Vasculitis—aims of therapy Meeting Report, Cambridge, 10–11 September 1999

S. E. Lane and R. A. Watts1,

Norfolk and Norwich Hospital, Norwich and
1 Ipswich Hospital, Ipswich and School of Health, University of East Anglia, Norwich, UK


    Introduction
 Top
 Introduction
 
The meeting opened with the announcement of the tragic death shortly before the meeting of Dr Martin Lockwood, a member of the organizing committee. Sir Keith Peters gave a tribute to Martin Lockwood and dedicated the meeting to his memory.

Charles Pusey (London, UK) introduced the first session by asking whether enough is known about the pathogenesis of systemic vasculitis to identify ‘targets of therapy’ and reviewed current knowledge of genetic and environmental factors together with cellular and cytokine mediators of inflammation in vasculitis. He suggested several approaches to improving therapy by modifying standard drug regimes, developing newer agents such as mycophenolate mofetil, biological agents and gene therapy. Successful clinical and animal studies have shown promising routes for the modulation of the immune and inflammatory response. T-cell activation has been targeted in several ways in animal models, including monoclonal antibodies (Mab) against CD4, CD8, interleukin-2 (IL-2) receptors (IL-2R), T-cell receptors, major histocompatibility complex (MHC) molecules and costimulatory molecules including CD40L, CD80/86. Both anti-CD52 (Campath 1) and anti-CD8 Mabs have been used successfully in patients. Antibodies to adhesion molecules leucocyte function associated antigen (LFA), very late antigen (VLA), intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) (LFA-1, VLA-4, ICAM-1, VCAM-1), and cytokines [tumour necrosis factor-{alpha} (TNF-{alpha}), IL-1ß] and the use of anti-inflammatory cytokines (IL-4, IL-10) have produced promising results in animal studies. Other anti-inflammatory approaches investigated in various models include complement, leukotrienes, platelet activating factor, reactive oxygen species (ROS) and nitrogen oxide. Antibodies to platelet derived growth factor and transforming growth factor-ß (TGF-ß) may prevent proliferation and scarring, respectively. He concluded that although lessons can be learned from other autoimmune diseases and transplantation, there is a lack of experimental models for systemic vasculitis and limited understanding of pathogenesis.

David Scott (Norwich, UK) provided an overview of current knowledge on the epidemiology of vasculitis. Until recently, difficulties of classification and definition have made the comparison of studies impossible. However, the increasing use of the Chapel Hill Consensus definitions and American College of Rheumatology criteria has made such comparisons possible. He observed that previously the term ‘polyarteritis nodosa’ was used as a generic name for all types of primary necrotizing vasculitis, this makes the interpretation of older studies difficult as many patients would now be considered to have another type of vasculitis. He noted that the majority of studies come from Europe and the USA, and there are very few data from elsewhere. Most of the data on giant cell arteritis come from Scandinavia where the incidence appears to be increasing. There are too few data on the primary necrotizing vasculitides to draw any firm conclusions as to whether there is a genuine increase in incidence or whether the observed differences reflect changing definitions. Overall, the annual incidence of the primary necrotizing vasculitides is around 20/million.

Richard Watts (Ipswich, UK) reviewed the role of environmental factors in the development of vasculitis, again there is a paucity of data. Giant cell arteritis has an increasing incidence with more northerly latitude; whether similar trends exist for the primary necrotizing vasculitides is unclear. However, polyarteritis nodosa and microscopic polyangiitis may be more common in southern latitudes. He reviewed studies looking for possible infectious triggers: cyclical periodic peaks have been described for both giant cell arteritis and the primary necrotizing vasculitides, but no triggering agent has been identified. In Denmark, mycoplasma pneumoniae infection has been associated indirectly with disease peaks. Hepatitis B and C infections are clearly associated with polyarteritis nodosa and cryoglobulinaemia, respectively. Silica exposure has been linked with microscopic polyangiitis and glomerulonephritis.

Herman Waldmann (Oxford, UK) described his vision of the future of immunomodulation in vasculitis, shared with Martin Lockwood, as achieving long-term remission from a single short course of therapy by promoting the resetting of the immune system and induction of tolerance. He highlighted the failings of standard immunosuppression, which penalizes the entire immune system, requiring long-term administration and has significant side-effects, including interference with tolerance. He explained the concepts of T-cell tolerance and that the immune system requires collaboration between B and T cells. The aim of immunotherapy is to reduce the number of collaborative (B and T cell) units to induce T cell tolerance and helplessness. In mouse models of acute skin graft rejection, anti-CD4 Mabs are able to make activated T cells tolerant, and skin grafts can be achieved across a complete MHC mismatch. Anti-CD4 Mabs alone are capable of inducing tolerance where there are small numbers of autoreactive T cells, but anti-CD8 Mabs are required in addition when there is a greater number of T autoreactive cells. Campath-1 was originally developed as a lymphocyte depleting Mab. It has now been used to treat multiple sclerosis, rheumatoid arthritis and vasculitis, as well as in transplantation medicine. He discussed the problem of immunogenicity. Humanized and chimeric Mabs are immunogenic as they still contain rodent sequences. Cell binding Mabs such as Campath-1H are immunogenic, whilst non-cell binding Mabs are not. Therefore, to overcome this problem it may be necessary to engineer a non-cell binding variant of Campath-1H. The use of such Mabs may enable the self-reactive immune system present in autoimmune disease to be reprogrammed to be self-tolerant.

Michel Kazatchkine (Paris, France) introduced the concept of natural autoantibodies. Autoreactive B and T cells are physiologically present in healthy individuals. These autoreactive repertoires are selected early in ontogeny. Natural autoantibodies are present in germ-free individuals, are highly polyreactive and show a high degree of connectivity. They are not produced in response to cross-reaction with non-self antigens. The specificity of natural autoantibodies is not random and does not vary with external antigen stimulation. Self-reactive autoantibodies against the acute phase response may lead to spontaneous remission in autoimmune disease, reproduction of this effect could potentially lead to a cure. Autoimmune disease may arise from an imbalance between effector/regulatory T cells, effector/regulatory antibodies, and host genes that define the autoimmunity of an individual patient. Identifying, selecting and stimulating the B- and T-cell subsets which are dominant for self-T cells offers a therapeutic opportunity for the future and underpins the rationale for lymphoid depletion, stem cell transplantation and intravenous immunoglobulin (IVIg). The mechanism of action of IVIg is still unknown, but IVIg contains autoantibodies which recognize a wide variety of specificities both soluble and membrane bound, together with idiotypes and anti-idiotypes. The interaction of these autoantibodies with the recipient's immune system may modulate autoimmune disease.

Ravinder Maini (London, UK) reviewed the genetics, function and receptor binding of both TNF-{alpha} and lymphotoxin. TNF-{alpha} was first cloned and sequenced in 1984/85 and shown to be identical to cachexin in 1985. The gene for TNF-{alpha} is located on chromosome 6 and polymorphisms have been associated with systemic lupus erythematosus (SLE), scleroderma and malaria. There are two receptors p55 and p75. Familial Hibernian fever is due to a mutation in the p55 receptor. TNF-{alpha} knockout mouse models develop severe inflammatory liver disease. The pathophysiological role of TNF-{alpha} overproduction results acutely in endotoxic shock, whilst chronic overproduction leads to inflammation and granuloma formation. TNF-{alpha} holds a key position at the top of the inflammatory cascade, making it an ideal candidate target for therapy. Two TNF-{alpha} inhibitors have been developed, an anti-TNF-{alpha} Mab (Infliximab), and a fusion protein between the p75 TNF-{alpha} receptor and the Fc region of human Ig (Etanercept). The Mab only binds to TNF-{alpha}, whereas the fusion protein also binds to lymphotoxin. These properties may have implications for side-effect profiles. Infliximab was approved for Crohn's disease in 1995 and submitted for consideration in rheumatoid arthritis in 1999. Entanercept was approved by the Federal Drug Administration for rheumatoid arthritis in 1998. Long-term side-effects remain to be evaluated, but at 1 yr patients can mount an acute response to infection. TNF-{alpha} inhibitors reduce C-reactive protein (CRP) after a single bolus, probably relating to the concomitant reduction in IL-6 and subsequently IL-8, E-selectin, ICAM and VCAM. The beneficial effects probably arise from reduction in trafficking and prevention of trapping of inflammatory cells within the joint. This is supported by the great reduction of activity in joints seen on isotope bone scintigraphy following treatment. Maini proposed that the use of TNF-{alpha} blockade in vasculitis would be a reasonable approach if a role for TNF-{alpha} in pathogenesis could be demonstrated.

Caroline Savage (Birmingham, UK) reviewed current knowledge of endothelial cell–leucocyte interaction in inflammation with particular reference to the involvement of adhesion molecules and transmigration of neutrophils. In vasculitis, normal mechanisms of inflammation appear to become dysfunctional, causing vessel wall damage. Biopsy studies of antineutrophil cytoplasmic antibody (ANCA)-positive small vessel vasculitis have supported the hypothesis that activated endothelium plays a role in the process. E-selectin expression is enhanced in dermal vessels, VCAM-1 has been described in glomerular capillary loops and the presence of TNF and IL-1 protein and mRNA in the vasculitic kidney has been demonstrated. Evidence for a potential role of ANCA in vasculitis was discussed, including the significance of T cells in the activation of neutrophils by ANCA and the importance of neutrophil priming by cytokines including TNF.

Sir Keith Peters (Cambridge, UK) concluded the day with a personal view into the future of therapy. He first reviewed work on Mab therapy of vasculitis carried out by Martin Lockwood, demonstrating that it is possible to induce long clinical remissions using short courses of Mab therapy. He highlighted a number of problems in developing new therapies for vasculitis, including: the heterogeneous clinical expression, ignorance of aetiology, rarity, variable response to therapy, drug toxicity, lack of surrogate markers of disease activity and difficulty in introducing novel therapies. He proposed a number of areas for future thought, including therapies to control and maintain primary remission, investigation of the actual mechanism of action of cyclophosphamide, how to take trials of novel therapies forward and especially whether their use can be extended beyond the prevention of relapse, and how to manage cyclophosphamide-resistant disease. He explored the concept of novel methods of statistical evaluation, perhaps involving use of the Internet to reduce confounding variables and raised the question of how to attract sufficient funding for trials for ‘minority diseases’.

The first session of the second day was dedicated to the imaging, diagnosis and evaluation of vasculitis. Dorian Haskard (London, UK) reviewed advances in the imaging of inflammation. Normal and MRL/lpr mice were used to demonstrate the variation of constitutive expression of ICAM and VCAM between organs with high expression of ICAM in the lung and VCAM in the kidney. Expression of both was found to increase with age and was higher in the MRL/lpr mouse. He described the use of 111In-anti-E-selectin Mab to image inflammation. E-selectin is an endothelial-specific, cytokine-inducible adhesion molecule which plays a role in the inflammatory process by promoting the selective recruitment of leucocytes prior to their migration into tissues. In rheumatoid arthritis, 111In-anti-E-selectin Mab is a sensitive method of detecting joint inflammation and is more specific than 99TcM-HIG.

Mike Peters (Cambridge, UK) gave an overview of the role of nuclear medicine in vasculitis—monitoring glomerular filtration rate; localization of inflammation; monitoring disease progression and response to treatment. He described the available methods of imaging, including indium-labelled leucocytes as a pre-endothelial target, a technique limited by the requirement for significant neutrophil infiltration. Indium-labelled leucocyte scans can demonstrate areas of disease activity particularly in the nose and respiratory tract, and can be used to monitor response to therapy. He described the use of adhesion molecules and human IgG (detecting endothelial permeability) as endothelial targets and the use of fluorodeoxyglucose positron emission tomography scans.

Jonathan Gillard (Cambridge, UK) described cranial involvement in Wegener's granulomatosis evident using magnetic resonance imaging in 22 cases. He demonstrated a variety of features including orbital/nasal destructive disease from direct invasion by granulomata; meningeal disease with thickened irregular meninges and plaques; stroke; white matter disease; intracerebral disease; pituitary disease; and cerebral atrophy. The appearances of white matter disease was non-specific and could not be identified as due to vasculitis unless there was a response to therapy. He concluded that meningeal disease, stroke, cerebral atrophy and white matter changes are common on magnetic resonance images in symptomatic patients but the appearances are non-specific. Magnetic resonance imaging can be beneficial in the monitoring of disease and for demonstrating that lesions are vasculitic as judged by their response to therapy.

Andoni Toms (Cambridge, UK) presented a study of five symptomatic, biopsy-proven Wegener's patients with meningeal thickening on magnetic resonance imaging. Comparison of the magnetic resonance images with indium-labelled white cell scans showed that magnetic resonance imaging was more sensitive for lesions of the falx tentorium but not for dural disease. In addition, standard total body gamma camera images were inadequate to demonstrate intracranial disease.

Paul Meyer (Cambridge, UK) gave a video-illustrated resume of real time imaging of microvascular blood flow. First, he demonstrated normal fluorescene angiography and haemoglobin video-imaging of the retina. This made clear that normal blood flow included the absence of laminar flow in arterial communications, interactive capillary loops, venules and collecting veins. Images in subjects with vasculitis demonstrated abnormal leakage of fluorescene and erythrocyte aggregation associated with slowed or arrested blood flow on haemoglobin video-imaging. Examples were shown of a patient with mild scleritis where abnormal erythrocyte aggregates retained abnormal shape, despite shear forces, until treatment, when flow returned to normal. A patient with ANCA-positive vasculitis but no ocular symptoms demonstrated aggregation and obstruction of limbal veins, whilst an ANCA-negative subject with focal scleritis had intense fluoroscopic leakage and oscillatory blood flow with endothelial necrosis at the point of reverse. Another subject with vasculitis suffered a stroke which was labelled as vasculitic following the discovery of a universally abnormal blood flow on haemoglobin video-imaging. Therefore these techniques may have a role in both the monitoring and diagnosis of vasculitis.

Wolfgang Gross (Bad Bramstedt, Germany) discussed the diagnosis and evaluation of vasculitis by describing a series of patients who fulfilled classification criteria for vasculitis but in whom other diagnoses were eventually made. He described the case of a young woman classified as Wegener's granulomatosis but whose disease was ANCA-negative, predominantly nasal, associated with bronchiectasis and resistant to treatment including cyclophosphamide, IVIg, interferon-{gamma} (IFN-{gamma}), IFN-ß and methotrexate. She was found to have a defect of the TAP 2 transporter protein and low MHC class I expression. Seven further cases of this ‘Wegener's alike’ syndrome have been identified, all of whom have bronchiectasis, destruction of nasal bridge, facial skin lesions, arthritis and occasional neurological involvement. He described other important but unusual problems in the differential diagnosis of vasculitis, including sarcoidosis, chronic infection of a pacemaker with Streptococcus inginensis and S. viridans in an ANCA-positive patient. Finally, he presented a woman who presented with a compartment syndrome of the leg, a biopsy showed polyarteritis nodosa and she subsequently developed granulomatous inflammation of the aorta. Gross concluded that whilst treating even ANCA-positive or biopsy-proven disease, secondary vasculitis and other diagnostic possibilities, including infection, must be considered.

Shirley Pearce (Norwich, UK) reviewed psychological aspects of vasculitis. She highlighted vasculitis as an interesting disease to study as a rare acute life-threatening disease which becomes chronic after therapy and is associated with drug side-effects. She described factors associated with chronic illness and the anticipated emotional responses. It has been suggested that a patient's appraisal of the degree of threat and the resources perceived as being available influence an individual's way of coping rather than disease severity. The SF36 has been studied in patients with vasculitis and she noted that the scores were significantly lower in this group than the general population, even in remission. In 80% of Wegener's patients, daily activities were significantly reduced or constrained. Early data from Norwich, using Hospital Anxiety and Depression scores, coping strategies, SF36 and pain and disability questionnaires found that vasculitis patients had a significantly lower quality of life using the SF36 and were significantly more anxious when compared with other chronic illness groups. There was a poor association of the Birmingham Vasculitis Damage Index (VDI) and disease activity with quality of life scores.

Gary Hoffman (Cleveland, USA) asked whether severe systemic vasculitis can be treated without cyclophosphamide. He reminded the audience that before the advent of corticosteroids mortality was 50% at 5 months, whereas after the introduction of cyclophosphamide and steroid therapy mortality improved to 80% survival at 8 yr. The illness was thus transformed from an acute life-threatening disease to a chronic illness with substantial morbidity. However, 15 yr of follow-up by the NIH found that despite only 13% mortality there was a 50% relapse rate and 100% permanent morbidity. Bladder toxicity included cystitis in 50% and carcinoma in 5% of patients. Therefore, re-evaluation of its use is necessary. He described the successful use of methotrexate as maintenance therapy once remission is achieved. However, there is a high relapse rate of 40% when steroids are stopped or methotrexate tapered and this has led to a tendency for prolonged maintenance treatment. Studies of methotrexate and azathioprine show a 78–88% success rate in retaining remission after 15–22 months. Hoffman described future developments, including TNF-{alpha} blockade and IFN-{gamma}. We are entering a new era in therapy, in which whilst cyclophosphamide remains important, its use should be limited to induction of remission and alternative maintenance therapy introduced.

Niels Rasmussen (Copenhagen, Denmark) explained the importance of the uniform assessment of patients for trials and described the methods employed by the European Vasculitis Study Group. In 1995, the VITAL (vasculitis integrated assessment log) was introduced combining a measure of activity [Birmingham Vasculitis Activity Score (BVAS)1, BVAS 2, Disease Extent Index], the Birmingham VDI and the SF36. The problem of inter-observer variation was highlighted and the need to provide training courses and to overcome language problems was discussed. The absence of adequate laboratory or radiological tests specific for vasculitis makes uniformity of clinical assessment difficult, in particular to differentiate vasculitis from infection.

David Jayne (London, UK) provided an overview and update on European trials in vasculitis. The first European Vasculitis (EUVAS) project in 1990 was to standardize ANCA testing throughout Europe leading to 95% specificity and 40% sensitivity for indirect immunofluorescence–enzyme linked immunosorbent assay (IIF–ELISA) testing combined. First wave trials to standardize treatment for ‘ANCA-associated vasculitis’ were commenced between 1994 and 1998. Studies were designed to compare a consensus regime with the best available alternative for four disease subtypes: early systemic disease (NORAM) comparing cyclophosphamide vs methotrexate at induction, generalized disease (CYCAZAREM) comparing cyclophosphamide vs azathioprine in remission, severe renal disease (creatinine > 500) (MEPEX) adding intravenous methylprednisolone or plasma exchange to standard immunosuppressive therapy and (SOLUTION) adding anti-thymocyte globulin. The results from CYCAZAREM indicate that 90% of patients had entered remission after 3 months of cyclophosphamide and 100% after 6 months. Results appear similar in terms of relapse, BVAS, VDI and creatinine clearance in both arms, a full report is awaited. A second wave trial (CYCLOPS) to compare daily oral to intravenous pulse cyclophosphamide is underway. Other trials underway include MUPIBAC to compare mupirocin ointment vs placebo and REMAIN to establish the duration required to continue immunosuppressive drugs after induction of remission. Third wave studies planned include comparison of leflunomide and methotrexate in early systemic disease; mycophenolate vs azathioprine in generalized/renal disease and pilot studies of TNF-{alpha} blockade in renal vasculitis and anti-CD40L in induction of treatment.

Carol Black (London, UK) shared her experience of autologous haemopoietic stem cell transplantation in scleroderma as part of an initiative to prevent organ damage in autoimmune disease. Scleroderma was felt suitable as there has been no effective treatment, but a partial response has been demonstrated to anti-thymocyte globulin, cyclophosphamide and mycophenolate. It has been considered to be a vascular disease with intimal thickening and reduplication of the elastic lamina. An activated immune system occurs early in disease leading to deregulated fibroblasts which may be responsible for progressive disease. Patients considered suitable for autologous stem cell transplantation were those with severe respiratory, cardiovascular, renal or systemic disease (i.e. carbon monoxide diffusing capacity > 40%, ejection fraction > 50%, glomerular filtration rate > 50%, <20% weight loss and liver function tests < 2 x normal). Cyclophosphamide at 200 mg/kg was given to prime patients prior to transplantation. Three of seven patients died, two before transplant through sudden cardiac death and cardiorespiratory failure and the third after 5 months due to rapid disease progression. The remaining four patients remain well. Further involvement was stopped in view of the mortality, pending results from a European protocol. Current therapy for systemic vasculitis does not always control disease and has significant side-effects, whereas stem cell transplant may offer a cure. World-wide this technique has been employed in four patients with vasculitis. Three with diagnoses of Wegener's granulomatosis, polyarteritis nodosa and cryoglobulinaemic vasculitis treated in 1997, 1996 and 1995, respectively, remain in remission. The other suffered a relapse but did not complete the conditioning regime. The current treatment for vasculitis is significantly more successful than the treatment available for scleroderma. Black therefore suggested that autologous stem cell transplantation should only be considered in patients with severe fulminant vasculitis.

Lees Kallenberg (Groningen, The Netherlands) closed the conference with some research aims, including prevention, cure and suppression, all of which rely on better understanding of aetiology, pathogenesis and pathophysiology. He reviewed the contradictory HLA studies and studies indicating a role for T-cell receptor Vß and Fc{gamma} RIIa polymorphisms. He described reports of silicosis and Staphylococcus aureus in association with vasculitis and relating to pathogenesis and the current knowledge of the role of ANCA. He recommended the development of genetic and epidemiological studies to provide a genetic risk profile and avoid exposure to inducing agents, and to identify the role of infection in aetiopathogenesis. He invited participants to the next ANCA workshop in Groningen in April 2000.


    Notes
 
Correspondence to: R. A. Watts. Back

Submitted 8 October 1999; revised version accepted 11 October 1999.



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