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Archives of Selected News and Articles 

YEAR 2011 (most recent news on top)

Upload all the 2011 CanVasc reviews in a printer-friendly pdf file by clicking HERE

The Spanish group from Gonzalez-Gay et al. reports that 71 (40.8%) of their 174 biopsy-proven GCA patients (diagnosed and followed between 1992 and 2006 at Lugo’s hospital) experienced at least 1 relapse or recurrence (the latter being defined as a relapse occurring more than 1 month after cessation of prednisone). More precisely, 14 (8%) of the patients had 2 or more relapses and recurrences occurred in 32 (18.4%) patients. Relapses or recurrences were defined as ESR >20 mm/1st hr with clear new, recurrent or worsening clinical manifestation(s). The median follow-up was of 104 months for the entire cohort (a minimum of 1 year was required); the median time from diagnosis to relapse was 16 months (patients were under a median of 5 mg OD prednisone when relapsing) and 23 months for recurrences. Pertinently, none of the patients had visual loss or amaurosis at the time of their relapse(s) or recurrence(s). Anemia (Hb <12 g/dl) at the time of diagnosis was the best (and only identified) predictor of relapse or recurrence (OR 2.17; 95% CI, 1.02-4.62).

These results remind us of the non-negligible rate of relapse in GCA. Although being a retrospective study, patients were treated quite homogeneously (single center study). Because focusing only on biopsy-proven GCA patients, the study of course does not inform us on the relapse rate of GCA patients who are not biopsy-proven. Eventually, one important finding of this study is that, whereas anemia was earlier reported as a protective parameter for ischemic complications and stroke, it seems associated with a higher risk of GCA relapse or recurrence. As discussed by the authors, this latter result may suggest that a strong initial inflammatory syndrome can be associated with a lower risk of ischemic events but a higher relapse rate. However, higher ESR, leukocyte or platelet counts at diagnosis were not found to be associated with relapses or recurrences and, importantly, CRP level was not studied and/or included in the model to identify potential predictors of relapse. - 21 july 2011. CPx

Martinez-Lado L, Calviño-Díaz C, Piñeiro A, Dierssen T, Vazquez-Rodriguez TR, Miranda-Filloy JA, Lopez-Diaz MJ, Blanco R, Llorca J, Gonzalez-Gay MA. Relapses and recurrences in giant cell arteritis: a population-based study of patients with biopsy-proven disease from northwestern Spain . Medicine ( Baltimore ). 2011 May;90(3):186-93. Link

What you wanted to know on FDG-PET scan in vasculitis

It has been and remains controversial whether testing for erythrocyte TPMT enzymatic activity or TPMT genotype prior to prescribing azathioprine was really of benefit, as compared to the regular and mandatory monitoring of CBC and liver enzymes. There have been several studies published over the past decade, but with conflicting results. In this systematic review published in the Annals of Internal Medicine, the authors (from Ottawa and Toronto) identified and analyzed 54 observational studies and 1 (the only one available so far) randomized control trial on this topic and found no evidence to support the systematic use of TPMT testing, even though they confirmed the clear association between leukopenia and myelotoxicity and TPMT reduced activity or variant genotype.
Four to 11% of the general population is heterozygous for a variant TPMT allele and 0.3% are homozygous (perhaps more often in Africans), and have reduced or absent enzymatic activity, that can lead to the accumulation of toxic active metabolite of the drug, no further degraded. Genotyping can identify 4 of the most common alleles, accounting for 80 to 95% of persons with decreased TPMT activity (other variants are thus usually missed). However, TPMT status does not reliably predict all adverse events and up to 70% of patients suffering of azathioprine-related adverse events do not have abnormal TPMT activity.
Seventy percent of the selected studies concerned patients with inflammatory bowel diseases; all but 2 included only white subjects. The OR to develop myelotoxicity is 19.12 (CI, 4.56-80.24) for patients with low TPMT activity as compared to those with normal activity, and 2.56 (CI, 1.41-4.67) to develop leukopenia. Heterozygotes had an OR of leukopenia of 4.29 (CI, 2.67-6.89) and homozygotes of 20.84 (CI, 3.42-126.89) as compared to noncarriers. Withdrawal of the drug is more likely to be required in heterozygotes than noncarriers (OR 6.54; CI, 2.53-16.91). Although specificity of TPMT genotyping approaches 100%, sensitivity of genotyping to identify patients with low TPMT activity was only 70 to 86%.
For vasculitis patients, some small studies (Stassen et al. Ann Rheum Dis 2009 - included in this systematic review) suggested that regular CBC and liver enzyme monitoring (liver toxicity is less obviously associated with TPMT activity) was effective to early detect adverse events and prevent further and/or more severe toxicity. Finally, authors remind us that one must not forget that several drug interactions can also increase the risk of azathioprine-associated toxicity (as an example, remember that the concomitant use of azathioprine and allopurinol or any other xanthine oxidase inhibitor are contra-indicated).
The accompanying Editorial further emphasizes the lack of evidence on the clinical effectiveness and cost-effectiveness of preemptive TPMT testing and most of other pharmacogenetic testing so far. - 26 June 2011. CPx

- Booth RA, Ansari MT, Loit E, Tricco AC, Weeks L, Doucette S, Skidmore B, Sears M, Sy R, Karsh J. Assessment of thiopurine s-methyltransferase activity in patients prescribed thiopurines: a systematic review. Ann Intern Med. 2011 Jun 21;154(12):814-23. Link
- McLeod HL, Isaacs KL. Preemptive pharmacogenetic testing: insufficient data equal unsatisfactory guidance. Ann Intern Med. 2011 Jun 21;154(12):842-3. Link
- Stassen PM, Derks RP, Kallenberg CG, Stegeman CA. Thiopurinemethyltransferase (TPMT) genotype and TPMT activity in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: relation to azathioprine maintenance treatment and adverse effects. Ann Rheum Dis. 2009 May;68(5):758-9. Link

Long- term (follow-up >10 years) outcomes of pediatric patients with ANCA vasculitis: the London UK experience on 8 patients.

ANCA-associated vasculitides are rare in childhood, but not exceptionnal (estimated annual incidence of 1 to 2 per million children below 15 years-old). The UK Londonian group of adult nephrology division reports on their 8 adult patients with ANCA-associated vasculitis diagnosed in childhood (before the age of 16 years) and followed for more than 10 years each (inclusion criteria). Mean age at diagnosis was 11.5 years; 6 were Caucasian and 2 African; 7 had GPA and 1 MPA; follow-up duration varied from 11 to 30 years after diagnosis (median 18.5 years). Five of them had renal involvement; only 4 had ENT manifestations at diagnosis and 1 developped subglottic stenosis. All patients received corticosteroids and all but one received cyclophosphamide as part of their therapies during the entire course of the disease. One patients never entered sustained complete remission and all of the remaining ones experienced at least 1 disease relapses, with a median of 4 relapses each (range 1 to 8 relapses). Whereas 1 patient died 25 years post-diagnosis (sudden death due to respiratory complications of GPA), only 1 progressed to end-stage kidney disease, but 4 became infertile (3 women and 1 man), 1 suffered of avascular necrosis of the hip and 1 developed malignancy (breast cancer at the age of 30 years). Infections were quite frequent, but none was severe.
In the second part of the article, authors made a review of the literature on ANCA-associated vasculitis in children, including only articles with information on outcomes (whatever the duration of follow-up).They thus identified a total of 86 additional patients. In those studies, female were also predominantly affected (up to 3/4 of the GPA patients), but outcomes were relatively variable, with frequent relapses and damage (hearing loss, subglottic stenosis, infertility or chronic kidney disease in up to 1/3 of the patients).
The article is interesting to read (and brief) but authors missed the largest series on pediatric GPA patients from Toronto including 25 children, but with a shorter median follow-up of 32.7 months, and published in 2007 (Akikusa et al. Arthritis Care & Research, 57:837–844). However, it is true that if you search on PubMed for paediatric (with an -a-) vasculitis, this reference will not be listed...

As concluded by the authors, prospective cohorts are warranted to further study this specific population. There is indeed one already ongoing in Canada and USA, named ARChiVe, which started in 2005 under the impulse of Dr. Cabral (core member of CanVasc). More than 100 young GPA patients have already been enrolled, across 36 recruiting centers. - 25 June 2011. CPx

- Arulkumaran N, Jawad S, Smith SW, Harper L, Brogan P, Pusey CD, Salama AD. Long- term outcome of paediatric patients with ANCA vasculitis. Pediatr Rheumatol Online J. 2011 Jun 19;9(1):12. Link (free text).
- Akikusa JD, Schneider R, Harvey EA, Hebert D, Thorner PS, Laxer RM, Silverman ED. Clinical features and outcome of pediatric Wegener's granulomatosis. Arthritis Rheum. 2007 Jun 15;57(5):837-44. Link (free text).

Levamisole-adulterated cocaine-induced vasculitis

While awaiting for the publication of the cocaine-induced vasculitis patients from Ottawa (Dr. Milman, core member of CanVasc), the reading of this article may be useful. It is well illustrated and didactic. Authors report their experience on 6 patients recently seen in Los Angeles or New York and who had levamisole-adulterated cocaine-induced disease, including retiform purpura, characteristically necrotic with eschars and involving ears, nose and cheeks, with frequent neutropenia (half the patients) and p-ANCA (sometimes with c-ANCA and/or both antiPR3 and antiMPO on ELISA). Skin biopsy was done in 2 patients and showed leukocytoclastic vasculitis, with immune-complex deposits on IF.
Levamisole-contaminated cocaine has been detected since 2003, and such vasculitis cases have been increasingly observed since 2008. Up to 70% of the cocaine currently circulating in the U.S. may be contaminated by levamisole, an anti-helminthic agent that may induce some dopamine release in the brain, thereby potentially enhancing psychoactive effects of cocaine. The interval between exposure to levamisole-adulterated cocaine and the appearance of the first skin lesions is usually brief (hours to days), with the lesions gradually worsening with the persistence of drug exposure (either snorted or smoked). Systemic treatment is often given (i.e. corticosteroids) because of the impressive necrotic skin lesions, but the clinical manifestations seem to resolve "spontaneously" in most of the cases, whether the drug exposure is completely and definitively stopped. Finally, it should be reminded that cocaine can also per se (i.e., even when not contaminated by levamisole) cause vasculitis, mainly skin vasculitis, but also cerebral vasculitis, potentially leading to severe and irreversible damage. - June 15, 2011. CPx.

Chung C, Tumeh PC, Birnbaum R, Tan BH, Sharp L, McCoy E, Mercurio MG, Craft N. Characteristic purpura of the ears, vasculitis, and neutropenia-a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol. 2011 Jun 7.[Epub ahead of print]

UK recommendations for the use of rituximab in ANCA-associated vasculitides

A group of 11 vasculitis experts from the UK, including 5 nephrologists and 1 pediatrician, ended up after a systematic and structured process (DELPHI exercise, systematic review of the literature, categorization of evidence) to 15 graded recommendations for the use of rituximab. Results of studies on rituximab published in 2010 and 2011 have not been included in this literature review (done in late 2009), nor, of course, those of the RAVE and RITUXVAS studies after 18 months of follow-up, recently revealed at the 15th ANCA workshop and EULAR. Those latter studies already add some new considerations and would deserve some additional comments, but these recommendations may be very helpful for other initiatives, in other countries, for either national recommendations or drug approval by regulatory organizations.

These recommendations, further detailed and commented in the article, are as follows:

Recommendation 1			Level of evidence
	What are the indications for rituximab as a treatment of ANCA-associated vasculitis?
< o:p > < /td >		In newly diagnosed ANCA-associated vasculitis: Rituximab is as effective as CYC for remission inductionof previously untreated patients. Rituximab may be preferred, especially when CYC avoidance is desirable.	1b
		In refractory and/or relapsing disease: Rituximab is an effective treatment of refractory and/or relapsing forms of ANCA-associated vasculitis andcan be recommended when conventional therapy has failed.	1b
		According to patient subgroups · WG with head and neck manifestations: Rituximab is an effective treatment of refractory head and neck manifestations of WG and can be recommended when conventional therapy has failed.	2b/4
		· Paediatric ANCA-associated vasculitis: Rituximab should be considered for the treatment of children with ANCA-associated vasculitis that fails to respond to conventional induction therapy with glucocorticoids and CYC; or for patients with relapsing disease where there is particular concern regarding cumulative glucocorticoid and/or CYC toxicity.	4
		· Churg-Strauss syndrome: Response rates in refractory and/or relapsing: Churg-Strauss syndrome appear similar to other vasculitides and rituximab may be considered when conventional therapy has failed.	4
Recommendation 2
	What is the optimal induction dosage regimen?
		Both commonly used rituximab protocols (375mg/m2/week for 4 weeks; 1000mg repeated after 2 weeks) appear equally effective for induction of remission, but have not been formally compared; therefore, both can be recommended.	4
Recommendation 3
	What are the longer term outcomes of treatment with rituximab?
		Relapse rate: The overall response to rituximab in refractory disease may be superior to that seen with alternative therapies in similar cohorts of patients. There is insufficient evidence on long-term outcomes with rituximab when compared with conventional therapy in newly diagnosed patients. Relapse after rituximab is common and patients should be monitored accordingly.	4
		Potential predictors of relapse: No biomarker reliably predicts relapse.	3
		Re-treatment with rituximab Repeat rituximab is recommended for a relapse following rituximab-induced remission.	4
		Pre-emptive re-treatment may be considered in order to reduce relapse rates.	4
Recommendation 4
	How should other immunosuppressive therapies be prescribed in patients treated with rituximab?
		Should CYC be administered concomitantly with rituximab? We do not recommend the routine use of CYC with rituximab. CYC may be considered in severe, life or organthreatening presentations such as rapidly progressive GN in order to achieve rapid disease control.	4
		Should other immunosuppressants be continued following rituximab? No conclusion can be drawn from current data regarding the prescription of other immunosuppressing drugs with rituximab.	N/A
		What glucocorticoid regimen should be adopted in patients treated with rituximab and can glucocorticoids be stopped? High-dose intravenous or oral glucocorticoids may be administered with the initial rituximab course in order to obtain rapid control of disease.	4
		There is no clear evidence to guide steroid tapering.	N/A
Recommendation 5
	How safe is rituximab in ANCA-associated vasculitis?
		There is no convincing evidence that rituximab increases the frequency of severe infections when used in the treatment of vasculitis. Other drug-related adverse events occur with similar frequency to that seen in other indications.	4
		We recommend that patients receive vaccinations at least 1 month before their first dose of rituximab.	3
Recommendation 6. Research agenda

Level of evidence 1 is from meta-analysis of randomized controlled trials.
Level of evidence 4 is from expert committee reports or opinions and/or clinical experience of respected authorities.

June 11, 2011. CPx.

Guerry MJ, Brogan P, Bruce IN, D'Cruz DP, Harper L, Luqmani R, Pusey CD, Salama AD, Scott DG, Savage CO, Watts RA, Jayne DR. Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford). 2011 May 25.[Epub ahead of print]

Cancers during the post-close-out period of WGET (etanercept trial): 13 additional cases, but also in the placebo group

Over the mean 43 months post-trial close-out, there were 13 additional solid malignancies among the 153 WGET patients (who were alive and not lost of follow-up from the initial 180 WGET patients = etanercept or placebo, on top of corticosteroids and cyclophosphamide or methotrexate, for GPA patients - the study showed no benefit of adding etanercept in term of relapse rate, and 6 cancers occurred during the trial period, exclusively in the etanercept group).
More precisely, there were 8 additionnal solid malignancies in the etanercept patients and 5 in the placebo group. Four (2 in each group) of these cancers were fatal. The risk of cancer in the etanercept recipients, after trial close-out, thus appears higher than in the general population (SIR=3.92) but not significantly different than in the placebo group (SIR=2.89; P= 0.39). Notaby, all these cancers occurred in patients who had received cyclophosphamide with quite high cumulative CYC doses (mean of 56 g prior to the trial and 16 g during the trial - the dose received after trial closure was not recorded). Indeed, patients who developed cancer were more likely to have been enrolled with a disease relapse, have a longer disease duration and a past history of cancer. Three of the total 19 cancers that occurred since the trial onset were cholangiocarcinomas (2 in the etanercept group, 1 in the placebo).
The risk of cancer under etanercept thus remains significant, at least as compared to the general population, but there is a clear relationship with the combined and/or previous use of cyclophosphamide (at quite huge doses!). Nowadays, almost no GPA patient is any longer treated with TNF alpha blockers, even others than etanercept (i.e, infliximab or adalimumab which both have been used previously as rescue therapy in some patients, with quite good results sometimes). - 4 May 2011. CPx

Silva F, Seo P, Schroeder DR, Stone JH, Merkel PA, Hoffman GS, Spiera R, Sebastian JK, Davis JC Jr, St Clair EW, Allen NB, McCune WJ, Ytterberg SR, Specks U; for the Wegener's Granulomatosis Etanercept Trial Research Group. Solid malignancies among patients with Wegener's granulomatosis treated with etanercept: Long-term follow-up of a multicenter longitudinal cohort. Arthritis Rheum. 2011 Apr 11 [Epub ahead of print]

Potential pathogenic role of TLRs (toll-like receptors) in initial phases of ANCA-associated vasculitides

Using a mouse model (C57BL/6 mice injected intraperitoneally with MPO, with or without TLR-2 or TLR-9 ligands, then with anti-GBM globulin to trigger glomerulonephritis), Summers et al. demonstrate that TLR-2 ligation induces a Th17 response and production of IL-17A, while TLR-9 ligation favours a Th1 response with production of IFN-gamma. Both TLR ligands enhanced the immune response and production of antiMPO Abs, but with different CD4 subsets and ANCA IgG isotypes. Finally, both TLR ligands enhanced glomerular disease induced by antiGBM globulin, which were attenuated by subsequent injection of anti-IFN-gamma (in the TLR-9 model) or anti-IL17A (in the TLR-2 model). As stated by the authors, these findings support the hypothesis that infection can act as cofactor in the development of autoimmunity and renal disease in AASV, through TLR ligation. Gram-positive germs, including Staphylococcus aureus, are among the germs that can ligate TLR-2, whereas bacterial hypomethylated DNA or viruses can ligate TLR-9. - 23 April 2011. CPx

Summers SA, Steinmetz OM, Gan PY, Ooi JD, Odobasic D, Kitching AR, Holdsworth SR. Toll-like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll-like receptor 9 drives Th1 autoimmunity in murine vasculitis.Arthritis Rheum. 2011 Apr;63(4):1124-35. Link

FDA approval for rituximab (in combination with corticosteroids) for adults with severe forms of granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis

The FDA approval for rituximab use for patients with severe forms of granulomatosis with polyangiitis (Wegener's) or microscopic polyangiitis is based on the National Institutes of Health-sponsored study known as RAVE (Rituxan in ANCA-Associated vasculitis). The news has been largerly disseminated in 'public' health media and journals over the past weeks. You can read the press release HERE. We hope that it will also soon be approved by Health Canada. However, based on expert opinion (including CanVasc), it should be clearly reminded here and emphasized that the indications of rituximab are (and should be for the moment) restrained to severe forms of these diseases that are, in addition, either refractoy to conventional therapies and/or when there is clear contra-indication(s) to conventional therapies. - 21 April 2011. CPx

Another and excellent review on pathogenesis of ANCA vasculitis! NOT to be missed

There have been several (good) reviews on the pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis over the past months, but this one is not to be missed, because written by one of the ANCA vasculitis “popes”, Dr. Charles Jennette. If you missed some steps in that moving topic, this is The article you need to read! Really updated, incisive, clear and complete. - 31 March 2011

Jennette JC, Falk RJ, Gasim AH. Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis. Curr Opin Nephrol Hypertens. 2011 Mar 18. Link

Is there any interest for a combination of rituximab and cyclophosphamide for induction therapy in ANCA-associated vasculitis?

Rituximab (RTX) has recently been shown as a potential alternative to cyclophosphamide (CYC) to induce remission of ANCA-associated vasculitis, based on their non-inferiority in the RAVE and RITUXVAS studies (New Engl J Med, 2010 – link). However, RTX use has not yet been approved in Canada and, thus, it remains at present restricted to refractory and/or multi-relapsing patients. Whether its combination with another immunosuppressive drug, like CYC (cf. RITUXVAS), during induction phase, has any interest, especially in severely affected patients and whether such a combination does not increase the rate of adverse event remain unanswered questions.
N Mansfield, from the London (UK) group, reports 23 consecutive patients with newly-diagnosed or relapsing (1 patient only) renal ANCA-associated vasculitis treated with a customized combination of RTX, CYC and corticosteroids for induction, then azathioprine for maintenance. One-third of the patients were Indo-Asian and their median creatinine at diagnosis was 227 micmol/l. Patients with creatinine >500 micmol/l, alveolar hemorrhage, CNS disease and/or history of previous treatment with RTX were excluded from this study. The customized regimen included RTX (1 g at Days 0 and 14), IV CYC (10 mg/kg at Days 0 and 14, with a maximum of 750 mg per pulse, then every 2 weeks – Days 28, 42, 56 and 70 –, with a maximum of 500 mg per pulse) and oral prednisone (1 mg/kg/d, with a maximum of 60 mg/d, with a subsequent tapering scheme, aimed at reaching a dose of 10 mg/d at week 13, then maintained until month 12). As of month 3, patients were started on azathioprine (2 mg/kg/d) for maintenance. This regimen was devised in 2006, with RTX being considered a CYC sparing agent (median cumulative dose of CYC 3.44 g for induction).
At 6 weeks, all but one patient achieved remission with the assigned regimen (1 suffered severe systemic illness just after his 2nd CYC and RTX doses and, thus, did not receive further doses; he died at month 19, in remission of his vasculitis). At month 6, all patients had a BVAS of zero and “only” one had end stage renal disease requiring definitive dialysis. The median time to reconstitute B cells was 13.8 months in 14 patients; 3 of them had renal and extra-renal relapses and 1 had minor relapse (mainly arthralgias), for each of them within the 6 months following B cell reconstitution and preceded by a rise in ANCA titers. The remaining 9 patients were still B cell depleted after a median follow-up of 78 [27-130] weeks; 1 of them had a minor relapse (mainly arthralgias), while ANCA titers remained stable. All 3 major relapsers achieved remission with a repeat treatment including RTX, and the 2 minor relapsers with a transient prednisone increase alone. Concerning safety, in addition to the patient with severe systemic illness after receiving his 2nd doses of CYC and RTX, there were 5 minor urinary infections and 1 minor lower respiratory tract infection during the first 3 months, then 7 additional non-major infections afterwards (including 1 shingles). Two patients had to stop azathioprine because of hypersensitivity or leucopenia.
It is difficult to conclude based on the results of this open-label study whether a combination of CYC and RTX for induction confers any further benefit than one of these agents used alone for inducing remission and, thus, whether such a poly-chemotherapy has a place in the therapeutic armamentarium for (severe) ANCA-associated vasculitis. Whereas the remission rate was very good (almost 100%), the relapse rate is non negligible (all relapses 22%, major relapses 13%), despite the use of azathioprine for maintenance. However, one would expect a rate of 35% after a similar follow-up of 39 months using conventional staged-treatment with CYC alone then azathioprine, and the overall safety profile of the combination was considered “acceptable”. The relapse rate after remission has been achieved with RTX alone and without any maintenance treatment (RAVE trial design) should be revealed soon, for some additional indirect comparison. - 26 March 2011. CPx

Mansfield N et al. Prolonged disease-free remission following rituximab and low-dose cyclophosphamide therapy for renal ANCA-associated vasculitis. Nephrol Dial Transplant. 2011 Mar 17. Link

Beware of crabs in Las Vegas: paragonimiasis as another (rare) cause of eosinohilic pneumonia after ingestion of crabs in the United States

Human paragonimiasis is a parasitosis (a plathelminthiasis) affecting the lungs (pleural effusion, pneumothorax, pleural and/or parenchymal lung nodules, possibly with cavitation, eosinophilc pneumoniae, sometimes with necrotizing granulomatous inflammation and/or eosinophilic vasculitis on histology). It can be acquired after ingestion of contaminated uncooked crabs, crayfishes or wild boar meat. Blood eosinophilia is usually present (but not constant). CNS, skin or other sites can occasionally be involved as well, depending on the migration of the flatworm. Endemic in several parts of the world, especially Southeast Asia and China, it has rarely been reported in North America, mainly in immigrants.
Authors report 4 patients, who had probably been infected within the United States, including one amazing 46-year-old patient who developed hemoptysia due to a cavitary lesion in his left upper lung 8 months after the ingestion of tiny live crabs served in a Martini at a sushi restaurant in Las Vegas! He suffered of cough for 2 months, then had hemoptysis, due to bilateral eosinophilic pneumonia and his lung cavity. He had blood eosinophilia, positive immunoblott CDC serology for Paragonimus westermani, and a lung wedge biopsy revealed eosinophilic infiltrates and granulomatous vasculitis (no paragonimus egg was observed). Usual treatment (praziquentel for 2 days) was given.
Human paragonimiasis is another, although rare in North America, possible differential diagnosis of eosinohilic pneumonia and Churg-Strauss syndrome. - 26 March 2011

Boland JM et al. Pleuropulmonary Infection by Paragonimus westermani in the United States: A Rare Cause of Eosinophilic Pneumonia After Ingestion of Live Crabs. Am J Surg Pathol. 2011 Mar 15. Link

Under the microscope: Epitope characterization of antiMPO ANCA

The lysosomal enzyme myeloperoxidase (MPO) is the main antigenic target of p-ANCA. Direct pathogenic role of antiMPO have been demonstrated in vitro and in animal models.
In this study, Bruner et al. attempted to better characterize antiMPO target epitopes, using serum samples of 12 p-ANCA positive patients (matched with 12 healthy controls). They synthesized 369 different peptides based on the published sequence of MPO and tested patient’s serum reactivity with each of them in a solid-phase assay and a modified conformatory ELISA. They eventually identified 7 major significant epitopes (bound by >33% of the patients), the 2 most significant ones (epitopes 2 and 6) being bound by 42 and 58% of the patients, respectively. None of these epitopes was bound among the controls. Based on the known and published crystal structure model of MPO (Fiedler et al. 2000, link), they further determined that only one of these 7 epitopes (epitope 3, i.e. SARIPCFLAG–aa 393-402) was within close proximity to the active site of MPO, and that another one (epitope 1) was located in the pro-peptide region, thus not present on the processed mature form of MPO. Two others (epitopes 6 and 7, i.e. RLDNRYQPMEPN–aa 511-522 and IFMSNSYPRD–aa 717-726, respectively) were close to each other in the structural form of MPO (i.e. the MPO heavy chain), with one or both of them being bound by 11 of the 12 patients. Biostatistitical epitope prediction tools further supported the identification of these major epitopes.
In Goodpasture disease, anti-GBM antibodies react with only 1 epitope of the GBM. The identification of >5 different potential targets for antiMPO ANCA is thus of interest and provide some (new) interrogations. Unfortunately, authors did not mention the precise disease status or characteristics of the tested patients, nor did they tested their patients at different disease stages or activity levels. As they acknowledge, it would now have to be further investigated, on a larger scale. - 26 March 2011. CPx

Bruner BF et al. Epitope specificity of myeloperoxidase antibodies: identification of candidate human immunodominant epitopes. Clin Exp Immunol. 2011 Mar 14. Link

 HCV-related vasculitis: prognostic factors

Among patients with active chronic hepatitis C (HCV) infection and related mixed cryoglobulinemia (MC), 5 to 10% develop symptomatic MC vasculitis (usually affecting small-sized vessels). Less frequently, vasculitis may occur in HCV-infected patients without cryoglobulinemia (often a PAN-like vasculitis). Benjamin Terrier and Fabrice Cacoub studied 151 consecutive patients with HCV infection and vasculitis (135 with MC, 16 without MC) followed-up between 1993 and 2009 in their Parisian center. The main HCV genotype was type 1 (62%), and 33% had severe liver fibrosis (Metavir score = 3). The main clinical vasculitis features were peripheral neuropathy (74%), purpura (69%), arthralgia/arthritis (50%) and kidney disease (33%).
With a median follow-up of 54 months, 21% of the patients died (26 patients with MC vasculitis and 6 with PAN-type vasculitis), mainly of infection and end-stage liver disease. Factors associated in multivariate analysis with a poor prognosis were the presence of severe liver fibrosis (HR 10.8), the Five Factor Score (HR 2.49 – however, in patients with Metavir score =3, FFS no longer had prognostic value), and the use of immunosuppressants (HR 4.05, after adjustment for severity of vasculitis). Conversely, the use of the Peg-interferon plus ribavirin combination was associated with a good prognosis (HR 0.34) and short-term corticosteroids, rituximab and/or plasmapheresis had no significant effect on outcome.
 As stated by the author, HCV-vasculitis has a negative impact on the global prognosis of HCV-infected patients, whose mortality rate is eventually as high as that observed in HBV-related PAN patients. In addition, their findings emphasize the higher frequency of severe liver fibrosis in these patients, that also impacts on their prognosis. The more optimistic finding is the beneficial effect of antiviral agents and the absence of negative effect of short-term corticosteroids, rituximab and/or plasmapheresis. Finally, the study “validates” the use of FFS in HCV-related vasculitis, at least in those patients without severe liver fibrosis, in whom liver disease overweights all other parameters. - 19 March 2011. CPx

Terrier B et al. Prognostic factors in hepatitis C virus patients with systemic vasculitis. Arthritis Rheum. 2011 Mar 11; Epub. Link.

Granulomatosis with polyangitiis (GPA): the new name of Wegener's granulomatosis

It is now official. In an effort to get rid of eponyms for disease names, starting from the most controversial ones, an international group of vasculitis experts has renamed Wegener's granulomatosis. It is now to be named Granulomatosis with polyangitis (Wegener's). The reference to Wegener will remain in brackets for several years, until being completely abandonned. Among other reason and justifications, its acronym wil thus be GPA, as opposed to its 'cousin' microscopic polyangiitis (MPA).  - March 5, 2011. CPx

Falk R et al. Granulomatosis with Polyangiitis (Wegener's): An alternative name for Wegener's Granulomatosis; Arthritis & Rheumatism 2011; Epub 3 March 2011.  Link 1 , link 2 . Annals of  Rheumatic Diseases 2011;70:704,link 1 , link2 .  JASN 2011;Epub 3 March 2011, link 1 . (these articles -similar- are not on free access now - you will need to have your own subscriber or institution access to read the full text of the articles).

Physiopathology Review of ANCA-associated Vasculitides

Cees Kallenberg, an internationnally renown expert on vasculitis from Groningen in the Netherelands, has extensively proven to write some of the best, most comprehensive, up-to-date and mind-opening reviews on vasculitis pathogenesis. Here is one of the latest, reviewing all most important findings since the discovery of ANCAs, in vitro and animal experience suggesting a potential pathogenic role of ANCA (at least antiMPO), and recent findings on the possible links with infection (molecular mimicry withStaphylococcus aureus , antiLAMP2antibodies and gram negative bacteria). Update your knowledge! - March 5, 2011. CPx

Kallenberg CG. Pathogenesis of ANCA-associated vasculitides.Ann Rheum Dis . 2011 Mar;70 Suppl 1:i59-63. Link .  (this article is not free of access - you will need to have your own subscriber or institution access to read the full text of the article).

Biologics for Churg-Strauss Syndrome?

There are very few data and studies on biologics such as rituximab (antiCD20, anti B cells) and mepolizumab (antiIL5) in Churg-Strauss syndrome. One recent article from the Boston group reports their experience with short-term use of mepolizumab (only 4 monthly infusions) on 7 patients. All were also receiving prednisone and methotrexate (chronic, moderately active disease) prior to and when receiving mepolizumab (adjunctive therapy). Safety profile appaeared good (transient headaches in 3, mild pruritus in 1, no infection or anaphylactoid reaction, no burst of CSS during treatment). All patients were able to taper prednisone dose while receiving mepolizumab, but on cessation of mepolizumab, CSS manifestations recurred in all but 1 patients. The Rochester group reported their experience with rituximab on 3 ANCA-positive patients with glomerular involvement (thus a specific subset of CSS patients). All patients achieved renal remission using RTX and corticosteroids (but no other immunosuppressant) and none developped severe adverse event (one common upper respiratory tract infection) at 1 year of follow-up. These are very preliminary data and focused on very selected patients. Mepolizumab is currently under investigation in ongoing trials.There have been several promising cases reported with rituximab, but also some more concerning (major bronchospams in some patients with ANCA-negative CSS; Bouldouyre et al. Ann Rheum Dis. 2009 Apr;68(4):606 - link ). - March 5, 2011. CPx

- Cartin-Ceba R et al. Rituximab for the treatment of Churg-Strauss syndrome with renal involvement. Nephrol Dial Transplant. 2011 Feb 16. [Epub ahead of print] Link (this article is not free of access - you will need to have your own subscriber or institution access to read the full text of the article).
- Kim S et al. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol. 2010 Jun;125(6):1336-43. Link (this article is not free of access - you will need to have your own subscriber or institution access to read the full text of the article).