We read with great interest the article on cortistatin (CST) treatment for collagen-induced arthritis by Gonzalez-Rey et al.(1) They reported that CST could decrease the frequency and reduce the severity of collagen-induced arthritis. In addition, they reported that CST treatment could induce the generation of regulatory T (Treg) cell in periphery. This is important, as little is presently known about th...
We read with great interest the article on cortistatin (CST) treatment for collagen-induced arthritis by Gonzalez-Rey et al.(1) They reported that CST could decrease the frequency and reduce the severity of collagen-induced arthritis. In addition, they reported that CST treatment could induce the generation of regulatory T (Treg) cell in periphery. This is important, as little is presently known about the factors and mechanisms controlling Treg cell expansion in periphery.(2) Treg cells have emerged as key players in the development of tolerance to autoantigens as well as to foreign antigens.(3) Until now, few investigations explored the immunomodulatory role of cortistatin in transplantation. We would like to share the results in our study on CST treatment for grafts rejection in a skin transplantation model. In our study, we find that CST treatment can induce more than two-fold increase of CD25+CD4+ T cells in the CD4+T cells of recipients (fig 1), up-regulate the expression of Foxp3, induce hyporesponsiveness to fully allogeneic antigens and prolong survival time of allogeneic skin grafts. Traditional immunosuppressive drugs, such as FK506 and cyclosporin A (CsA), treatment may be accompanied by several side effects, including interfering with the generation of Treg cell.(4) Thus, the establishment of additional strategies for immunosuppression of allograft rejection to minimize complications is desirable. AS an effectively suppressive neuropeptide in transplant rejection and one of the endogenous factors controlling the peripheral expansion of the Treg cells, CST may become a new modality in controlling allograft rejection.
Figure 1. The percentages of CD25+CD4+T cells in the CD4+T lymphocytes of skin transplant recipients. T lymphocytes enriched from splenocytes of BALB/c recipients treated with PBS, various doses of CST(0.02, 0.2 or 2 mg/kg) were isolated on day 7 post-transplantation and stained with three-color fluorescence labeled antibodies against mouse CD3, CD4 and CD25. The percentages of CD25+CD4+T cell were analyzed by flow cytometry. Recipients treated with PBS were acted as control group. A representative experiment of three is shown.
References
1. Gonzalez-Rey E, Chorny A, Del Moral RG, Varela N, Delgado M. Therapeutic effect of cortistatin on experimental arthritis by downregulating inflammatory and Th1 responses. Ann Rheum Dis 2007;66:582-588.
2. Sykes M. Immune tolerance: mechanisms and application in clinical transplantation. Journal of internal medicine 2007;262:288-310.
3. Kang SM, Tang Q, Bluestone JA. CD4+CD25+ regulatory T cells in transplantation: progress, challenges and prospects. Am J Transplant 2007;7:1457-1463.
4. Lim DG, Joe IY, Park YH, Chang SH, Wee YM, Han DJ, et al. Effect of immunosuppressants on the expansion and function of naturally occurring regulatory T cells. Transplant immunology 2007;18:94-100.
We thank Dr. Rutkowska-Sak and colleagues for their comments on the use of ultrasound (US) for the diagnosis of enthesitis in juvenile idiopathic arthritis (JIA). The purpose of our article [1] was to bring together a global perspective on magnetic resonance imaging (MRI) for
enthesitis at different sites using different methods.
Firstly, we are interested in their comments that enthesitis...
We thank Dr. Rutkowska-Sak and colleagues for their comments on the use of ultrasound (US) for the diagnosis of enthesitis in juvenile idiopathic arthritis (JIA). The purpose of our article [1] was to bring together a global perspective on magnetic resonance imaging (MRI) for
enthesitis at different sites using different methods.
Firstly, we are interested in their comments that enthesitis is especially common in JIA on US. This fits with the suggestion that JIA should be split into two major categories of joint involvement - synovial and entheseal, rather than the current scheme which includes 7 subgroups based on clinical rather than pathological features [2].
However, this raises the issue of validation of US for the diagnosis of enthesitis [3]. Further work is needed in different patient groups where observers are blinded to the pattern of disease and where intra- and inter
-observer reproducibility studies are performed.
Secondly, we fully agree that US may be the method of choice for the diagnosis of enthesitis in the lower limbs and at some other sites also, especially in JIA. However, for small joint disease the diffuse ostetiis pathology that accompanies enthesitis will not be appreciated on US,
especially in early disease. Also, many insertions in the lower limb including many of those in the knee are inaccessible to the ultrasound probe. Furthermore, apart from the spinous processes, virtually all of the spine is otherwise inaccessible to the probe. This limits the utility of US in these settings. However, we entirely agree with Dr. Rutkowska-Sak et al. about the advantages of US and its use in certain circumstances as a
first-line imaging test.
References
[1] Eshed I, Bollow M, McGonagle DG, Tan AL, Althoff CE, Asbach P, et al. MRI of enthesitis of the appendicular skeleton in spondyloarthritis. Ann Rheum Dis 2007;66:1553-9.
[2] McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet 1998;352(9134):1137-40.
[3] Scheel AK, Schmidt WA, Hermann KG, Bruyn GA, D'Agostino MA, Grassi W, et al. Interobserver reliability of rheumatologists performing musculoskeletal ultrasonography: results from a EULAR "Train the trainers"
course. Ann Rheum Dis 2005;64(7):1043-9.
Felson et al make a good case for choosing continuous, rather than dichotomous, variables as the primary outcome measures in randomised controlled trials in rheumatoid arthritis but outcome measure also need to be meaningful to the clinical community. In TICORA we chose two ‘co-primary’ end-points: firstly, we employed the mean change in DAS because this was the most sensitive outcome measure available at...
Felson et al make a good case for choosing continuous, rather than dichotomous, variables as the primary outcome measures in randomised controlled trials in rheumatoid arthritis but outcome measure also need to be meaningful to the clinical community. In TICORA we chose two ‘co-primary’ end-points: firstly, we employed the mean change in DAS because this was the most sensitive outcome measure available at the time; we also used the achievement of a “good” response according to EULAR criteria because we believed that differences in response rates would be more readily understood. Interestingly, our understanding of the clinical relevance of the outcome measures has been borne out: the results of the trial are (almost) never quoted as showing that the mean fall in DAS was 1.6 units (95% CI, 1.1 to 2.1) greater in the intensive arm - commentators almost invariably refer instead to the higher response rates. Consequently, I would urge some caution on the clinical trials community not to rely on sensitive (but intuitively difficult to understand) outcome measures to the exclusion of response rates. This is acknowledged by Felson et al when they recognise that such measures can be secondary outcome measures but it may still be important that some trials (depending on their purpose) are large enough to be able to detect clinically significant differences in response rates.
There has been a growing tendency for the therapeutic research agenda to become dominated by the pharmaceutical industry in their pursuit of marketing authorisation for new products. Felson et al point out that using sensitive outcome measures may avoid the need for ‘mega-trials’. Importantly, smaller and cheaper trials will help to safeguard the role of independent, investigator-initiated research which has been so fruitful in recent years. The second impact of designing smaller trials is, however, less helpful because it demands a degree of expertise in interpreting trial results. TICORA was a small trial, and so the magnitude of the benefits could not be assessed with any precision. The odds ratio for an ACR 70 response with intensive therapy was 11, but the 95% confidence interval for that odds ratio was 4.5 to 27. Rather than describe the trial as an ‘outlier’ the authors should perhaps have commented that the results should be interpreted carefully in light of the confidence intervals described in the paper.
I would add one further observation about dichotomous variables when the cohort average is close to a cut-off point. After 12 months, 44% of the TICORA intensive group were in DAS remission (data on file). At this point, the median DAS in the intensive group was 1.7, just above the cut-off for DAS remission. At 18 months, the median DAS had fallen to 1.3, just below the cut-off. This modest improvement in DAS was probably of limited clinical significance yet it resulted in a substantial increase in the remission rate (from 44% to 65%).
In conclusion, I would endorse the authors’ recommendation to use continuous measures of disease activity as primary outcome measures. This should ensure that smaller trials will be possible, and in turn this may help to safeguard the role of independent investigator-initiated research. However, trialists should continue to make sure that their measures are comprehensible and relevant, and the clinical community must be careful to interpret the results of trials thoughtfully.
References
1. D Felson, B Zhang and J Siegel. Trials in rheumatoid arthritis: choosing the right outcome measure when minimal disease is achievable. Ann Rheum Dis 2008;57:580-582.
2. C Grigor, H Capell, A Stirling et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004;364:263-269.
3. D Porter. Targeting persistent disease activity in early RA: a commentary on the TICORA trial. International Journal of Advances in Rheumatology. 2005;3:2-6.
For complex syndromes, such as fibromyalgia, knowledge about pathophysiology and other maintaining factors is limited and there is still no optimal treatment option on how patients have to be treated.
Consequently, it is important to develop guidelines based on empirical evidence or (in the case of lacking evidence) expert opinions from different disciplines. An expert team on fibromyalgia was formed and d...
For complex syndromes, such as fibromyalgia, knowledge about pathophysiology and other maintaining factors is limited and there is still no optimal treatment option on how patients have to be treated.
Consequently, it is important to develop guidelines based on empirical evidence or (in the case of lacking evidence) expert opinions from different disciplines. An expert team on fibromyalgia was formed and developed recommendations for the management on fibromyalgia syndrome at the Eular 2007. However, the present expert groups did not come to the same conclusions as several published meta-analyses, namely that non-pharmacological treatments, particularly a combination of cognitive-behavior therapy and exercise therapy, were more effective than pharmacological treatments (1-5). Although possible new evidence may be a
reason for this altered conclusion, it may at least partly be ascribed to the way the recommendations and guidelines were developed in the present article. For example, the authors state that the contribution of cognitive behavior therapy was based on expert opinion, because “the only two
studies identified for our review with pure cognitive behavioral therapy (CBT) were of poor quality”. However, this conclusion might be mainly ascribed to the type of the selection and quality criteria (in addition to the expert opinions) used for the present recommendations.
With regard to the quality of trials, the recommendations are based on 3 main criteria, including randomization, blinding and allocation concealment. However, with regard to the blinding criteria, it is rather impossible in cognitive-behavioral interventions to include blinding in a (placebo) control condition, since patients have to be aware about the content of the intervention. This largely explains the differences in
quality scores between the pharmacological and non-pharmacological trials (1-5). Consequently, different quality criteria for pharmacological and non-pharmacological studies in RCTs have to be used, in line with previous quality criteria developed for non-pharmacological pain treatments (6).
Relying on the quality criteria for pharmacological studies results in a selection bias of studies on which the recommendations are based and the exclusion of trials that showed positive effects of non-pharmacological
treatments. Also with regard to the selection process, only those studies were selected that used outcome measures of “VAS pain” and “FIQ” as a measure of pain and disability. As a result, several high-quality studies
using other (better validated) outcomes measures are now excluded (1-5).
Moreover, randomization is usually a prerequisite for a study to be included in meta-analyses instead of being used as a quality criterion.
However, non-randomized open trials were included for the recommendations, which may largely interfere with the results of other high-quality studies. As a consequence, the selection and judgments of the analyzed studies from more than 140 studies in this review is not entirely clear.
Finally, high-quality studies of combinations of cognitive-behavior therapy with exercise therapy, which was previously recommended as the highest priority, have not been included (1-5). As an multidisciplinary expert group on fibromyalgia, we consequently suggest to update the
published EULAR 2007 recommendations and to re-evaluate the contribution of multidisciplinary treatments for fibromyalgia syndrome, in favor of the well-being of patients with fibromyalgia.
References
1. Rossy LA, Buckelew SP, Dorr N, et al. A meta-analysis of fibromyalgia treatment interventions. Ann Behav Med 1999;21:180-91.
2. Hadhazy VA, Ezzo J, Creamer P, et al. Mind-body therapies for the treatment of fibromyalgia. A systematic review. J Rheumatol 2000;27:2911-8.
3. Sim J, Adams N. Systematic review of randomized controlled trials of nonpharmacological interventions for fibromyalgia. Clin J Pain 2002;18:324-36.
4. Koulil S. van, Effting M, Kraaimaat FW, Lankveld W van, Helmond Tvan, Cats H, Riel PLCM, van, de Jong AJL, Haverman JF, & Evers AWM. A review of cognitive-behaviour therapies and exercise programmes
for fibromyalgia patients: State of the art and future directions. Ann Rheum Dis 2007;66:571-581.
5. Scascighini L, Toma V, Dober-Spielmann S, Sprott H. Multidiscplinary treatment for chronic pain: a systematic review of interventions and outcomes. Rheumatol 2008, doi: 10.1093/rheumatology/ken021
6. Yates SL, Morley S, Eccleston C, et al. A scale for rating the quality of psychological trials for pain. Pain 2005;117:314-25.
We read with interest the work by Balada et al. publishedin Ann Rheum Dis 2008 Feb 13; [Epub ahead of print].
Although we noticed the authors pointed out in the title and along the text that anti-PDGFR antibodies in their study were detected by non-functional assays, we thought necessary a comment on their findings, for a
better understanding of the subject, mainly for those readers who may n...
We read with interest the work by Balada et al. publishedin Ann Rheum Dis 2008 Feb 13; [Epub ahead of print].
Although we noticed the authors pointed out in the title and along the text that anti-PDGFR antibodies in their study were detected by non-functional assays, we thought necessary a comment on their findings, for a
better understanding of the subject, mainly for those readers who may not be familiar with the immunological methods described in the manuscript.We have noticed several methodological problems, that might limit or
question the authors’ conclusions.
1. The authors did not provide information on the specificity of binding assays employed in their study, since no control peptide (e.g. EGFR extracellular domain) was included in either assays. This is a mandatory and important control, considering that the immunoassays, chosen by the authors to detect anti-PDGFR antibodies, were performed under denaturing conditions. In fact, it is likely that once the 550 aa PDGFR polypeptide is used to coat plastic wells (ELISA assay) or is denatured prior to electrophoresis (western blot) several linear epitopes are
unmasked which non specifically bind highly concentrated IgG contained in 1:5 diluted human serum. Immunoprecipitation and immunoblot will solve this problem by using these assays, we did not find anti PDGFR binding antibodies in normal subject (2).
2. Carrying out the experiments using a serial dilution of sera would better discriminate between positive and negative samples: the authors used a 1:5 serum dilution in all the experiments! Considering 1:5 dilution, the serum IgG concentration is approximately 2 mg/ml, that is at
least ten fold higher than the one we used in our report (2) to discriminate IgG purified from serum of SSc patients from IgG purified from serum of controls.
3. We would like to point out that in supplemental data (2) we also used a highly sensitive ECL detection system to reveal the immunoblots.
The main difference between our and their immunoassay in detecting denatured PDGFR, is in the primary reagent: we used immunopurified IgG at a concentration of 200 micrograms/ml, whereas Balada et al. used sera at
1:5 dilution (1). This may account for the different results.
In conclusion, we wish to call attention to the conditions that may be used by the authors to reproduce our experimental data on the detectionof specific anti PDGFR antibodies. In the absence of adequate controls,
the presence of specific of anti-PDGFR autoantibodies in healthy humans is questionable.
References
1. Balada E, Simeón-Aznar CP, Ordi-Ros J, Rosa-Leyva M, Selva-O'Callaghan A, Pardos-Gea J, Fonollosa-Pla V, Vilardell-Tarrés M.Anti-PDGFR-{alpha} antibodies measured by non-bioactivity assays are not specific of systemic sclerosis. Ann Rheum Dis 2008 Feb 13 [Epub ahead of print].
2. Svegliati Baroni S, Santillo MR Bevilacqua F, Luchetti M, Spadoni T, Mancini M , Fraticelli P, Sambo P, Funaro A , Kazlauskas A, Avvedimento EV, Gabrielli A Stimulatory autoantibodies to the PDGF receptor in
systemic sclerosis (scleroderma). N Engl J Med 2006;354;2667-2676.
This review focuses on the diagnostic role of magnetic resonance imaging (MRI) in early diagnosis of enthesitis [1]. The authors make interesting observations about the role of MRI of enthesitis –related spondyloarthritis.
Enthesitis is a distinctive pathological feature of spondyloarthritis (SpA) and may involve synovial joints, cartilaginous joints, syndesmoses and extra-articular entheses.
Spondyloarth...
This review focuses on the diagnostic role of magnetic resonance imaging (MRI) in early diagnosis of enthesitis [1]. The authors make interesting observations about the role of MRI of enthesitis –related spondyloarthritis.
Enthesitis is a distinctive pathological feature of spondyloarthritis (SpA) and may involve synovial joints, cartilaginous joints, syndesmoses and extra-articular entheses.
Spondyloarthritis affects interspinal and supraspinal ligaments of the vertebral spine and interosseous ligaments in the retroarticular space of the sacroiliac joints.
According to our experience, in children peripheral enthesitis may be observed in all forms of spondyloarthritis, including undifferentiated
forms, and may be the only longstanding clinical manifestation of spondyloarthritis. Enthesitis may occur in degenerative and inflammatory conditions and is a major symptom in patients with juvenile idiopathic arthritis (JIA). Juvenile spondyloarthritis is observed in 20% patients with JIA [2, 3].
Peripheral extra-articular enthesitis which is a clinical hallmark of spondyloarthropathy, could be found in 70% children with early spondyloarthritis [4]. Therefore, the ability to image the sites of peripheral enthesitis accurately, i.e. ultrasound and magnetic resonance
imaging could be useful in early diagnosis of spondyloarthritis. This is important in interpreting imaging findings in early inflammatory lesions.
We agree with the authors that magnetic resonance imaging (MRI) is the first choice method to evaluate acute enthesitis, which describes both soft-tissue changes and intraosseous abnormalities. MRI is sensitive enough to depict early inflammatory condition but this method is expensiveand not available in many hospitals. Magnetic resonance imaging can also frighten many children and special planning is necessary for sedation and
anaesthesia.
Therefore, we may suggest that ultrasonography (US) is a reliable and useful diagnostic tool for the assessment of early inflammatory lesions. It is commonly used both in children and in adults. US is particularly useful as a first hand tool for the evaluation of peripheral enthesitis.
However, US assessment is limited to the entheses of the knee and heel using a standard midline. We can agree with Balint et al. that 19–22 US examination has been more sensitive in the detection of enthesitis of the lower limbs in SpA and may provide a more objective and reliable index of enthesitis [5]. US may also show the swelling of the enthesitis, alternations of the echo texture consisting of decreased echogenicity owing to inflammation, the distension of the adjacent burse by fluid collections and peritendinous soft tissue swelling.
Our preliminary observations have shown that the MRI which was performed within two – three weeks after US could confirm enteritis diagnosed by US in 70% children. We have observed about 100 children with clinical symptoms of enthesitis which has confirmed using US in 75%.
We can conclude based on our observations of the children that US is widely available, inexpensive, readily demonstrates soft tissue inflammation such as enthesitis with sensitivity comparable to MRI.
References
1. Eshed I, Bollow M, McGonagle DG, Tan AL, Althoff CE, Asbach P, Hermann KG.MRI of enthesitis of the appendicular skeleton in spondyloarthritis. Ann Rheum Dis 2007;66:1553-9.
2. Petty RE, Southwood TR, Baum J, Bhettay E, Glass DN, Manners P, Maldonado-Cocco J, Suarez-Almazor M, Orozco-Alcala J, Prieur AM. Revision of the proposed classification criteria for juvenile idiopathic arthritis:
Durban, 1997. J Rheumatol 1998;25(10):1991-4.
4. Cabral DA, Oen KG, Petty RE. SEA syndrome revisited: a longterm followup of children with a syndrome of seronegative enthesopathy and arthropathy. J Rheumatol 1992;19(8):1282-5.
5. Balint PV, Kane D, Wilson H, McInnes IB, Sturrock RD. Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 2002;61:905-10.
We read with interest the review on anti CD-20 monoclonal antibody treatment for cryoglobulinemic vasculitis by Cacoub et al. We share our experience with two cases of cryoglobulinemic vasculitis associated with
Sjogren’s syndrome which were treated successfully with Rituximab. An 80-year-old man with Sjogren’s syndrome (SS) for 15 years, (anti-Ro/La positive, with peripheral neuropathy and immune thr...
We read with interest the review on anti CD-20 monoclonal antibody treatment for cryoglobulinemic vasculitis by Cacoub et al. We share our experience with two cases of cryoglobulinemic vasculitis associated with
Sjogren’s syndrome which were treated successfully with Rituximab. An 80-year-old man with Sjogren’s syndrome (SS) for 15 years, (anti-Ro/La positive, with peripheral neuropathy and immune thrombocytopenia), was on treatment with azathioprine and corticosteroids. He presented with
multiple, rapidly progressive, painful, non-healing, necrotic ulcers on both shins, severe Raynaud’s, petechial rash on the legs, fatigue and worsening neuropathy. Blood and protein was present in his urine. He had raised CRP, impaired renal function, very low complement, Rheumatoid
factor (RF) >1000, and positive ANA (1:80 titre). Cryoglobulins Type I-IgM kappa, were positive - 5.4 g/l. Investigations for hepatitis C, lymphoproliferative disorders, malignancies and other causes of cryoglobulinemia were negative. He was treated with high dose intravenous corticosteroids and iloprost for SS associated cryoglobulinemic vasculitis. He did not improve substantially and was treated with Rituximab (2 doses of 1000mg each at 2-week interval). His renal function,fatigue, rash and neuropathy improved significantly. His ulcers started healing rapidly. At 6 months follow up, his ulcers have healed and he has
mild residual weakness of hand grip. The second case is a 48-year-old lady with primary SS who presented with a painful, blotchy rash on her legs.
Investigations revealed elevated globulins, RF and presence of mixed cryoglobulins (type II). After initial plasmapheresis she was switched to prednisolone and azathioprine. Her painful rash and sialadenitis recurred,
cryoglobulinemia persisted. Following a course of rituximab (2 doses of 1000mg each at 2-week interval) she remained symptom free for 8 months. A relapse warranted a second course-she is now asymptomatic for over 2 years.
Cryoglobulins are present in upto 20% of patients with SS. Systemic features are more common in patients of SS with cryogloulinemia. Their 5-year survival is reduced as compared to those without, (1, 2) making it important to recognize and treat this complication of SS, to reduce
morbidity and mortality.
Rituximab has been used safely and effectively in cryoglobulinemias due to various causes, particularly HCV related. (3, 4) It is used successfully in primary Non-Hodgkin’s lymphomas, and those associated with SS (5). Very
few cases of cryoglobulinemia associated with SS, treated successfully with rituximab, have been reported. Pijpe et al suggested that rituximab was effective in the treatment of primary SS. (6) Another study of 16 patients with systemic complications of primary SS, of which 5 had
cryoglobulinemia, showed rituximab to be efficacious, well tolerated and allowed for marked reduction in corticosteroid use (7). B-cell activation is a consistent immunoregulatory abnormality in SS. Oligoclonal B-cell
expansion in the form of monoclonal light chains or immunoglobulins in the serum and urine are found in 80-100% patients of SS with systemic involvement and 25-40% of those with glandular disease. (8).
Controlled trials are needed to gather enough evidence for the successful treatment of cryoglobulinemia with rituximab (B-cell depletion therapy) as demonstrated by our cases.
References
1. Vasilev VI, Khodarev NV et. al. Cryoglobulinemia in Sjogren’s syndrome. Ter Arkh 1990;62(5):66-70.
2. Ramos-Casals M, Cervera R, Yagüe J, García-Carrasco M, Trejo O, Jiménez S, Morlà RM, Font J, Ingelmo M. Cryoglobulinemia in primary Sjögren's syndrome: prevalence and clinical characteristics in a series of 115 patients. Semin Arthritis Rheum 1998;28:200-5.
3. Zaja F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi G, Michelutti A, Baccarani M, Fanin R, Ferraccioli . Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003;101(10):3827-34.
4. Bryce AH, Dispenzieri A et. al. Response to rituximab in patients with type II cryoglobulinemia. Clin Lymphoma Myeloma 2006;7(2):140-4.
5. Voulgarelis M, Giannouli S, Anagnostou D, Tzioufas AG. Combined therapy with rituximab plus
cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjögren's syndrome-associated B-cell aggressive non-Hodgkin's lymphomas. Rheumatology (Oxford) 2004;43:1050-3. Epub 2004 Jun 8
6. Pijpe J, van Imhoff GW, Spijkervet FK, Roodenburg JL, Wolbink GJ, Mansour K, Vissink A, Kallenberg CG, Bootsma H. Rituximab treatment in patients with primary Sjogren’s syndrome: an open-label phase II study.
Arthritis Rheum 2005;52:2740-50.
7. Seror R, Sordet C, Guillevin L, Hachulla E, Masson C, Ittah M, Candon S, Le Guern V, Aouba A, Sibilia J, Gottenberg JE, Mariette X. Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s syndrome. Ann Rheum Dis 2007;66:351-7.
8. Manoussakis MN, Moutsopoulos HM. Sjogren’s syndrome: autoimmune epithelitis. Baillieres Best Pract Res Clin Rheumatol 2000;14:73-95.
Dear Editor,
We read with great interest the recent article by Bonilla et al. about hypoglycaemia after initiation of tumour necrosis factor alpha (TNFα) blockade.[1] As many patients worldwide with rheumatic diseases are treated
successfully with TNFα antagonists, there is a growing interest for possible “side” effects of these therapies, e.g. the influence of TNFα on glucose metabolism and insulin resistance. Several studi...
Dear Editor,
We read with great interest the recent article by Bonilla et al. about hypoglycaemia after initiation of tumour necrosis factor alpha (TNFα) blockade.[1] As many patients worldwide with rheumatic diseases are treated
successfully with TNFα antagonists, there is a growing interest for possible “side” effects of these therapies, e.g. the influence of TNFα on glucose metabolism and insulin resistance. Several studies [2,3], but not all [4], have demonstrated associations between circulating TNFα, obesity, insulin resistance and type 2 diabetes. TNFα-infusion impairs glucose uptake in human skeletal muscle by altering insulin signal transduction.[3] Moreover, it is suggested that TNFα-
antagonists, in addition to their known powerful anti-inflammatory effects, may have beneficial effects on insulin resistance in rheumatic diseases.[5]
The observed decrease in insulin requirement in the case report is interesting and in line with our recent report of two cases of RA patients with concomitant diabetes mellitus in which a substantial decrease in fructosamine levels, a marker for long-term glycaemic control,was seen during TNFα blocking therapy with adalimumab.[6] However, it is peculiar that, in the patient described by Bonilla et al., a substantial decrease in glucose levels (and hence insulin requirement) was found only the morning after etanercept administration, as serumlevelsof etanercept tend to be rather steady between administrations and time ofpeak after injection is after about 48 to 60 hours.[7] As a measure for long-term glycaemic control, e.g. fructosamine or glycosylated haemoglobin was lacking this aspect remains to be elucidated by future studies. In addition, another recent report did not show modifying effects of etanercept on insulin secretion and insulin sensitivity in psoriatic patients with risk factors for type 2 diabetes mellitus.[8]
Therefore, as the amount of case reports suggesting ”side” effects of anti-inflammatory treatment with TNFα antagonists on glucose metabolism is increasing, further prospective research of the (clinical)
role of TNFα antagonists on insulin resistance and glucose metabolism in rheumatic diseases in larger patient groups is required.
References
1. Bonilla E, Lee YY, Philips PE, Perl A. Hypoglycaemia after initiation of treatment with etanercept in a patient with type 2 diabetes mellitus. Ann Rheum Dis 2007;66:1688.
2. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, and Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt
substrate 160 phosphorylation. Diabetes 2005;54:2939–45.
3. Rask-Madsen C, Dominguez H, Ihlemann N, Hermann T, Køber L, Torp-Pedersen C. Tumor necrosis factor-alpha inhibits insulin’s stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans.
Circulation 2003;108:1815–21.
4. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 1996;45:881-5.
5. Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, Garcia-Porrua C, Sanchez-Andrade A, Martin J, Llorca J. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol 2006;24:83-6.
6. van Eijk IC, Peters MJ, Nurmohamed MT, van Deutekom AW, Dijkmans BA, Simsek S. Decrease of fructosamine levels during treatment with adalimumab
in patients with both diabetes and rheumatoid arthritis. Eur J Endocrinol 2007;156:291-3.
7. Zhou H. Clinical pharmacokinetics of etanercept: a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein. J Clin Pharmacol 2005;45:490-7.
8. Esperanza Martínez-Abundis E, Reynoso-von Drateln C, Hernández-Salazar E, González-Ortiz M. Effect of etanercept on insulin secretion and insulin sensitivity in a randomized trial with psoriatic patients at risk for
developing type 2 diabetes mellitus. Arch Dermatol Res 2007;299:461–465.
We read with interest the most recent consensus statement on the use of biological agents in rheumatoid arthritis, stating that improvement should be achieved by 12 weeks of therapy [1]. The most recent guidelines
issued this year in the UK by the National Institute for Health and Clinical Excellence (NICE) state that anti-TNF agents should only be discontinued if an adequate response (defined as a DAS...
We read with interest the most recent consensus statement on the use of biological agents in rheumatoid arthritis, stating that improvement should be achieved by 12 weeks of therapy [1]. The most recent guidelines
issued this year in the UK by the National Institute for Health and Clinical Excellence (NICE) state that anti-TNF agents should only be discontinued if an adequate response (defined as a DAS28 reduction of <1.2) is not obtained after 6 months of therapy [2]. This replaced earlier NICE guidelines which stated that treatment should be withdrawn ifa response was not obtained at 3 months of therapy [3]. The British Society for Rheumatology (BSR) have questioned whether 3 or even 6 months is long enough for an adequate therapeutic trial [4].
The randomised controlled trials on which anti-TNF guidelines are based reported in most instances only cumulative responses at 3 and 6 months, and
due to the attrition rate seen on anti-TNF agents for reasons such as adverse events, may underestimate the number of patients whose first response was between 3 and 6 months. Our own data has shown that a substantial proportion (55%) of rheumatoid arthritis patients who fail to meet NICE criteria for a response at 3 months go on to achieve a response by 6 months [5]. This would suggest that an extension of the trial period to 6 months rather than 12 weeks would benefit a significant number of
patients whose disease does not show a response to anti-TNF in the first 3 months of therapy, supporting such a change in the guidelines.
References
[1] Furst DE, Breedveld FC, Kalden JR et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2007. Ann Rheum Dis 2007;66 Suppl 3:iii2–22.
[2] National Institute of Clinical Excellence. Adalimumab, etanerceptand infliximab for the treatment of rheumatoid arthritis. October 2007.
http://www.nice.org.uk/nicemedia/pdf/TA130guidance.pdf.
[3] National Institute of Clinical Excellence. Guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis. March 2002. http://www.nice.org.uk/pdf/RA-PDF.pdf
[4] Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFa blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005;44:157–63.
[5] Pocock JM, Östör AJK. Assessment of anti-TNF efficacy in rheumatoid arthritis – Is three months sufficient? [abstract 143] BSR 2007.
The introduction of biological agents resulted in a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-tumor necrosis factor (TNF)-α monoclonal antibody, has become an
established effective therapy for RA. However, despite its role in chronic inflammatory diseases, evidence shows that TNF-α is also a critical factor in host defense. TNF-α initiates the inflammator...
The introduction of biological agents resulted in a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-tumor necrosis factor (TNF)-α monoclonal antibody, has become an
established effective therapy for RA. However, despite its role in chronic inflammatory diseases, evidence shows that TNF-α is also a critical factor in host defense. TNF-α initiates the inflammatory cascade by stimulating the production of other pro-inflammatory cytokines and
influencing the maturation of cytokines that provide defense against pathogens. For this reason infliximab is contraindicated in patients with ongoing infections and its use should be delayed until a full improvement of acute infections [1,2].
The frequent use of infliximab in clinical practice has identified Pneumocystis jiroveci pneumonia (PcP) as a serious complication [3], even though initial clinical trials failed to find this association. In this study that included 5,000 Japanese patients treated with infliximab, there was a higher incidence of PcP than of Tuberculosis [1]. Clinical practice guidelines recommend the systematic screening for Tuberculosis before starting the treatment, but there is no strategy for screening patients for PcP [4]. A recent Japanese Guideline has proposed screening patients through the blood beta-D-glucan test, but this essay is non specific for PcP [2].
Another study identified age of at least 65 years, use of corticosteroids and coexisting of chronic pulmonary diseases as risk factors for PcP in patients treated with infliximab [5]. This association can be explained because of the high prevalence of colonization by Pneumocystis jiroveci in patients with chronic pulmonary disease [6,7].
The use of corticosteroids is also related to a higher prevalence of colonization [8]. Because of these findings we think that patients treated with infliximab that develop PcP might have been previously colonized by
P. jiroveci.
The identification of patients colonized by P. jiroveci before starting the treatments with infliximab could be a strategy for PcP prevention. Oral washes have been confirmed to be an useful high specificity and sensibility non invasive procedure for the detection of
Pneumocystis colonization through the use of molecular techniques [9].
Thereby, detection of Pneumocystis colonization by PCR on oral washes and treatment with cotrimoxazol could be a practical strategy for PcP prevention in patients undergo infliximab therapy. This strategy for PcP prevention deserves further research to assess its clinical usefulness.
References
1. Takeuchi T, Tatsuki Y, Nogami Y, Ishiguro N, Tanaka H, Yamanaka H, et al. Post-marketing surveillance of the safety profile of infliximab in 5,000 Japanese patients
with rheumatoid arthritis. Ann Rheum Dis 2008;67:189-194.
2. Koike R, Takeuchi T, Eguchi K, Miyasaka N. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod Rheum 2007;17:451-458.
3. Kaur N, Mahl TC. Pneumocystis jiroveci (carinii) pneumonia alter Infliximab therapy: a review of 84 cases. Dig Dis Sci 2007;52:1481-1484.
4. Ledingham J, Dheigton C, British Society for Rheumatology standards, guidelines and audit working group. Update on the British Society for Rheumatology guidelines for prescribing TNF alpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005;44:157-163.
5. Harigai M, Koike R, Miyasaka N. Pneumocystis pneumonia associated with Infliximab in Japan. N Engl J Med 357;1874-1876.
6. Calderón E, de la Horra C, Medrano FJ, López-Suárez A, Montes-Cano MA, Respaldiza N, et al. Pneumocystis jiroveci isolates with dihydropteroate synthase mutations in patients with chronic bronchitis. Eur J Clin Microbiol Infect Dis 2004;23:545-549.
7. Morris A, Wei K, Afshar K, Huang L. Epidemiology and clinical ignificance of Pneumocystis colonization. J Infect Dis 2008;197:10-17.
8. Maskell NA, Waine DJ, Lindley A, Pepperell JC, Wakefield AE, MillerRF and Davies RJ. Thorax 2003;58:594-597.
9. Respaldiza N, Montes-Cano MA, Friaza V, Muñoz-Lobato F, Medrano FJ, Varela JM, Calderón E, and de la Horra C. Usefulness of Oropharyngela Washings for identifying Pneumocystis jirovecii carriers. J Eukaryot Microbiol 2006;53:100S-101S.
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Dear Editor,
The introduction of biological agents resulted in a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-tumor necrosis factor (TNF)-α monoclonal antibody, has become an established effective therapy for RA. However, despite its role in chronic inflammatory diseases, evidence shows that TNF-α is also a critical factor in host defense. TNF-α initiates the inflammator...
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