TNF.
We use the phrase bone damage, as the most impressive aspect of the illustrated pathology2 is the general cortical resorptive phenomenon. We have examined the skeletons of hundreds, if not thousands of humans and
other animals with rheumatoid arthritis and spondyloarthropathy, [4,5] without ever finding such bone resorption.
That is not to say that we have not seen this pathology. Actually, we have - in the skeleton of an individual with hyperparathyroidism in the pathology reference series "Galler collection."[6] This 58 year old female (Galler Collection Number 412) had substantial bone remodeling, with severe skeletal deformation and multiple fractures due to an adenoma of the parathyroid at the aortic arch, associated with renal calcinosis.
Micro-CT of bone7 revealed generalized bone resorption (Figure 1). The surface of this severely affected individual had the same resorption of surface cortical bone, exposing underlying trabeculae as seen in the
human tumor necrosis factor transgenic mice model illustrated by Schurigt et al. [2]
We suggest that the tumor-necrosis factor transgenic mouse model illustrate by Schurigt et al. [2] may actually be a model for the bone changes of hyperparathyroidism, if it does not actually represent that disease. We concur with Kollias et al. [1] as to the position of animal
models, but also suggest the value of avoiding tunnel vision (related to what they were designed to model) when analyzing the results.
References
1. Kollias G, Papadaki P, Apparailly F, et al. Animal models for arthritis: Innovativetools for prevention and treatment. Ann Rheum Dis 2011 doi: 10.1136/ard.2010.148551.
2. Schurigt U, Hummel KM, Petrow PK, et al. Cathepsin K deficiency partially inhibits, but does not prevent, bone descrtuction in human tumornecrosis factor-transgenic mice. Arthritis Rheum 2008;58:422-434 and cover.
3. Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumournecrosis factor: A predictive genetic model of arthritis. EMBOJ 1991;10:4025-4031.
4. Rothschild BM, Martin LD. Skeletal Impact of Disease. Albuquerque, New Mexico: New Mexico Museum of Natural History, 2006.
5. Nunn C, Rothschild BM, Gittleman J. Why are some species more commonly afflicted by arthritis than others? A comparative study of spondyloarthropathy in primates and carnivores. J Evol Biol 2007;20:460-470.
6. Ruhli FJ, Hotz G, Boni T. The Galler Collection - A little known historic Swiss bone pathology reference series. Amer J Phys Anthropol 2003:121:15-18.
7. Ruhli FJ, Kuhn G, Evison R, et al. Diagnostic value of micro-CT in comparison with histology in the qualitative assessment of historical human skull bone pathologies. Amer J Phys Anthropol 2007;133:1099-1111.
Figure 1. Micro-CT of hyperparathyroidism (Galler Collection Number 412), (Ruhli et al., Am J Phys Anthropol, Vol 133, 2007; Copyright: American Journal of Physical Anthropology / Wiley-Liss). Bar is 5 mm.
Conflict of Interest:
We have no competing interests, but could not load the picture to accompany text. How do I accomplish that?
In a recent paper dealing with long term outcome of vasculitis, the authors conclude that "despite recent advances in treatment, patients with ANCA-associated vasculitis continue to have an excess mortality, ..." and
..."it is unclear to what extent improved treatments will have an impact on later mortality" [1].
On the basis of our experience on 101 patients with vasculitis, 94 with histological dia...
In a recent paper dealing with long term outcome of vasculitis, the authors conclude that "despite recent advances in treatment, patients with ANCA-associated vasculitis continue to have an excess mortality, ..." and
..."it is unclear to what extent improved treatments will have an impact on later mortality" [1].
On the basis of our experience on 101 patients with vasculitis, 94 with histological diagnosis ( 15 classic polyarteritis, 29, microscopic polyangiitis, 24 Wegener granulomatosis and 33 pauci-immune necrotizing
glomerulonephritis) diagnosed from 1975 to 2002 with a mean follow-up time of 7 years, we would like to comment that, even if still sub-optimal, patients survival form the onset of the disease has considerably improved over time when compared with the general age-and sex-matched
population of the same area [2].
In fact, risk of death decreased by 10% at each year of follow-up after 1975, and Poisson-based multinomial analyses confirmed the highly significant risk during the periods of diagnosis from 1975-1983 (HR 4.381,
95%CI 1.274-15.061) and 1984-1992 (HR 3.462, 95%CI 1.052-11.397), as compared to 1993-2002. In particular, life expectancy of patients young women with vasculitis has undergone a dramatic improvement over time, now
approaching that of the sex- and age-matched general population: in fact, relative survival of the cohort of women under age 60 was sharply lower in the first period (relative survival at 10 years = 0.339) and increased in
the second (0.929), as it did during the 5 years in the third period, when they experienced a survival of 91.6%, comparable to that of the general population (98.1%), the opposite of that observed for men of all ages, showing a relative survival at 5 years from 0.491 to 0.546. The
increasing survival rate is chronologically related to two breakthrough advancements at our center: the availability of the ANCA test (after 1986) allowing earlier diagnosis, and the implementation of combined oral pulse
steroid/cyclophosphamide association as a first-line strategy for induction (after 1989).
Also in our patients the need for dialysis at diagnosis was a significant risk facto for patient mortality (HR 4.055, 95%CI 1.493-11.013).
Therefore, beside improved treatment, a crucial point to be stressed in order to obtain further improvement in prognosis is the need for early diagnosis. In our experience, delay in diagnosis is a significant risk
factor for a worse prognosis, as mean delay from clinical manifestation to diagnosis for all vasculitis significantly decreased during the three periods (from 283? 260 days to 166?170, and to 100 ?64, p<0.01). With
respect to renal function, significant associations with renal survival were the percentage of glomeruli involved by crescents (?2=16.5, p=0.0009) and the percentage of sclerosed glomeruli (?2=9.701, p=0.007), and multivariate Cox analysis showed that risk of renal death decreased by 6% at each year of follow-up after 1975, and increased by 5.7% for each year of patient age after 22 years. In sum, cases diagnosed in the later period and with fewer severe lesions at biopsy progressed better, underscoring the importance of an early diagnosis for prompt treatment.
Therefore, kidney involvement must be seen as a key feature in planning the intensity of treatment the prevention of end-stage renal disease could be seen as a means not only to reduce disability but also to improve survival.
References
1. Flossmann O, Berden A, de Groot K, et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis 2011;70(3):488-94.
2. Stratta P, Marcuccio C, Campo A, Sandri et al. Improvement in relative survival of patients with vasculitis: study of 101 cases compared to the general population. Int J Immunopathol Pharmacol 2008;21(3):631-
42.
In response to the eLetter of Felson and collaborators, we wish to point out that the methodologies used in the present study have been extensively validated and found to be reliable in the context of multicenter clinical trials [1-3]. Most of the comments made by Felson and collaborators reflect their experience from observational studies which may or may not apply to clinical trials.
In response to the eLetter of Felson and collaborators, we wish to point out that the methodologies used in the present study have been extensively validated and found to be reliable in the context of multicenter clinical trials [1-3]. Most of the comments made by Felson and collaborators reflect their experience from observational studies which may or may not apply to clinical trials.
Regarding the balance of the two treatment groups, table 1 of the published article shows that baseline characteristics were similarly distributed with the exception of age. In consequence, age has been introduced into the model. There is, however, no need for correction of all other statistically evenly distributed characteristics including BMI. Meniscal extrusion and meniscal tears were evaluated and found to be similarly distributed as well. When assessed by Fisher’s exact test, the presence of medial meniscal extrusion at baseline for placebo and CS, are respectively 64.7% and 54.3%, p=0.465; lateral meniscal extrusion: 8.8%, 0%, p=0.114; presence of medial meniscal tear: 97.1%, 100%, p=0.493; lateral meniscal tear: 97.1%, 82.9%, p=0.106. Therefore, the randomization process performed well. We do agree, however, that it would be optimal to know about the anatomical axis assessed by weight bearing X-rays of the entire leg. Such a measurement was not performed in this pilot trial nor is this routinely done in any clinical trials; this remains a limitation. Because it was a small cohort, we did not stratify for the most affected compartment, which was the medial one.
Concerning the measurement of the cartilage volume, the trained readers were never unblinded to the treatment. In regard to the loss of cartilage volume, it is clearly stated in the manuscript that this is in the upper range in comparison to other cohorts. For instance and as stated in the manuscript patient inclusion criteria, the patients had to have signs of synovitis, which may very well have impacted on the rate of cartilage volume loss. Thus, the population in the present study does not compare to the OAI cohort; therefore, the findings are not unusual. Interestingly, a co-author of the eLetter has recently reported an even higher loss in the OAI cohort using an ordered values approach [4]!
With regard to the sequence used for BML assessment, the advantages and disadvantages of the method used have already been reported in extenso [5-7] and have also been used by other experienced investigators [8]. The comments made by Felson and collaborators are without support from appropriate comparative head-to-head studies. Therefore a thorough study should be performed which would lead to an appropriate evaluation.
Several experienced investigators including Felson’s group are using a non contrast-enhanced method to score synovitis in knee OA patient studies [9-11]. We are therefore surprised by the comment made in the letter. The methods used in this study have been validated and can reliably assess synovial thickness and changes over time without gadolinium enhancement [12]. As previously reported [12, 13], data from the non contrast- and contrast-enhanced methods gave similar results. Moreover and in line with the FDA recommendation, which has issued a warning (blackbox) regarding the use of gadolinium, we consider a larger validation cohort as suggested by Felson and collaborators to be questionable from an ethical point of view.
References
1. Raynauld JP, Martel-Pelletier J, Bias P, et al. Protective effects of licofelone, a 5-lipoxygenase and cyclo-oxygenase inhibitor, versus naproxen on cartilage loss in knee osteoarthritis: a first multicentre clinical trial using quantitative MRI. Ann Rheum Dis 2009;68:938-47.
2. Raynauld JP, Martel-Pelletier J, Beaulieu A, et al. An Open-Label Pilot Study Evaluating by Magnetic Resonance Imaging the Potential for a Disease-Modifying Effect of Celecoxib Compared to a Modelized Historical Control Cohort in the Treatment of Knee Osteoarthritis. Semin Arthritis Rheum 2010;40:185-92.
3. Raynauld JP, Martel-Pelletier J, Berthiaume MJ, et al. Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period. Ann Rheum Dis 2008;67:683-8.
4. Wirth W, Buck R, Nevitt M, et al. MRI-based extended ordered values more efficiently differentiate cartilage loss in knees with and without joint space narrowing than region-specific approaches using MRI or radiography - data from the OA initiative. Osteoarthritis Cartilage 2011.
5. d'Anjou MA, Troncy E, Moreau M, et al. Response to the Letter to the Editor by Roemer and collaborators entitled ‘‘MRI based semi-quantitative assessment of subchondral bone marrow lesions in osteoarthritis research’’ concerning the article published by d’Anjou et al. entitled ‘‘Temporal assessment of bone marrow lesions on magnetic resonance imaging in a canine model of knee osteoarthritis: impact of sequence selection.’’. Osteoarthritis Cartilage 2009;17:416-17.
6. Wildi LM, Raynauld JP, Martel-Pelletier J, et al. Relationship between bone marrow lesions, cartilage loss and pain in knee osteoarthritis: results from a randomised controlled clinical trial using MRI. Ann Rheum Dis 2010;69:2118-24.
7. Tanamas SK, Wluka AE, Pelletier JP, et al. Comment on: Bone marrow lesions in people with knee osteoarthritis predict progression of disease and joint replacement: a longitudinal study: reply. Rheumatology (Oxford) 2011.
8. Tanamas SK, Wluka AE, Pelletier JP, et al. Bone marrow lesions in people with knee osteoarthritis predict progression of disease and joint replacement: a longitudinal study. Rheumatology (Oxford) 2010;49:2413-9.
9. Hill CL, Gale DG, Chaisson CE, et al. Knee effusions, popliteal cysts, and synovial thickening: association with knee pain in osteoarthritis. J Rheumatol 2001;28:1330-7.
10. Kornaat PR, Ceulemans RY, Kroon HM, et al. MRI assessment of knee osteoarthritis: Knee Osteoarthritis Scoring System (KOSS)--inter-observer and intra-observer reproducibility of a compartment-based scoring system. Skeletal Radiol 2005;34:95-102.
11. Fernandez-Madrid F, Karvonen RL, Teitge RA, et al. Synovial thickening detected by MR imaging in osteoarthritis of the knee confirmed by biopsy as synovitis. Magn Reson Imaging 1995;13:177-83.
12. Pelletier JP, Raynauld JP, Abram F, et al. A new non-invasive method to assess synovitis severity in relation to symptoms and cartilage volume loss in knee osteoarthritis patients using MRI. Osteoarthritis Cartilage 2008;16 Suppl 3:S8-13.
13. Pelletier JP, Raynauld JP, Abram F, et al. Response to the Letter to the Editor by Roemer and collaborators entitled ‘‘Semiquantitative assessment of synovitis in osteoarthritis on non contrast-enhanced MRI’’ concerning the article published by Pelletier et al. entitled ‘‘A new non-invasive method to assess synovitis severity in relation to symptoms and cartilage volume loss in knee osteoarthritis patients using MRI’’. Osteoarthritis Cartilage 2009;17:822-24.
Conflict of Interest:
JPP and JMP are consultants for and shareholders in ArthroLab Inc. and ArthroVision Inc. JPR is a consultant for ArthroVision Inc. AB, LB and FM received honoraria from ArthroLab Inc. FA is an employee of ArthroVision Inc. MD is a consultant for ArthroVision Inc.
We read with great interest the article of Petri et al [1] addressing the effect of atorvastatin 40 mg daily on subclinical atherosclerosis (ATS), systemic inflammation and disease activity in patients with systemic lupus
erythematosus (SLE). Contrary to expectations, atorvastain had no effect on any of these parameters after 2 years of follup-up. Although these findings are clinically relevant, some issues...
We read with great interest the article of Petri et al [1] addressing the effect of atorvastatin 40 mg daily on subclinical atherosclerosis (ATS), systemic inflammation and disease activity in patients with systemic lupus
erythematosus (SLE). Contrary to expectations, atorvastain had no effect on any of these parameters after 2 years of follup-up. Although these findings are clinically relevant, some issues should be considered in order to better interpret the results.
First, the authors provide no information about the treatments received by patients during the 2 years of follow up, especially in regard to the use of prednisone, inmmunosupresive agents and hydroxychloroquine. All these
drugs have a direct effect on inflammation and disease activity and potentially on subclinical ATS. Thus, the negative results found in this clinical trial could be due to an imbalance in the use of these drugs in both arms, rather than the lack of effect of atorvastatin on these
parameters.
Second, the mean SELENA SLEDAI value for all patients at baseline was ~2 (range 0-24), indicating that most patients had inactive or moderately active disease status and consequently a low-moderate grade of systemic
inflammation [2]. Moreover, 87% of patients had an intima-media thickness < 0.7 mm, and only 20% of them had plaque at baseline. Therefore, perhaps the ability of atorvastatin to improve these parameters in this context is limited, and it is likely that the results would have been better if patients had had a higher lupus activity, inflammation and a higher ATS burden at baseline.
This concept emphasizes the desirability of stratifying SLE patients according to cardiovascular (CV) risk in order to adjust the measures to prevent the development of CV diseases rather than applying them
indiscriminately in all SLE patients. Perhaps one of the most important lessons from this clinical trial is that statins should not be used in the prevention of CV disease in SLE patients with normal lipid levels, inactive or low active disease and low ATS burden.
References
1. Petri MA, Kiani AN, Post W, et al. Lupus Atherosclerosis Prevention Study (LAPS). Ann Rheum Dis 2010 Dec 21:[Epub ahead of print].
2. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med 2005;353:2550-8.
Dear Editor,
We are interested in the risk of sepsis in prosthetic joints after the use of biologic purposes for RA. We were therefore interested to read the study by 'Galloway et al (1). Galloway and colleagues have used data from the BSR biologics registry to examine the frequency of septic arthritis in anti - TNF treated patients and have found that both anti TNF therapy and previous prosthetic joints increase the...
Dear Editor,
We thank Poubelle et al for their interest in our publication "Cytokine mRNA profiling identifies B cells as a major source of RANKL in rheumatoid arthritis "[1]
We share an enthusiasm with Professor Poubelle for the role of neutrophils in the pathophysiology of rheumatoid arthritis and agree that neutrophils are often the dominant cell population in rheumatoid synovial fluid.
However, we disagr...
Dear editor,
Merrill, et al. [1] reported that sifalimumab with safety profile and clinical activity was used in the phase I, multicentre, double-blind randomised study as an anti-IFN alpha monoclonal antibody in systemic lupus erythematosus (SLE), in which sifalimumab neutralized overexpression of the type I IFN signature in SLE patients in a dose-dependent manner as well as USP18/ESI-1 were inhibited, providing furthe...
Dear editor,
We read with interest the study by Petri et al. (1), which showed absence of effect of atorvastatin on the change in coronary artery calcium and carotideal intima media thickness in lupus patients treated for 2 years. Lupus was been considered a coronary heart disease (CHD) equivalent by some authors given the major increase of cardiovascular risk in this disease (2).
The authors reported that patie...
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Dear Editor,
In a paper recently published online (Ann Rheum Dis, doi: 10.1136/ard.2011.153312), the authors found that B lymphocytes from rheumatoid arthritis (RA) synovial fluids and tissues expressed RANKL.
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Dear Editor,
Kollias et al. [1] presented an eloquent discussion of animal models of arthritis, remarking on their imperfect modeling of rheumatoid arthritis.
Among the models discussed was the human tumor necrosis factor (TNF) transgenic mice model. Examination of images of bone damage2 in this model3 suggested a previously unrecognized, intriguing effect/role of TNF. We use the phrase bone damage, as the most imp...
Dear Editor,
In a recent paper dealing with long term outcome of vasculitis, the authors conclude that "despite recent advances in treatment, patients with ANCA-associated vasculitis continue to have an excess mortality, ..." and ..."it is unclear to what extent improved treatments will have an impact on later mortality" [1].
On the basis of our experience on 101 patients with vasculitis, 94 with histological dia...
Dear Editor,
In response to the eLetter of Felson and collaborators, we wish to point out that the methodologies used in the present study have been extensively validated and found to be reliable in the context of multicenter clinical trials [1-3]. Most of the comments made by Felson and collaborators reflect their experience from observational studies which may or may not apply to clinical trials.
Regarding the...
Dear Editor,
We read with great interest the article of Petri et al [1] addressing the effect of atorvastatin 40 mg daily on subclinical atherosclerosis (ATS), systemic inflammation and disease activity in patients with systemic lupus erythematosus (SLE). Contrary to expectations, atorvastain had no effect on any of these parameters after 2 years of follup-up. Although these findings are clinically relevant, some issues...
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