This week’s medicine grand rounds was given by Dr. Peter Merkel, M.D., M.P.H., Associate Professor of Medicine, Section of Rheumatology and Clinical Epidemiology Unit, Boston University School of Medicine and Director, Vasculitis Center, Boston University School of Medicine.
Dr. Merkel prefaced his discussion by highlighting the evolving movement among academics to change the name of Wegener’s Granulomatosis to an alternative given recent discoveries that Friedrich Wegener had willingly volunteered and actively participated in the Nazi movement beginning in 1932. The efforts to rename this disease process have been stifled given the universal acceptance in medical literature of the term Wegener’s granulomatosis describing the well known vasculitic syndrome.
The following discussion focused on the pathogenesis, symptomology, workup and treatment of Wegener’s (WG) and microscopic polyangiitis (MPA), the ANCA associated small vessel vasculidities (AAV). Churg Strauss, another AAV was not discussed given the different clinical presentation, treatment and prognosis. Dr. Merkel remarked that much is still unknown about the pathogenesis of WG and MPA. Many theories have suggested either environmental exposures, infectious triggers and/or genetic components (eg. autoimmune) as precipitating factors, however the jury is still out.
As WG and MPA are both pulmonary renal syndromes that share many clinical and pathological findings, Dr. Merkel discussed some distinguishing features. WG is a systemic necrotizing granulomatous inflammation of small and medium vessels of the upper and lower respiratory tract as well as the kidneys. It is associated mostly with cANCA and anti-proteinase 3 (PR3) antibodies (90% of WG cases). In contrast, MPA causes a non-granulomatous inflammation of small vessels and is more often associated with pANCA and anti-myeloperoxidase (MPO) antibodies.
Classically, WG and MPA present with a host of clinical findings which include ocular inflammation (episcleritis, conjunctivitis, uveitis), sinusitis, lacrimal gland involvement, oral and/or nasal ulcers, midline palatal desctruction, hearing loss (sensorineural and conductive), subglottic stenosis, tracheal stenosis, pulmonary nodules, and mononeuritis multiplex. The ANCA associated vasculitic emergencies include pulmonary hemorrhage, RPGN, CNS findings (CVA, meningitis), bad eye infections, subglottic stenosis and gangrene.
Dr. Merkel outlined the initial workup of the suspected AAV patient. This included thorough history and physical, basic laboratories, urinalysis (underscoring the importance to look at the urine sediment yourselves as laboratories frequently miss casts), CXR (but more definitive is a non-contrast Chest CT which he orders on his patients), ENT exam (by otolaryngology) and audiogram. He underscored the underestimation of hearing loss in AAVs and the devastating morbidity associated with it. As with many disease entities, most often definitive diagnosis often relies on biopsy (eg. dermatologic, pulmonary or renal).
The mainstay of treatment is, of course, steroids. If confronted with any of the AAV emergencies (especially RPGN or pulmonary hemorrhage) even without a diagnosis, Dr. Merkel recommends starting pulse dose steroid treatment (methylprednisolone 500mg IV daily for three days) while working up the patient. Standard of care is to switch to 60mg oral prednisone daily thereafter and taper in the upcoming months after a response is acheived. Steroids are not enough, however, and immunosuppressives are needed to control the disease process. Dr. Merkel went on to analogize the rheumatological approach to AAV treatment to the oncologist approach to chemotherapy with an induction-remission phase and a maintenance phase. The only two medications with data to support their use in the induction-remission therapy for AAVs are cyclophosphamide (CYC) and methotrexate (MTX). The data is more compelling for CYC which is why it is the initial therapy of choice, however, the side effects are greater and limit its use. Given these side effects, CYC therapy should be limited to 3 to 6 months once remission is achieved and then maintenance therapy is initiated. Currently used maintenance drugs include azathioprine, MTX and mycophenolate. If not limited by toxicity, CYC can be used if remission is not achieved within 6 months.
During his discussion, Dr. Merkel described some of the findings related to AAV that he has published from his work with vasculitic patients. One observation was the increased incidence of thrombosis noted in AAV patients. He published a prospective observational study called the Wegener’s Clinical Observance of Thrombosis (WeCLOT) study (Ann Intern Med, Apr 2005; 142: 620 – 626) which observed a greater than 20-fold incidence of venous thromboemobolism (VTE) as compared to normal cohorts and a 7-fold increase in VTEs when compared to patients with Lupus. Another observation was that VTEs were most likely to occur within the first three months of active disease.
Dr. Merkel went on to address the utility of ANCA titers as a measure of disease activity. He reported that early data seemed positive correlating vasculitic flares with higher ANCA titers, however, a recent study published by Dr. Merkel suggests the contrary (Ann Intern Med, Nov 2007;147: 611-619). The study was a prospective observational cohort study which followed 156 WG patients over a median of 34 months measuring their anti-PR3 levels every three months over the course of their disease flares and remissions. They found that decreases in PR3-ANCA levels during induction-remission therapy were not associated with shorter times to remission and increases in PR3-ANCA levels were not associated with relapse in the following year, suggesting that ANCA levels cannot be used to guide therapy in WG.