by John H. Stone, M.D., M.P.H.
Associate Professor, Division of Rheumatology
Johns Hopkins University School of Medicine.
Release Date: July 12, 2006
Expiration Date: July 12, 2008
Dr. Stone has no significant financial interest or relationships to disclose.
In telling this patient’s story, I’m going to take a page from the book of Quentin Tarantino (Director of the movie “Pulp Fiction”) book and tell the story in a non-linear fashion. If you’ve seen “Pulp Fiction”, you’ll recall that the movie started in the middle of the characters’ story line, proceeded through the end ot the story line, then went back to the beginning, concluding in an unforgettable scene in which an attempted robbery had just occurred in a restaurant full of people. The ploy was a very appealing storytelling device, and also eased the blow of the fact that Vincent Vega, played by John Travolta, was killed in the coursed of the movie. The moviegoer had an uplifted feeling at the end of the show because, through the non-linear storytelling device, Vega (Travolta) still sauntered out of the restaurant at the end of the movie. With regard to this presentation today, I am not foreshadowing the death of the patient I am going to tell you about, although as you will see he has had a couple of close brushes when I thought he might not make it.
Scene 1: Red Eyes
In May, 2003, the patient first appeared in clinic. (Remember: this being a “Pulp Fiction” case presentation, we begin in the middle of his medical story, some time after he had already been diagnosed with his underlying illness.)
He presented that May with six days of sinus congestion, fever to 102oF, and complaints of aches and pain, malaise, myalgia. This was definitely a change from his baseline, as his underlying disease had been stable then for many months. The patient had a diffuse, erythematous, maculopapular rash. He also had a creatinine of 3.8 mg/dL, which was up from his baseline creatinine of 2.0 mg/dL. He was admitted promptly to the hospital.
On hospital day 2, the patient had some nasal crusting on physical examination and his creatinine had risen even higher, 4.5 mg/dL. He also was noted to have elevations of his hepatic transaminases; they ultimately peaked several days into his hospitalization at >900 mg/dL. He was neutropenic and thrombocytopenic, with white blood cell and platelet counts of 3.5 x 109/mm3 and 169 x 109/mm3, respectively. Both of these counts declined somewhat further during his hospitalization. On hospital day 2, he also developed voluminous, non-bloody diarrhea.
On hospital day 4 there was still no answer to his acute illness. He became progressively short of breath; it worsened throughout the day. An arterial blood gas showed pO2 of 66 and a pCO2 of 29. The patient became tachypneic. A cardiac event of some type was suspected, and assays for cardiac enzymes revealed a very high CK (1842 U/L; normal < 200 U/L) and a whoppingly high troponin I (>200 mg/mL; normal < 5 mg/mL). An electrocardiogram showed no pattern of acute myocardial injury, but an echocardiogram performed just prior to transfer to the Cardiac Care Unit showed an ejection fraction of 15%.
Thus, Scene 1 ends, with the underlying diagnosis unrevealed, the cause of his acute presentation unknown, the etiology of his rapid decompensation in the hospital unclear, and the patient in florid congestive heart failure.
Scene 2: Holiday Party
The patient traced the start of his underlying illness to a holiday party several years earlier: December, 2001. In fact, the patient blamed the onset of his illness on the candles and perfume that were present at the party. He had been seized at the party with intense nasal and sinus congestion – entirely new for him – which persisted for weeks after the party. Ultimately, his primary care doctor referred him to an otolaryngologist for evaluation of his persistent upper respiratory complaints. Upon examination of the patient, the otolaryngologist found brown, bloody nasal crusts.
The otolaryngologist recommended that the patient undergo sinus surgery to correct the problem, presumably diagnosed as chronic sinusitis of some sort. In preparation for the surgery, the otolaryngologist ordered a routine pre-operative chest radiograph, which showed a mass. Following discovery of the lung mass on chest X-ray, the patient underwent a computed tomography scan of the chest (below), leading to other referrals.
In short, the patient was told that he probably had lung cancer, and that he was needed to have a needle biopsy to secure the diagnosis and determine the cell type. He underwent a biopsy and, as you are probably guessing by now, no cancer was revealed. Rather, the biopsy showed a large area of necrosis the pathologist referred to as “geographic necrosis.” (shown below)
In the right setting, this finding suggests the diagnosis of Wegener’s granulomatosis (WG). There were also Langerhans giant cells in the tissue, typical of WG, and other parts of the biopsy revealed pulmonary vasculitis.
Only a few days later, then, the patient had made his way to the Johns Hopkins Vasculitis Center, where we evaluated him. The immediately striking feature of his appearance was the redness of his eyes — episcleritis.
The eyes were not painful or tender, but they were obviously red. His hands and joints, however, were painful.
In fact, his joints were so painful that he could not even get up on the examining table without assistance and once we had finally hoisted him onto the table, he could not get back off. His arthritis resembled that of a patient with florid, untreated, polyarticular rheumatoid arthritis.
The tips of his fingers were cyanotic because of ischemia, and his fingernails manifested multiple splinter hemorrhages. Perhaps his worst discomfort, however, was a tongue ulcer that was incredibly painful.
Although oral ulcers are part of the ACR classification criteria for WG, but in fact oral ulcers are not usually a prominent part of the clinical presentation. Finally, the patient had one of my favorite physical examination findings in WG (shown below): nodules on the elbows that are not rheumatoid nodules, but rather cutaneous extravascular necrotizing granulomas, known more commonly as “Churg-Strauss granulomas”.
The presence of Churg-Strauss granulomas – which may occur over any extensor surface and even within internal organs (but which are found most often over the olecranon area, precisely where rheumatoid nodules are found) – often leads to the misdiagnosis of rheumatoid arthritis early on in the course of WG.
Even without laboratory data at that point, we realized immediately that the patient needed to be hospitalized because of the diffuse nature of his condition. We sent directly to the Emergency Room for his first dose of methylprednisolone because there was no bed available in the hospital at that moment. In the Emergency Room when we began to get the results of routine laboratory tests, we discovered that the patient had 2+ proteinuria, 40-50 red blood cells per high-powered field, and urinary red blood cell casts. Fortunately, his serum creatinine was only 1.3 mg/dL. Ultimately, after two days in the hospital, an immunofluorescence assay for anti-neutrophil cytoplasmic antibodies (ANCA) was found to be positive in a cytoplasmic (C-ANCA) pattern, with an antibody specifity for proteinase-3.
There was no question about the diagnosis: the patient had WG, characterized by many classical features of that disease, positive for the autoantibody strongly correlated with that condition, and proven by lung biopsy. The only question, given the general approach to therapy today, was whether to give him daily cyclophosphamide (CYC) administered orally along with his glucocorticoids, or to administer the CYC in an intermittent, intravenous fashion. On this debate in the medical literature, however, there is no clear resolution. A trial has been completed in Europe known as “CYCLOPS” compared oral daily CYC to intermittent CYC. The regimen of intermittent CYC employed in CYCLOPS was differs somewhat (i.e., is more intensive) from the National Institutes of Health protocol for intravenous CYC in lupus. The European investigators gave pulses of CYC every three weeks for six months: a total of 10 pulses during that time. Preliminary results, still not published in a peer-reviewed manner, purport to indicate that the intermittent administration of CYC, at least in the regiment employed in CYCLOPS, is more effective and less toxic than daily CYC. If these results hold up under the scrutiny of peer review, then this study is extremely important and certainly runs against the grain of accepted remission induction strategies for WG in the United States, where daily CYC regimens remain the standard. Because the data are not yet all in on the CYCLOPS study, I’m reserving judgment and continue to use daily CYC therapy for the remission induction in WG. Some evidence – admittedly from underpowered studies – indicates a higher likelihood of sustained remission with daily regimens. Moreover, with the use of daily CYC the dose is titratable to the white blood cell count and therefore conducive to avoiding profound neutropenia.
The patient was treated with pulse methylprednisolone and daily CYC. In addition, because of the very limited ability of conventional medications to sustain remissions, he was enrolled in an ongoing trial, the Wegener’s Granulomatosis Etanercept Trial (WGET). I will discuss this trial in greater detail later. As it turned out – though we did not know this until the end of the trial – the patient was in the etanercept group. Therefore, his therapy consisted of CYC, glucocorticoids, and etanercept.
During the patient’s initial hospital stay, he received three doses of methylprednisolone. His serum creatinine, 1.3 mg/dL on admission, was 1.4 mg/dL at discharge. He felt dramatically better almost immediately after starting treatment, with essentially complete resolution of his arthritis. My sense was that we had detected and treated his WG just in time. Five days later in clinic, however, his creatinine was 2.7 mg/dL. I remember telling his wife, “It takes a while to turn the train around when it is steaming fast in the wrong direction.” I evaluated the patient again a few days later, by which time the serum creatinine had risen to 5.1 mg/dL. Quite concerned now, I admitted him to the hospital again for three more doses of methylprednisolone. Three weeks after his initial hospitalization, his serum creatinine continued to rise inexorably, to 7.4 mg/dL.
Thus ends Scene 2, with the newly-diagnosed WG patient now in florid renal failure.
Scene 3: The Past Several Years
In this scene, I will take a step outside the story to review some of the recent evidence-based data that have accumulated in the past few years with regard to the treatment of WG. The discussion will center around the results of three major clinical trials: 1) CYCAZAREM [CYC versus Azathioprine for the Maintenance of Remission]; 2) NORAM; and, 3) the Wegener’s Granulomatosis Etanercept Trial [WGET].
If one were to take 100 WG patients with this or a similar presentation and treat them according to the current standard of care, what would be the likelihood of getting them into remission? Among the first studies to present controlled data on this point was CYCAZAREM – (Jayne et al. N Engl J Med 2003; 346(1):36-44). Although CYCAZAREM was not a blinded study, 143 of the 155 patients (93%) of the patients in both groups achieved disease remission. All patients in the trial were treated initially with 2 mg/kg of CYC and high doses of glucocorticoids. Upon achievement of remission, the 143 patients were randomized either to continue CYC for up to 1 year, or to switch to azathioprine (AZA) after 3 to 6 months. All participants in the trial remained on not less than 10 mg/day of prednisone for the first year, and then 7.5 mg/day. There was no difference between the two treatment arms in the number of patients who flared during the period of follow-up, demonstrating that AZA is good as continued CYC for the maintenance of remission.
The second informative study is known as NORAM (Groot et al. Arthritis & Rheumatism 2005; 52(8):2461-2469). NORAM was a comparison of CYC with methotrexate (MTX) for early-generalized, ANCA-associated vasculitis. Of the 95 patients enrolled, 89 had WG; 6 had microscopic polyangiitis. NORAM was also not a blinded trial, but 90% of the patients in both treatment arms achieved disease remission. The prednisolone was tapered a little bit faster in this trial than in CYCAZAREM, down to 7.5 mg/day by month 6, and then all after 1 year. In the MTX group, patients were treated with an identical prednisolone tapering regimen, and both CYC and MTX were tapered off after 10 months.
We can compare these three trials for their steroid regimens and their flare rates.
|Treatments||CYC vs. AZA||CYC vs. MTX||Etanercept plus standard of care|
|Remission Rate||93%||90% MTX|
|Steroids 6 mos.||>10 mg prednisolone||7.5 mg|
|Steroids 12 mos.||7.5 mg|
|Flare Rate||15%||70% MTX|
As noted, CYCAZAREM patients stayed on 10 mg prednisolone for the entire first year (not just 6 months but the first year), and then 7.5 mg after that. The flare rate in that trial was only 15%. In NORAM, patients had a faster prednisolone taper – off prednisone by 1 year – and had a dramatically higher flare rate. In the WGET trial (WGET Research Group, N Engl J Med 2005; 352(4):351-61.), a trial in which prednisone was tapered to discontinuation after 6 months, 91% of the patients achieved disease remission. Thus, WGET, which had the most aggressive tapered regimen of steroids, had a 51% flare rate. One of the things I would like you to take away from this talk is that we probably fail to appreciate the immense value of maintenance glucocorticoids – even low doses of prednisone – for the maintenance of remission. We put a lot more faith in steroid-sparing agents employed for the purpose of maintaining disease remissions, e.g., methotrexate and AZA, than perhaps is warranted. Perhaps even low doses of glucocorticoids would maintain remissions better.
Back to our patient. His creatinine is now 8.1 mg/dL, and rising on a daily basis. What do we do? Options included:
- Give him more steroids. (He had already gotten six pulses of methyprednisolone)
- Give him more CYC. (He was already on a sizeable dose: 125 mg/day)
- Perform a kidney biopsy (thinking that maybe he has anti-glomerular basement membrane disease).
- Initiate a course of plasmapheresis.
An argument that we sometimes have on the ward is about whether or not plasmapheresis or plasma exchange is indicated in these situations. There are little data regarding either one of these interventions. Data from the MEPEX trial (methylprednisolone versus plasma exchange), completed several years ago, have still not been published in a peer-reviewed format albeit some results have been presented at subspecialty meetings. Inclusion criteria for MEPEX were a new diagnosis of ANCA-associated vasculitis and advanced renal dysfunction (serum creatinine of >4 mg/dL). Patients were treated with oral CYC and glucocorticoids in addition to either 7 plasma exchanges over 14 days, or pulse methylprednisolone, 1-3 doses. The data show no difference in survival between the two treatment arms. Only 52% of patients were dialysis-free at 12 months — perhaps not surprising because they had such advanced renal dysfunction at the beginning. Between the two groups, 45% of the patients treated with methylprednisolone were dialysis-free at 1 year compared with 59% of those in the plasma exchange group at 1 year. Again, this is not statistically significant. These data, the most objective to date, do not indicate any clear advantage to the addition of plasma exchange to standard therapies of CYC and prednisone.
For my patient, we actually decided to lower the dose of CYC despite his continued renal worsening, and to hold off on any other treatments. We hoped that in due time his renal function would begin to improve, just as the rest of his disease had (the arthritis, tongue ulcer, digital ischemia, for example, were gone, and the lung lesion rapidly disappearing). The purpose of lowering his CYC dose was to avoid potentially lethal complications of this treatment as his serum creatinine worsened and his ability to excrete CYC metabolites declined. The daily CYC dose was lowered to 50 mg, and held there. Approximately six weeks after starting treatment for his WG, the patient started dialysis on an elective basis.
One day about six weeks later, the patient mentioned to me that his serum creatinine that day at dialysis had been 4.7 mg/dL. I noted to myself that this was lower than one would expect for a patient on chronic hemodialysis, and thought perhaps we were seeing the first sign of a renal recovery. Sure enough, over the next few weeks the patient’s renal function improved sufficiently for him to discontinue hemodialysis. His baseline creatinine settled out at 1.9 mg/dL. After 5 months of CYC, I switched him to AZA. But remember, we are still in the middle of this course, and there is more to come…. Before the next scene, though, I will review the major results of the WGET.
In the WGET, 180 patients were enrolled, making it the largest prospective study conducted to date in this disease. Patients were treated with standard of care therapies plus either etanercept or placebo in the remission maintenance phase. The conventional therapy was tapered off as patients continued the etanercept or placebo, with the primary outcome being to determine whether etanercept could sustain remissions better than placebo. As noted, the WGET protocol called for the discontinuation of prednisone by 6 months. Patients switched from CYC to either MTX or AZA after 3 to 6 months if they had achieved remission. Patients with limited disease treated with MTX from the start of enrollment and began to taper this medication after they had been in a sustained remission for 1 year. In both groups, 90% of the patients achieved disease control or remission. Whether they were newly diagnosed or whether they had pre-existing disease before trial entry, 90% of them achieved disease remission.
Could we keep them there (in remission) with etanercept? The group did pretty well: about 70% of them with a 6-month period of no disease activity. Unfortunately, the control group actually did a little bit better, at least numerically: 75% achieved sustained remissions. Another remarkable point was that, taking both groups together, only 49% of the patients achieved remissions and maintained them throughout the trial. There was no difference in flare rates between the two groups (66 per 100 patient years vs. 74 for 100 patient years) or in the number of severe flares between the two groups. There were virtually no outcome measures, in fact, that distinguished the two treatment groups. In terms of adverse events, during 22 months of patient follow-up, 56% of the patients in the etanercept group had an adverse event that was severe, life-threatening, or fatal. The control group was no different: 57% of the patients in that group had a severe or life-threatening event or died. Thus, the WGET data indicate that, even using CYC and the other conventional medications in a more moderate way than the NIH longitudinal protocol did, the adverse event rate associated with these conventional medications is still quite alarming.
Additional interesting data to emerge from the WGET trial involved venous thrombotic events (VTEs). We demonstrated that WG patients actually have a much higher incidence of VTEs: deep-vein thromboses and pulmonary emboli (Merkel, et al. N Engl J Med. 2005; 352(4):330-2). Most of these events in the WG patients occurred rather early on after their inclusion in the trial, suggesting an association with active disease. In addition, the VTEs occurred mostly in patients with severe (as opposed to limited) disease – the type of patients with a vasculitic kind of presentation rather than a granulomatous one. This may be because the vasculitis associated with WG, unlike that of other forms of disease associated with vasculitis, involves veins as well as arteries. The relative risk for VTE was 7 times higher among the WG patients than among a comparable group of patients from the Johns Hopkins Lupus Center cohort, a group of patients we know suffers from a hypercoagulable state. The relative risk in WG was also 23 times higher than that of healthy Scandinavian males in a population-based study, and 23 times higher than rheumatoid arthritis patients treated with etanercept. The incidence in WG was approximately equivalent to patients who had already had one VTE, which predisposes them to others.
With regard to deaths in the WGET trial, there was no difference between groups. One important point, however, is that not a single one of the 180 patients died of overwhelming WG. All deaths in WGET were the result of causes not directly related to WG: complications of treatment and events that were perhaps incidental (e.g., cardiac arrest), but mostly complications of treatment. With regard to malignancy, however, there was another issue. Six solid malignancies developed in the etanercept group. All etanercept patients who developed malignancies during the trial also received CYC. In contrast, no solid malignancies occurred in the control group. There is some biological rationale for believing this might be a real finding, of course, because the cytokine we targeted specifically for inhibition in the trial was tumor necrosis factor. Perhaps it should not be altogether surprising that patients on CYC and a TNF inhibitor might be more at risk for solid malignancies.
We compared these findings and the incidence of solid malignancy in the WGET group to the SEER database. The numbers of events in the WGET were small, of course, but the standardized incidence ratio for solid malignancy in the WGET group was 3.12 – highly statistically significant (P = 0.01). We are preparing to conduct a follow-up study of the WGET cohort now.
Returning to our patient: Three years after getting off dialysis, he was doing beautifully. He had served as the Best Man in his son’s wedding. He and his wife had recently been shopping for retirement properties on the Eastern shore of Maryland. He had become ANCA negative.
Should ANCA negativity be reassuring for a WG patient in remission? The WGET trial has given us more data on ANCA. In terms of making the diagnosis, ANCA can be extremely helpful. The presence of ANCA actually obviates the need for biopsy in some patients now who present with classic disease manifestations. In the WGET, 96% of the patients with severe disease were ANCA-positive; 83% of those with limited disease were ANCA-positive.
In terms of predicting disease flares, we now have data through the WGET indicating that ANCA are useless for this purpose. At entry into the trial, 134 patients were PR3-ANCA-positive. (For the purposes of this analysis, we excluded the 24 patients who were MPO-ANCA-positive and only evaluated the PR3-ANCA-positive patients.) Of the 134 patients, 101 (75%) achieved sustained remission, a percentage quite comparable to the rest of the cohort. And among the 101 who achieved sustained remission, 67 had no increase in ANCA through the remainder of the trial, with serology checked every 3 months. Yet 30 of those 67 patients eventually suffered disease relapses during the WGET. Furthermore, 34 of these 101 patients had increases in PR3-ANCA titers, but 18 of those did not relapse; 9 relapsed within 1 year of the rise in ANCA titer. So, how does one interpret a flare 11 months after a rise in ANCA titer? I think it is hard to point to a true association there. Four relapsed in more than 1 year after the ANCA rise, and there were 3 who flared either right before or concurrently with the rise. Unfortunately, I think the data show that, in terms of predicting imminent flares, ANCAs are not helpful.
Scene 4: Red Eyes Redux
We return now to the patient going to the CCU in 2003 for congestive heart failure.
He had 6 days of sinus congestion before this presentation, but it was rather mild; not the intense kind of nasal and sinus problems he had had at the time of his original diagnosis. Then again, maybe we were just catching him early this time. He did not have arthritis. He had myalgia and malaise. He did not have tongue lesions or elbow nodules. Chest imaging showed no nodular or cavitary lesions or other types of infiltrate (his heart failure developed after his hospitalization). He did not have active urine sediment, and his ANCA was negative. He did have nasal crusting, however, which I concluded was probably due to the effect of dry hospital air on damaged nasal mucosa rather than active nasal inflammation. He had a striking fever, to 104°F. He had a skin rash that really looked more like a viral rash (diffuse, erythemaous, blanching, maculopapular), and he did not have purpura. He had low platelets and elevated liver function tests. At this point he was on etanercept and AZA, but he had not had any cytopenias or liver function test abnormalities before, except at diagnosis (when his liver function tests were elevated). Then, as he became increasing short of breath during his hospitalization, I became increasingly mystified.
The diagnostic serology returned from the lab after the patient had been transferred to the CCU. The serology was not an ANCA (for the record, the patient was still ANCA negative during this hospitalization), but rather a serological test for IgM antibodies to Ehrlichia chaffeensis. During a trip to the Eastern Shore to hunt for a retirement property, the patient had been bitten by a tick that transmitted the etiologic agent of human monocytic ehrlichiosis, shown below.
Further history revealed that his wife had pulled a tick off of herself, but he obviously had missed the tick that was on him. Outpatient presented in May 2003, exactly when most ehrlichiosis cases are reported – late spring, early summer – owing to the life cycle of the tick. Doxycycline is remarkably effective in treating Ehrlichiosis; one dose completely abolished his fever. Over the next 2 to 3 months, his cardiomyopathy resolved completely; he had an ejection fraction of 15% to 55% three months later.
- The great majority of patients with WG achieve at least temporary disease control with currently available immunosuppressive therapy.
- Even the shorter courses of CYC now used for the induction of remission are associated with substantial treatment-induced morbidity.
- Disease relapses are common, whatever the remission used for remission induction. Discontinuation of glucocorticoids appears to correlate well with disease relapses in many patients.
- In the remission maintenance phase, AZA or MTX can generally be used safely as substitutes for the more toxic CYC.
- Etanercept is not effective for the maintenance of remission in patients with WG. Further investigation of the potential association among TNF inhibition, CYC, and the induction of malignancy is appropriate.
- Although ehrlichiosis may or may not be regarded as an “opportunistic” infection in the true sense of the term – after all, the infection would not have occurred without a tick bite – infection should always be a leading concern when WG patients present with clinical decompensation.