By Anisha Dua, MD, MPH
Assistant Professor of Medicine
The University of Chicago Medicine, Rheumatology
Research in ANCA vasculitis has gained significant momentum in the last decade with the discovery of new insights into disease mechanisms, targets for therapy, and it has resulted in better outcomes for patients. We have made great advances in the treatment of ANCA-Associated Vasculitides (AAVs) in the past decade, but we still have many patients who suffer from recurrent relapses, incomplete response to treatments, and complications from the disease and therapies we are using to control it.
This year, the International Vasculitis and ANCAWorkshop was held in March in Tokyo, Japan and there were 451 abstracts presented from 29 different countries. The conference focused on discoveries being made in clinical care and basic science research , as well as bridging the expertise of subspecialists that are involved in caring for vasculitis patients. By integrating the understanding and research being done in different countries and across other research fields, we can further advance our ability to treat patients and minimize toxicities.
While a great deal of information was presented at this year’s conference, there were four main themes that were highlighted. These included:
- Classification of AAVs
- Pulmonary Limited Microscopic Polyangiitis
- Takayasu Arteritis and Giant Cell Arteritis spectrum of disease
- Eosinophilic Granulomatosis with Polyangiitis
We tend to rely heavily on autoantibodies (PR3 and MPO) to help guide us in classifying patients, enroll in clinical trials, and to help us predict the risk of relapse and which organs may be involved. This is easier when a patient has a classic presentation with organ involvement and a tissue diagnosis that fits.
It becomes much more difficult when there are overlapping features, no tissue for biopsy, or an unusual presentation of the disease. Instead of forcing patients into a category, we can glean more information by combining the serotype (MPO, PR3) and the clinical/pathologic phenotype. This will allow us to categorize patients better not just based on a blood test or pathologic finding or clinical picture, but rathe r use all this information in trying to understand the nature of these diseases.
By being more descriptive and open to the variations in disease serologies and clinical presentations, we can learn more about the shapes that the ANCA vasculitides take and hopefully enhance our understanding of the nuances of the disease presentations and treatment options.
Professor Raashid Luqmani, Oxford University Hospitals, gave us an update on UKIVAS, a longitudinal registry in the United Kingdom and Ireland, with over 3,000 cases of vasculitis. This can be a source for making comparisons between different countries and possibly biomarker studies in the future. With the increase in the use of ANCA testing, we have been able to diagnose patients earlier, carry out more clinical trials, and improve patient outcomes and survival. But, as patients live longer with the disease, we need to be vigilant about chronic damage and comorbidities. Registries such as this one will capture this important information so that we can better study vasculitis including damage from the disease and the therapies we are using to try and control it.
Pulmonary Limited Microscopic Polyangiitis (MPA)
Collaboration between rheumatologists and our pulmonary colleagues has shown that there is a subset of patients who have an interstitial pulmonary disease and positive MPO-ANCA antibody– sometimes without any other manifestations of vasculitis. These patients can go on to develop other systemic manifestations of MPA and should be monitored closely for symptoms outside of the lungs.
It can be difficult to distinguish active vasculitis versus fibrotic lung disease in MPO+ patients, but this distinction is important. Treatment of inflammation can prevent damage, but once there is already damage or fibrosis in the lungs, other agents that target fibrosis may be more effective. There are a few clues on CT imaging that are seen with more prevalence in ANCA-positive interstitial pneumonia patients, including more honeycom bing and cysts compared to those with idiopathic pulmonary fibrosis. Pathologic evidence has been scarce. To date, the only known risk factor for developing full blown vasculitis in these patients is a high titer of MPO antibody.
This entity of “pulmonary limited MPA” is important to recognize because limited disease presentations may be treated differently than a diffuse disease, as is the case with limited granulomatosis with polyangiitis (GPA). No clear treatment guidelines for MPA patients presenting with exclusively lung disease, and some may go on to develop other disease manifestations, or it could stay in the lung.
There are multiple studies being carried out in various countries in patients who have lung disease or “limited MPA.” We need to see if we can better identify predictive factors in those patients who will go on to develop a systemic vasculitis or if they respond differently to therapeutic regimens targeting fibrosis .
Takayasus (TAK) and Giant Cell Arteritis (GCA) – Spectrum of Disease?
Early recognition and diagnosis of vasculitis leads to prompt management and better patient outcomes. Currently the delay to diagnosis is significant (258 days in TAK and 56 days in GCA) and there are overlapping clinical features including weight loss, fatigue, fevers, claudication and angiograms (blood vessel studies) with stenosis (areas of narrowing). As a community, we are re-appraising the ACR classification criteria for TAK and GCA to try and improve our accuracy in recognizing and diagnosing these patients.
Dr. Tanaz Kermani, director of the UCLA Vasculitis Program, discussed the many overlapping
features of GCA and TAK, but noted some important distinctions that can help us in properly classifying these patients. GCA and TAK are similar in that they affect branches of the aorta and while GCA classically affects older individuals, and TAK affects younger adults, there is a gap of people in the middle (age 40-50).
Clinically it has been easier to diagnose GCA because the headache symptom is more common, with higher inflammatory markers and more polymyalgia symptoms. Some important differences between TAK and GCA include that TAK patients tend to have more lower extremity claudication and more damage and bruits on exam with a larger number of vascular beds affected. Patients with TAK are often females (9:1) and of Asian/Turkish descent. GCA tends to affect Caucasians and there is a female predominance, about 2:1. There are also some genetic distinctions between these two diseases.
By appreciating some of the differences in susceptibility, imaging findings, and increasing awareness of the entity of late onset-TAK, we hope to decrease the time to diagnosis for patients who have these diseases. This will make us better equipped to differentiate them so they can be studied closer in clinical trials.
Dr. Carol Langford, director of the Cleveland Clinic Vasculitis Clinic, discussed some of the therapeutic regimens that are in use for management of GCA and TAK. Treatment of both diseases has heavily relied on high doses and prolonged courses of steroids, which have many known detrimental side effects.
Methotrexate has been of modest benefit in both diseases. While TNF inhibitors looked promising in case reports, randomized clinical trials did not show any benefit. This highlights the importance of doing more randomized trials in vasculitis, so we can get clear answers about which treatments are beneficial. A randomized clinical trial looking at abatacept showed that it was better than placebo at 12 months in preventing relapses in GCA, but this benefit was not seen in terms of relapse free survival in Takayasus.
As we have learned more about the pathophysiology of these diseases, there has been greater understanding of the role of IL-6, a cytokine (small protein) that is found in higher levels in the serum and blood vessels of patients with vasculitis. IL-6 is secreted by T-cells and macrophages and drives inflammation and fever. Tocilizumab is a drug that binds to the receptor of IL-6 and blocks its downstream actions. It has been approved for use in patients with rheumatoid arthritis and Dr. John Stone, Director, Clinical Rheumatology, Massachusetts General Hospital, discussed the landmark trial “GIACTA” which evaluated the role of tocilizumab in patients with GCA.
The GIACTA trial enrolled 250 patients from 14 countries with new or relapsing GCA. Patients treated with tocilizumab did better than the steroid only arm with more sustained remission, no increase in adverse events, and better quality of life measures. There have been no new therapies for GCA in more than 50 years, and tocilizumab was just approved by the FDA. The landscape is truly changing and we hope to improve the lives of our patients based on these trials with the goal of less or even possibly no steroids in the future. While this represents a major advance in our armamentarium for treating GCA, many questions still remain: which patients to treat, what types of patients would benefit most, how long to treat for, and of course the high cost of treatment cannot be ignored.
Eosinophilic Granulomatosis with Polyangiitis (EGPA)
EGPA/Churg Strauss Syndrome is the rarest of the AAVs and is associated with late onset asthma, pulmonary infiltrates, neuropathy and peripheral blood eosinophilia. About a third of patients have a positive p-ANCA, and those with the positive antibody classically have vasculitic manifestations (neuropathy, skin). ANCA negative patients more frequently have cardiac manifestations, including cardiomyopathy or myocarditis.
The disease features and response to therapies is different in EGPA, and these patients have often been excluded from larger clinical trials evaluating MPA and GPA. We have tried using many immunosuppressive agents including cyclophosphamide, azathioprine, and methotrexate to control the disease, but manifestations such as chronic asthma or rhinosinusitis frequently require long-term high dose steroids.
Steroids are used like an umbrella to shut down inflammation in a broad sense in EGPA and vasculitis in general. What we want to do is find a targeted therapy that shuts down what is driving the disease specifically. This will lead to less long-term toxicities and side effects.
We have learned that environmental exposures in both asthma and EGPA trigger the immune system though cells in the airway secreting inflammatory cytokines. This response also occurs in the cells lining the nasal cavity and can cause polyps or other ear, nose and throat involvement. The immune system activation results in T cells producing inflammatory cytokines such as IL-4, IL-13, and IL-5.
IL-5 is a cytokine that regulates growth, activation and survival of eosinophils. Levels of IL-5 are increased in patients with EGPA and are associated with disease activity. Therefore, reducing eosinophils and preventing their activation by inhibiting IL-5 is a rational approach to treatment. Mepolizumab, a monoclonal antibody specific for IL-5, has been studied in two pilot studies in EGPA with promising results, achieving a steroid sparing effect and remission maintenance, with a favorable safety profile. This has led to the MIRRA trial, the first ever double-blinded, placebo controlled trial in EGPA patients, to evaluate the efficacy and safety of mepolizumab in relapsing and refractory EGPA. 130 patients were enrolled in this trial which is now completed, and results will be available in late 2017. This means a possible medication outside of steroids, that is tailored to, and targets the mechanisms that drive disease in EGPA.
This is a brief summary of some of the exciting research that was highlighted at the 2017 ANCA Vasculitis conference. New insights into disease mechanisms, genetic variability and targeted therapies were presented and discussed. Sharing of ideas and research between different countries and subspecialists is key to moving forward in our understanding of vasculitis.
We have been steadily gaining ground in clinical trials and applying our knowledge to make real-life decisions in clinic. The science presented sheds new insights and raises many important questions that remain to be answered about how we can improve the lives of people with vasculitis.