General Information on Vasculitides

Vasculitides are a group of diseases, being all potentially life-threatening and/or affecting vital organs, like heart, lungs or brain, with frequent irreversible damage. Vasculitides are characterized by inflammation of vessel walls , mainly arteries, but sometimes also veins, with or without fibrinoid necrosis and/or granulomas.

Vasculitis can be secondary (to several infections, but also other systemic diseases or cancers, or as a reaction to some medications or toxic exposures, like levamisole-tainted cocaine). Primary vasculitides are presently classified based on the size of the predominant affected vessels:

Large vessel vasculitides affect the aorta and its major branches and include two main conditions: Giant Cell Arteritis which is seen almost exclusively in individuals older than 50 years and which can cause irreversible blindness in up to 15-20 percent of cases, and Takayasu’s arteritis, which affects mostly woman younger than 40 years and is a cause of extremity claudication and strokes.
Medium vessel vasculitides include Polyarteritis Nodosa which can affect individuals of all ages and cause infarction of multiple organs, including the gut, kidneys, heart, muscle and nerves. Before the development of anti-hepatitis B virus vaccine, and the subsequent massive vaccination campaign worldwide, more than half the cases of polyarteritis nodosa were due to HBV infection. In contrast, Kawasaki Disease is seen mostly in children younger than 4 years and it has a predilection for the coronary arteries.
Small vessel vasculitides include several entities. The most "famous" ones are associated with the presence of antineutrophil cytoplasm antibodies (ANCA) in the serum of affected patients (at least some of them). These ANCA-related vasculitides include Granulomatosis with Polyangiitis (Wegener’s) , Microscopic Polyangiitis and Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). These diseases are the most frequent cause of pulmonary-renal syndrome which is characterized by lung hemorrhage and rapidly progressive renal failure. Non ANCA small vessel vasculitides include many different entities, including Henoch-Schönlein purpura which is usually a self–limited disease seen mostly in children, and cryoglobulinemic vasculitis (most commonly associated with chronic hepatitis C virus infection). Recently, Goodpasture syndrome (anti-glomerular basement antibody disease) has been added to the list of small-sized vessel vasculitides. This disease is also characterized by pulmonary-renal syndrome, but other type of auto-antibodies (anti-GBM, rather than ANCA) and usually no other organ involvement.
Other vasculitides: Behcet's disease is a particular vasculitis that can affect vessels of all sizes, including the veins.Isolated CNS vasculitis is an extremely challenging condition as it diffusely affects the vessels of the brain giving rise to a host of different clinical manifestations. Buerger's disease (obliterans thromboangiitis) causes digital ischemia and gangrenous lesions, due to medium- and small-sized artery vasculitis and thrombosis, but also superficial vein thromboses and concern almost exclusively smokers (classified as a medium-sized vessel vasculitis in Japan). Anti-GBM (glomerular basement membrane) antibody disease (sometimes named Goodpasture disease when it affects lung and kidney) has been recently included officially in the list of vasculitides, mainly affecting small sized vessel, and causing renal disease (with linear deposition of antiGBM antibodies) and/or alveolar hemorrhage.

Vasculitides are rare diseases. There is no epidemiological study on vasculitides in adults in Canada, and few have been done in the United States. However, based on European, Australian, New-Zealander and Japanese studies, one can estimate the overall prevalence and annual incidence ranges of these vasculitides as follows:

Vasculitis Prevalence (per million) Remarks Annual Incidence (per million) Remarks

GCA 1,400-16,000
(of population >50 y-o) Crude estimates (no specific study) 100-300
(of population >50 y-o) Down to 5 in Israel in late 1960s; Up to 370 in Norway in mid 1990s; 20 in subjetcs <60 and up to 520 in those >80 y-o in Minnesota

Takayasu 4-8 4.7 to 7 in the UK in early 2000s; Up to 40 in Japan (no epidemiological data for India, but probably at least the same) 1-2 Down to 0.4 in Germany; Up to 2.6 in Minnesota in late 1970s, and 3.3 in Kuwait

PAN 22-31
(in the late 1990s) HBV-related PAN almost disappeared 0.9- 6.8 Up to 8 in the UK, 16 in Kuwait in the late 1990s, and 77 in Alaska in late 1980s (HBV endemy)

Kawasaki - Acute disease (in general, but damage)
50-200
(of children <5 y-o)
Down to 16 in Czech republic in late 1990s; Up to 1800 in Japan; in US, 91 in Caucasian vs. 320 in Asian children in early 2000s

GPA 50-90 Down to 23 in Paris in 2000, 30 in NYC in 1990; Up to 160 in Sweden in 2007 5-10 Down to almost 0 in Japan, 2.9 in Spain; Up to 11 in Australia and Minnesota

MPA 25-50 Down to 25 In Paris in 2000; Up to 94 in Sweden in 2007 5-10
Down to 2.7 In Germany;Up to 15 in Japan, and 24 in Kuwait

CSS 10-15 Down to 7 in Germany in 1994; Up to 22 in Australia in 2004 1-2 Down to 0 in Japan; Up to 2.7 in the UK in late 1990s, and 4 in Minnesota in late 1970s

Behçet 10-500 Extremely wide ethnic variations (from 6 in the UK in late 1970s to 4,200 in Turkey in 2000); 100-300 in US , mainly in immigrants; 24 in European-descent vs. 175 in Asian-descent vs 350 in Norh-African- descent French population - No precise estimation (chronic disease and wide geographical differences); around 4 in Minnesota in mid 2000s

CNS-V - No data 2.4 Only 1 study, in Minnesota

Because research on vasculitides is a rapidly moving field, we do not intend to provide here more information on pathophysiology, treatment, outcomes on vasculitides. This would be rapdily outdated and potentially misleading for physicians and/or patients. Excellent reviews are regularly published and will be listed in the news (see below on this page) for you to update your knowledge on vasculitides. Attending the Annual CanVasc meetings or lectures given by its members is also another very valuable option to update your knowledge on this hot topic! (see meetings page ). You can also refer to a selection of other websites with good content (see links page ).

Selected News and Articles ("CanVasc Journal watch")

NOTE: Due to copyright policies, we can not directly provide here the full texts of the commented articles. Links will lead you to the Journal pages of the articles, where you will be able to get acces to them, through a single article purchase or through your own subscriber account or that of your institution. In case of major, vital and urgent need to get access to one of the articles, you still may try to contact us by email if you have no other options.

Quick overview of main abstracts presented at past ACR meeting (Chicago, IL) in November 2011 -> click here

This summary is for you to have a quick overview of the main abstracts but, of course, we invite you to read the full abstracts, of which you are interested in, and have a look on the (few) ones not included in this selection (including the very good abstract #2372, page S925 of the abstract book and to be publish soon in extenso ++++ and the one on rituximab in vasculitis-associated rheumatoid arthritis, whose article has been published since and is commented below on this page). - CPx, January 17, 2012.

Link to downwload the 2011 ACR abstract book HERE (free access for the moment).

Health Canada approves rituximab for induction of remission of severe GPA and MPA in adults

A Notice of Compliance (NOC) has been issued on December 13th, 2011, for rituximab following Priority Review for the following indication: rituximab (RITUXAN) in combination with glucocorticoids is indicated for the induction of remission in adult patients with severely active granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis) and microscopic polyangiitis (MPA). As a reminder, this same indication for rituximab has been approved in April 2011 by the FDA, based on the simultaneously published results of the RAVE and RITUXVAS trials. As stated at the end of official communication, consideration should be given to current treatment guidelines for vasculitis.
This approval may eventually facilitate the access and coverage of this expensive drug (rituximab) for patients with severe GPA or MPA for whom it is indicated and there is no safe or appropriate alternative. However, this approval is only a (huge) first step. Now, it has to be approved by each Canadian province separately, before it changes anything in the patient access to rituximab and the coverage of the drug costs. - CPx, December 13, 2011.

More information soon on Health Canada website http://www.hc-sc.gc.ca

Neutrophil microparticles as potential pathogenic players in ANCA vasculitis (GPA)

Microparticles are membrane vesicles released upon activation or apoptosis from various cells, including platelets, endothelial cells or neutrophils. The two former types have been reported to be increased in the plasma of children with active ANCA vasculitis. Hong et al. studied here plasma neutrophils MPs from 9 children with active ANCA+ GPA (median age 16 years), 4 with inactive ANCA+ GPA, and 4 with other active (ANCA-) vasculitis (3 PAN, 1 KD). Eight healthy pediatric subjects were used as controls.
In vitro, freshly isolated neutrophils from healthy adults released large amounts of MPs after being primed with TNF-alpha then exposed to polyclonal antiMPO or antiPR3 Abs from children with active GPA, but not if unprimed or after exposure to healthy control polyclonal IgG. These released MPs overexpressed PR3, MPO and CD11b as compared to spontaneously released neutrophil MPs. When incubating these MPs (released from primed neutrophils exposed to antiPR3) and HUVEC (human umbilical vein endothelial cells), a binding of MPs to HUVEC was observed, mediated by CD18 expression by MPs. Moreover, following this binding, HUVEC endothelial cells showed upregulation of ICAM-1 expression, an adhesion molecule which is also a surrogate marker for endothelial activation. The binding of MPs to HUVEC was also associated with an increased secretion by endothelial cells of IL6 and IL8. Notably, antiCD18 monoclonal Abs were able to block this binding of MPs to HUVEC as well as the activation of endothelial cells after the binding of MPs and the release of IL6 and IL8 by HUVEC. Authors further demonstrated that the upregulation of ICAM-1 after binding of MPs was related to the induction and increased production of intracellular endothelial reactive oxygen species, which could be inhibited by HUVEC pre-treatment with antioxydants (either a SOD mimetic manganese derivative (MnTBAP) or apocynin). Finally, authors showed that these neutrophil MPs generated thrombin (suggesting a potential pro-thrombotic effect of MPs) and that children with active GPA had higher plasma levels of neutrophil MPs as compared to both children with inactive GPA or other vasculitis.
Neutrophil MPs may thus contribute to the pathogenesis of ANCA vasculitis (at least pediatric antiPR3+ GPA). After both neutrophil priming and exposure to ANCA, these MPs expressed PR3 and MPO, thereby potentially eliciting auto-immune and inflammatory response, and bound to endothelial cells, activating these latter. However, non-bound MPs have been previously shown by other groups to possibly exert opposite anti-inflammatory effects. The balance between the different MPs may thus be more subtle in vivo... New therapeutic agents, including antiCD18 m-Abs and anti-oxydant agents, or mechanisms by which adjuvant approaches act , such as plasma exchange to clear MPs, have to be further investigated based on these results. - CPx, December 11, 2011.

Hong Y, Eleftheriou D, Hussain AA, Price-Kuehne FE, Savage CO, Jayne D, Little MA, Salama AD, Klein NJ, Brogan PA. Anti-Neutrophil Cytoplasmic Antibodies Stimulate Release of Neutrophil Microparticles. J Am Soc Nephrol. 2011 Nov 3. [Epub ahead of print]. Link

Induction therapy for GPA/MPA based on oral cyclophosphamide is associated with a lower relapse rate, as compared to IV pulse cyclophosphamide, 4 years after CYCLOPS study closure

The EUVAS group reports on the follow-up of the patients enrolled in the CYCLOPS trial, which compared continuous oral cyclophosphamide (2 mg/kg/d until remission, then 3 additional months for consolidation, followed by azathioprine for maintenance) versus pulse IV cyclophosphamide (15 mg/kg on days 1, 14 and 28 then every 3 weeks until remission, then 3 additional pulses for consolidation, followed by azathioprine for maintenance) for induction in patients with either granulomatosis with poylangiitis (GPA, Wegener) or microscopic polyangiitis (MPA). At 9 months, the same proportion of patients achieved remission (BVAS=0, around 88% in each arm). Only the rate of leukopenia was more frequent in the oral CYC arm, but which was not associated with a higher risk of infection. At 18 months, 15% of the patients experienced a relapse, with a non-significant difference between groups (19% in the IV versus 9% in the oral group).
With a follow-up post-closure of the trial of 4.3 years, this difference in the rate of relapse has become significant: 40% of the IV pulse recipients have experienced a relapse, as compared to only 21% of those having received continuous oral cyclophosphamide (HR=0.50, p=0.03). AntiPR3+ patients were also more likely to have experienced relapses, as compared to antiMPO+ patients. Conversely, there was no difference between arms for the frequency of infection, the progression to end stage renal disease (ESRD, IV 13% versus oral 11%), VDI scores, or rates of other adverse events. As a reminder, oral cyclophosphamide recipients had received a cumulative dose of 16 g, as compared to only 8 g for the IV pulse cyclophosphamide patients (the cumulative dose of prednisone was comparable between groups, as was the use of immunosuppressant drugs after trial closure, even though they have not been extensively gathered).

This follow-up analysis is interesting but was not planned on a statistical point of view and thus the results of this study remain only indicative and not definitive. This difference in the rate of relapse does not dismiss pulse IV cyclophosphamide as induction therapy, but illustrates the subtle balance between safety and toxicity of cyclophosphamide. A higher cumulative dose (using oral cyclophospamide) is associated with a reduced relapse rate, but a lower cumulative dose could also reduce the risk of infection (even though no difference in infection rate was observed in the CYCLOPS and in this follow-up studies) and the risk of delayed cyclophosphamide-related toxicity, such as infertility or late cancers (even though a cumulative dose of 16 g is certainly not as toxic as what was used in the past, when patients were given oral cyclophosphamide for more than 1 year). - CPx, December 11, 2011.

Harper L, Morgan MD, Walsh M, Hoglund P, Westman K, Flossmann O, Tesar V, Vanhille P, Groot KD, Luqmani R, Flores-Suarez LF, Watts R, Pusey C, Bruchfeld A, Rasmussen N, Blockmans D, Savage CO, Jayne D; on behalf of EUVAS investigators. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis. 2011 Nov 29. [Epub ahead of print] Link

Rituximab for systemic vasculitis associated with rheumatoid arthritis

Xavier Puéchal et al. (France) report their experience with rituximab for the treatment of 17 patients with systemic vasculitis associated with rheumatoid arthritis (RA). These patients have been enrolled in a larger prospective cohort of 1,994 RA patients treated with rituximab at least at one occasion during the course of their disease (AIR registry).
Mean age of these 17 patients, when receiving their first rituximab infusion, was 63.5 years and mean duration of RA was 29.5 months. Clinical manifestations of vasculitis mostly included mononeuritis multiplex (n=13) and/or cutaneous lesions (n=12). None had renal or CNS manifestations. Approximately one-third of the patients (only) had previously received cyclophosphamide and/or a TNF blocker. Rituximab induction regimens slightly varied, with 13 of the patients having received 1g, 2 weeks apart, in combination with corticosteroids in all but one of the patients and/or methotrexate in 8, cyclophosphamide in 1, and azathioprine in 1.
Twelve (71%) of the patients achieved complete remission (modified BVAS for RA, not including arthralgias or arthritis, BVAS/RA= 0) at month 6; 4 (24%) achieved partial remission at month 6; 1 patient died at month 5 from gangrene and sepsis (active vasculitis with necrotic leg ulcers and mononeuritis multiplex). BVAS/RA fell from 9.6 at baseline to 3.6 at 3 months and 0.6 at 6 months; mean daily prednisone dose was reduced from 19.2 mg at baseline to 9.7 mg at month 6. Patients who received rituximab as first line therapy responded better than the relapsers and/or patients refractory to more conventional agents (87.5% achieved complete remission as compared to only 50%, respectively). Concerning RA itself, DAS28 synovitis score fell from 4.81 at baseline to 3.79 at month 6. Whether response to rituximab differed based on ACPA status was not studied/reported.
Preemptive maintenance therapy was given to 6 of the patients who achieved complete remission, with a repeat infusion every 6 months. None of them relapsed. Conversely, 3 out of the 9 patients who received only methotrexate for maintenance or no maintenance therapy at all relapsed. Repeat rituximab induction therapy achieved complete remission again in these latter.
In addition to the patient who died from gangrene with sepsis, 2 patients experienced severe infections (subcutaneous abscess due to Fusobacterium nucleatum at day 4 post-first rituximab infusion; relapse of an elbow prosthesis infection at month 6).- CPx, December 10, 2011.

Puéchal X, Gottenberg JE, Berthelot JM, Gossec L, Meyer O, Morel J, Wendling D, de Bandt M, Houvenagel E, Jamard B, Lequerr T, Morel G, Richette P, Sellam J, Guillevin L, Mariette X; on Behalf of the Investigators of the AutoImmunity and Rituximab registry. Rituximab therapy for systemic vasculitis associated with rheumatoid arthritis. Results from the autoimmunity and rituximab registry. Arthritis Care Res (Hoboken). 2011 Nov 10. [Epub ahead of print] Link

Two excellent reviews: one on the pathogenesis of ANCA vasculitides and the other one on Churg-Strauss syndrome

The annual theme issue on vasculitis of Current Opinion in Rheumatology includes two excellent reviews by specialists in the fields. The first one on the pathogenesis of ANCA vasculitis is complete, updated and very clear. The second one on the Churg-Strauss syndrome is quite original and focused mainly on the latest data on pathogenesis. An issue not to be missed, especially for these two articles. - CPx, December 2, 2011.

Vaglio A, Moosig F, Zwerina J. Churg-Strauss syndrome: update on pathophysiology and treatment. Curr Opin Rheumatol. 2011 Nov 13. Link
van Timmeren MM, Heeringa P. Pathogenesis of ANCA-associated vasculitis: recent insights from animal models. Curr Opin Rheumatol. 2011 Nov 13. Link

Interleukin-2 as a potential treatment for HCV-induced vasculitis

Every article on vasculitis published in the New England Journal of Medicine deserves to be highlighted. Such an event emphasizes the growing interest for vasculitis in the medical community and the fast-pace advances in therapeutic management of these rare but potentially severe diseases. David Saadoun and Michelle Rosenzwajg et al. (Paris, France) report their experience with IL-2 in 10 patients with HCV-related vasculitis (open-label, phase 1-2 trial). This research group is already world renowned for its studies on HCV infection and HCV-related vasculitis.
IL-2 is a potent T effector cell stimulator, increasing immune responses against cancer and infections, but it also induces survival of Tregs, that can exert opposite effects in cancer patients or hamper the clearance of infectious agents. Experimental model of IL2 knock-out mice suggested that IL-2 was essential for the development, expansion, activation and survival of Tregs to greater degree than for the stimulation of effector T cells.
In HCV infected patients, mixed cryoglobulin can be detected in 40-60%, but only 5-10% of them will suffer of cryoglobulinemic vasculitis, ranging from arthralgias, purpura to severe mononeuritis multiplex or glomerulonephritis. HCV-induced vasculitis has been shown to be associated with a Treg quantitative deficiency. Therefore, the attempt to treat such patients with IL-2.
Ten patients with chronic HCV infection (HCV RNA+ in sera, mixed cryoglobulinemia >0.05 g/l, active vasculitis, resistance to previous treatment with antiviral drugs - including Peg-IFN-alpha and ribavirine - and rituximab, absence of cirrhosis, and no co-infection with HIV or HBV) received IL-2 at low doses (1.5 million units per day of SQ aldesleukin for 5 days over one week, followed by 3 other 5 day-courses of 3 million units per day, given at weeks 3, 6 and 9). They were aged a median of 58.5 years, with 1:1 sex ratio. None were receiving concurrent antiviral drugs, immunosuppressant or corticosteroids. Eight of them had purpura, 8 had peripheral neuropathy and 1 had renal disease. All had type II cryoglobulin (median of 0.53 g/l with MC IgM kappa in all cases). The mean duration of HCV infection was 30.2 years, and most of the patients (n=7) had genotype 1 virus. Main adverse effects of IL-2 injections were minor and transient, including asthenia (n=4), flu-like syndrome (n=4) and hypertension (n=1). There was no vasculitis flare and a modest decrease in HCV viral load was observed, as well as of cryoglobulin levels. Tregs CD4+ CD25high FOXP3+ increased from 3.6% of the circulating CD4+ T cells at baseline (lower than in healthy blood donors) to 11.8% at week 9 (primary study end point, p= 0.004). This increase in Tregs peaked after the 3rd IL-2 course and corresponded to a 420% increase in the proportion of Tregs. In addition, at day 150 (week 19), the proportiong of Tregs remained significantly higher (6.1%) thanat baseline, i.e. close to the normal range of values for healthy subjects. These Tregs were demonstrated as functionnal< EM> in vitro< /EM> , and accompanied by an increased in suppressor CD8+ CD25+ FOXP3+ T cell count. A decrease in (marginal-zone) B cell number and an increase in NK cell were also observed, both of which returned to normal after cessation of IL-2. Eventually, 8 of the 10 patients showed clinical improvement (purpura disappeared in all the 8 patients with skin lesions; only 2 patients with isolated neuropathy - both with type 4 HCV genotype - did not respond to IL-2 therapy). Improvement was noted as of the first infusion in two patients and after the 2nd course in the remaining six who improved.
This study remains small-sized, rather exploratory and concerned patients with refractory vasculitis, but it elegantly demonstrates the safety (at least after 4 months of follow-up) and potential benefit of low-dose IL-2 treatment in such condition. At such dose, IL-2 favoured the development of Tregs rather than the stimulation of T effector cells, which would be potentially harmful in auto-immune and/or inflammatory diseases. - CPx 30 November 2011.

Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, Sene D, Cacoub P, Klatzmann D. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. New Engl J Med 2011;365:2067-77 - December 1st, 2011. Link.

Granulomatous manifestations of GPA are less responsive to rituximab than vasculitic ones.

The impression that granulomatous GPA manifestations could be less often (or not as rapidly) responsive to rituximab has already been occasionnaly reported (Brihaye et al. Clin Exp Rheum 2007; Aries et al. Ann Rheum Dis 2006), but this larger retrospective study from the German group on 59 patients who received rituximab for refractory GPA is more demonstrative. The overall response to rituximab in these patients was 61.3% (26.7% were refractory) after a median of 7 months of follow-up post-rituximab, with no try of a second induction course in case of non-response and no rituximab-based maintenance regimen. Notably, 54.7% of the patients received concommittantly cyclophosphamide. The absence of response was more frequent in patients with retro-orbital tumors (33.3%) and/or pachymeningitis (33.3.%), as compared to those with lung nodules ("only" 16.7%), alveolar hemorrhage (8.3%), renal disease (15.4%), neuropathy (0%) or arthralgias (0%). Surprisingly, subglottic stenosis was refractory in "only" 12.5% of the patients (1 among 8 patients). Globally, vasculitic manifestations were refractory or unchanged (stable but not improved) to rituximab in 9.4% of the cases as compared to 41.8% for the granulomatous manifestations (the same patients could have both types of manifestations of course - with 37% of the patients having 2 refractory manifestations or more). Finally, among the 36 patients who achieved complete remission, after a median follow-up of 13.5 months, 44.4% relapsed (at a median time of 13.5 months [3-54] post-rituximab induction). Three-quarters of these relapsers received a repeat rituximab-induction course and achieved again a good response. All patients had a decrease in their IgG/M levels but not correlated with infections (that occurred in 28.9% of the patients).

Whether patients with such refractory granulomatous manifestations who do not achieve remission (complete or partial) at month 4 to 8 post-rituximab should receive a second induction course of rituximab or be considered as failure to rituximab and switched to another treatment (which one?) remains to be determined. Subsequent treatments and outcomes of these rituximab-refractory patients are not mentioned in this, however, very interesting and good article. - CPx 20 November 2011.

Holle JU, Dubrau C, Herlyn K, Heller M, Ambrosch P, Noelle B, Reinhold-Keller E, Gross WL. Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann Rheum Dis. 2011 Oct 21. [Epub ahead of print] Link

Lebrikizumab: a new kid on the block for (a specific subset of) asthma patients

This article is not on vasculitis, but might lead to some future researches in Churg Strauss syndrome (CSS). Results of the study have also been presented orally at the European Respiratory Society meeting, on September 26, 2011. Asthma is indeed the background condition of CSS, present in more than 90% of the patients at diagnosis (usually, late onset asthma). Lebrikizumab is a humanized IgG4 monoclonal antibody, further altered by a single point mutation in the hinge region to enhance its stability, and that specifically binds to IL-13 and inhibits its function. IL-13 is produced by Th2 helper T lymphocytes, which contribute to many key features of asthma (and also CSS).
This double-blinded randomized placebo-controlled study evaluated 219 patients with uncontrolled asthma (Asthma control questionnaire - ACQ5 score higher than 1.5, despite the use of inhaled corticosteroids for at least 6 months, with FEV1 between 40% and 80%). Patients on maintenance oral corticosteroids were not eligible. Mean age of the patients was 44 years and ACQ5 was 2.5. All were taking inhaled corticosteroids and 80% were also on long-acting beta-agonists.
Given subcutaneously once a month and for 6months, lebrikizumab at the dose of 250 mg per injection achieved a greater increase in prebronchodilator FEV1 by a mean of 5.5% (95% CI, 0.8-10.2) as compared to placebo at week 12 (primary outcome measure). Notably, this improvement was mainly, if not exclusively, observed in patients with high level of periostine at baseline (a surrogate marker for IL-13 level, which is difficult to measure). Those latters with high periostine level represented almost half of the enrolled patients and achieved a 8.2% (95% CI, 1.0-15.4) increase of their FEV1 as compared to placebo, whereas those with lower baseline periostine level had their FEV1 increased by only 1.6% (95% CI, –4.5-7.7) as compared to placebo. These differences were observed as soon as week 1 after the 1st injection and were sustained until the end of patient follow-ups at week 32. However, changes in ACQ5 and in the rate of asthma exacerbations were not significantly different between arms (there was a trend for a lower rate of exacerbation in those patients with higher periostine level). Whereas IgE level decreased, eosinophil count slighlty increased in the lebrikizumab recipients (by a mean of 0.11x109/l as compared to placebo, p<0.001). Safety analysis yielded similar results for both lebrikizumab and placebo (2 major asthma exacerbations requiring hospital admission in both arms; 1 patient in the lebrikizumab arm had pneumonia, whereas 1 in the placebo had shingles and another one had acute purulent meningitis).
In summary, lebrikizumab led to a significant, though modest, improvement of the primary paraclinical outcome measure (FEV1) in patients with uncontrolled asthma, that was sustained over time and after the cessation of the drug (at least until month 26 post-termination of the injections). Clinical benefit was less obvious (no change in ACQ5 or rate of exacerbation). Patients with higher periostine at baseline (i.e., though indirectly, with higher IL-13 level) responded better to the biological agent. There was no particular safety issue, but eosinophil count slightly increased under lebrikizumab (because the blockade of IL-13 leads to less influx of eosinophils from the blood into the lungs, as suggested by authors? but one cannot exclude that an increase production of some other cytokine or chemokine causes this increase in eosinophil count, to compensate the inhibition of IL-13 signal); However, none of the patients developed vasculitis manifestation or CSS. The action of the drug in patients taking oral corticosteroids now deserves to be studied (most of the CSS patients because of persistent asthma), as well as in patients with more pronounced hypereosinophilia (allergic asthma or, again, CSS patients). – CPx, 26 Sept 2011.

Corren et al.Lebrikizumab Treatment in Adults with Asthma. N Engl J Med 2011;365:1088-1098. Link
Editorial by Monica Kraft (Asthma Phenotypes and Interleukin-13 — Moving Closer to Personalized Medicine) - link.

A comprehensive review on the roles of TH1 (IFN-gamma) and TH17 (IL17) pathways in GCA

C. Weyand et al. provide an excellent review on GCA pathogeny, emphasizing that both IFN-gamma- and IL17-producing T lymphocytes are implicated and respond differently to corticosteroid therapy. Whereas TH17 pathways is rapidly disrupted by corticosteroids, mainly through suppression of IL1-beta, IL6 and IL23, TH1 (IFN-gamma) pathway remains almost unaltered. As stated by authors,GCA is thus a chronic disease characterized by persistent TH1-inducing signals. Aspirin and supra-high doses of corticosteroids can alter TH1 pathway, but to a very limited degree. Hence, combined/new therapies are needed for better disease control (such as agents targeting TH1 pathways, like perhaps anti-IL12 or anti-IL32, or both TH1 and TH17 pathways, like NOTCH blockers/inhibitors). - CPx. 08 August 2011.

Weyand CM, Younge BR, Goronzy JJ. IFN-? and IL-17: the two faces of T-cell pathology in giant cell arteritis. Curr Opin Rheumatol. 2011 Jan;23(1):43-9. Link
Further reading: Piggott K, Deng J, Warrington K, Younge B, Kubo JT, Desai M, Goronzy JJ, Weyand CM. Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis. Circulation. 2011 Jan 25;123(3):309-18. Link

Smell and taste alterations in granulomatosis with polyangiitis (Wegener's)

Many of our patients with GPA complain of smell and/or, less often, taste alterations. The reasons can be multiple, including adverse events of medications, sinusitis, sometimes with cacosmia or phantosmia due to mucosal crusting, or olfactive and/or gustatory nerve involvement(s). In this study, 16 GPA patients were evaluated for their smell and taste using visual analogue scales (VAS) and different "Sniffin' sticks" (for 16 common odours) or paper taste strips (impregnated in 4 variable concentrations of sweet, sour, salty or bitter taste). Normative values for these tests are known and 16 healthy age- and gender-matched subjects were used in addition as controls.
At the time of investigations, none of the patient had crusting rhinitis, but 62% had nasal septum perforation as damage. None was current smoker. Subjective olfactory function was rated a mean of 65.7/100 (vs. 83.8 for controls; p=0.03) and gustatory function 67.2 (vs. 83.5 for controls; p= 0.02). For olfactory functions, all tests were affected but odour threshold was the main affected one, prior to odour discrimination and identification. For gustatory functions, there was no major difference between GPA patients and controls. There was only a non-significant tendency for GPA patients to have lower scores in the qualities of sour, salty and bitter sensations. For all these tests, there was no difference according to the other extra-ENT disease characteristics. Even though treatments were recorded in this study, authors were not able, due to the small sample size, to identify any association with taste or smell abnormalities and any of the received drugs. In the discussion, they mention studies on olfaction in rheumatoid arthritis that showed that low-dose corticosteroids, rather than anti-TNF-alpha or methotrexate, were associated with some olfactory threshold abnormalities. The impact of these gustatory and olfactory disorders on the patient quality of life should be taken into account more than it is at present. - CPx. 06 August 2011.

Fasunla JA, Hundt W, Lutz J, Förger F, Thürmel K, Steinbach S. Evaluation of smell and taste in patients with Wegener's granuloma tosis. Eur Arch Otorhinolaryngol. 2011 Jul 12. [Epub ahead of print]. Link.

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