Fewer Steroids, Longer Remission: Staying Ahead of Vasculitis

The most recent American College of Rheumatology-endorsed criteria for the classification of vasculitis were published in 1990. At the American College of Rheumatology Annual Meeting last year, a novel set of criteria were rolled out in a comprehensive 90-minute session, but the document is under review and will not be presented until the 2017 annual meeting.

In the meantime, an increasing body of information on vasculitides is emerging. Experts are investigating everything from advanced diagnostic tools to duration of immunosuppressive therapy. Case reports and meta-analyses on topics including cocaine use; rare vasculitides, like Behçet’s disease; and the use of hepatitis C therapies in vasculitis proliferated the American College of Rheumatology (ACR) Annual Meeting last year, with more data currently being published.

Current Discussion

Peter Grayson, MD, head of the Vasculitis Translational Research Program at the NIH, has focused exclusively on vasculitis from both a clinical and research perspective. He laid out parameters of the current discussion.

“For some kinds of vasculitis, the field has made a lot of progress in terms of clinical care; but for other forms of vasculitis, clinical trial data is lacking. For all forms of vasculitis, there remains major unmet needs; however, pace of progress in certain types of vasculitis has outpaced progress in other forms of vasculitis.”

There are more than 30 different types of vasculitis that are generally categorized by their size of affected blood vessels: small, medium or large. Healio Rheumatology will address larger vessel vasculitides in an upcoming issue. For the current discussion, experts weigh in on smaller vessel vasculitis.

“We have made considerably more progress with small vessel vasculitis than we have with giant cell arteritis and other medium or large vessel vasculitides,” Grayson said. He noted that the prototypical small vessel vasculitis is antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis. At the moment, much of the focus of both the clinical and research arenas revolves around minimizing steroid use and expanding the options of steroid sparing therapies.

“There have been a number of clinical trials in ANCA-associated vasculitis and physicians have a lot of treatment options for these diseases. Putting a patient into remission with available therapies is now the expectation for these conditions,” he said.

However, “We still do not know the cause of these vasculitides, and still do not have what could be called a cure,” he said.

The answer may lie in technology. “We are using a lot of high-throughput genetic and genomic techniques,” Grayson said. “We are also just starting to develop potential personalized medicine approaches. The field is definitely becoming more advanced.”

New Technology, Treatments

Grayson suggested that several groups, including Ken Smith and colleagues in the United Kingdom, are looking at RNA sequencing for a deeper understanding of the pathogenesis and clinical manifestations of vasculitis.

“They are developing a gene expression signature that can tell us which patients are likely to flare and which patients may achieve sustained remission,” he said. “While these kinds of data have not been incorporated into a clinical trial setting, hopefully those kinds of study designs will be coming in the next several years.”

Grayson added that the NIH conducts tissue-based analysis. “We have been studying vasculitic tissue, particularly from the nose, kidneys and skin,” he said. “We hope that molecular-base information at the tissue level will uncover biomarkers that can be used to predict future events and tailor treatment strategies accordingly.”

These novel approaches may help guide future studies like the MAINRITSAN2 trial, which was conducted by Pierre Charles, MD, of Service de Médecine Interne of Cochin Hospital in Paris, and colleagues. They aimed to assess rituximab use adapted to several factors, including ANCA-positivity and/or titer and/or reappearance of circulating CD19 B cells. The goal was to achieve remission of antibodies-associated vasculitis (AAV) in a cohort of 162 patients with granulomatosis with polyangiitis or microscopic polyangiitis in complete remission after induction therapy with glucocorticoids and cyclophosphamide, rituximab or methotrexate (MTX).

Eighty-one patients in the experimental group were treated with 500-mg rituximab infusions on day 0 after randomization, then every 3 months until month 18, when CD19 lymphocytes exceeded 0 mm³ or ANCA status (reappearance)/titer (higher) differed from the previous determination, according to the results. The 81 patients in the control group received 500 mg of rituximab on days 0 and 14 after randomization and then 6 months, 12 months and 18 months after the first infusion. The number of relapses at month 28 served as the primary endpoint. There were 22 relapses reported among 21 patients. The rates were 17.3% in the experimental arm and 9.9% in the control arm. Patients in the experimental arm underwent a median of three rituximab infusions compared with five rituyimab infusions for controls. The researchers concluded there were no significant differences between the two arms in terms of relapse, but the total rituximab dose was lower in the experimental group.

“We compared these two rituximab infusion strategies to see which could maintain remission in this patient population,” Charles said in an interview with Healio Rheumatology. “At 28 months, there were no significant differences between the experimental arm and the systematic infusion arm. Importantly, though, there were fewer infusions in the individually tailored arm, three against five.”

Charles reported no safety concerns with the experimental arm.

“This was not the outcome we expected,” Charles said. “We did not expect such a good result for the experimental arm. Usually with a strategy such as this one, where you wait for a period before reinfusion, you see minor relapses, but that was not the case with our patient population.”

As for what these data add to the current body of knowledge on vasculitis, Charles suggested this is the first study to investigate an individually tailored infusion approach that is based on patient characteristics, including the biologic characteristics.

“The results show that this approach is possible,” he said. “It is too early to recommend this strategy, but it is important to see that we can try this approach again.”

The study is moving forward not with the tailored-therapy approach, but with the systematic infusion therapy approach, according to Charles.

“We are going to re-randomize patients at 28 months, and it will be 2 years before these results come,” he said. “We had to make a choice between the individually tailored strategy and the systemic strategy. We have chosen the systemic strategy mainly because it is easier for patients and physicians.”

CNS Vasculitis

Several studies were reported from the Center for Vasculitis Care and Research at the Cleveland Clinic.

Rula A. Hajj-Ali, MD, FACP, of the Department of Rheumatic and Immunologic Diseases and director of the multidisciplinaty CNS Vasculitis Clinic at the Cleveland Clinic, presented two abstracts on the comparison between neurosarcoidosis and central nervous system (CNS) vasculitis. The researchers suggested neurosarcoidosis mimics primary angiitis of the CNS (PACNS) in terms of presentation, imaging and pathologic results. The current study included 79 patients with primary angiitis of the CNS and 51 patients with neurosarcoidosis. Several demographic and cerebrospinal fluid characteristics underwent analysis, including blood C-reactive protein, erythrocyte sedimentation rate, antinuclear antibodies (ANA) and rheumatoid factor levels.

Results indicated statistically significant differences between the two diseases regarding two variables. The first was race. Black patients were more likely to be diagnosed with neurosarcoidosis, whereas white patients were more likely to be diagnosed with primary angiitis of the CNS. The second was ANA levels. Researchers observed higher ANA was associated with neurosarcoidosis, while lower levels demonstrated an association with primary angiitis of the CNS. Researchers also observed non-significant associations that may be useful for distinguishing the two diagnoses: those were total nucleated cells and neutrophils. Higher nucleated cell counts trended toward neurosarcoidosis, while lower values trended toward angiitis. Similarly, high neutrophil counts were associated with neurosarcoidosis and lower neutrophils corresponded more frequently with primary angiitis of the CNS.

Hajj-Ali and colleagues further reviewed distinguishing MRI features in both cohorts. They found patients with PACNS had a higher frequency of cerebral and basal ganglia enhancement and parenchymal hemorrhage than neurosarcoidosis. Patients with neurosarcoidosis demonstrated more frequent spinal cord, basal meningeal and cranial nerve involvements.

Hajj-Ali said the researchers were looking for “any distinguishing feature at the level of blood tests,” along with demographic and MRI findings.

“We wanted to differentiate between these diagnostic parameters,” she told Healio Rheumatology. “Our findings are important because they can give physicians more confidence to differentiate between these two diagnoses that can be treated differently.”

The understanding that black patients are more likely to get neurosarcoidosis more severely than white patients will help guide treatment decisions, according to Hajj-Ali. “Sometimes treatment can be tricky on the pathologic level, but we feel these findings will help clarify some of the confusion,” she said.

Grayson commented more broadly on these findings.

“Neutrophil is thought to be a key cell,” he said. “There has been a lot of work trying to see if this is developing autoantibodies.”

Elisabeth Ray, MD, a fellow in of the Department of Rheumatology and Immunology, working with a long-standing CNS vasculitis cohort accrued by Hajji Ali and Leonard H. Calabrese, DO, tried to further understand functional capabilities, quality of life and parameters of long-term outcomes of 78 patients with cerebral angiitis and to determine the impact of treatment duration on patient outcomes. The final analysis included 27 patients who met all inclusion criteria and completed the questionnaires. Results indicated approximately half of the cohort had no issues with mobility, while two-thirds had no problems with self-care and 55.6% had no problems with usual activities. About half of patients had no problems with pain, but less than 30% had no problems with anxiety. Approximately 70% reported minimal or no depression, according to the results. A slight positive association was reported between several outcome measures and duration of immunosuppressive therapy, but this association failed to reach statistical significance.

“The data shows a slight tendency toward better scores being associated with longer treatments,” the researchers concluded. “However, larger studies are needed to verify the extent and strength of these relationships.”

“We collected a group of patients with CNS vasculitis,” Ray told Healio Rheumatology. “Eligible patients had to have a positive brain biopsy or typical angiographic findings along with evidence of inflammation in the spinal fluid to confirm the vasculitis after ruling out mimics of this disease.”

Ray suggested most patients had some sort of mild long-term disability. “Most had minimal to no depression, but about one-third had moderate to severe depression,” she said. “These findings are similar to the stroke or acute neural injury patient cohorts.”

Regarding the contribution of these data to the larger body of information, Ray said most patients were treated during a long period and the results are reflective of that treatment duration.

“Most patients respond well to treatment and have minimal disability in the long-run,” she said. “Most patients with CNS vasculitis tend to do well on treatment.”

HCV Therapies in Vasculitis

David Saadoun, MD, of Sorbonne University, UPMC University of Paris, UMR 7211 and the Inflammation – Immunopathology-Biotherapy Department of F-75005 in Paris, and colleagues aimed to assess whether an oral interferon-free direct-acting antiviral regimen of sofosbuvir (Sovaldi, Gilead Sciences) 400 mg per day plus daclatasvir (Daklinza, Bristol-Myers Squibb) 60 mg per day to the treat hepatitis C virus (HCV) was effective in cryoglobulinemia vasculitis. There were 41 patients included of whom up to 90% achieved a complete clinical response and 50% cleared cryoglobunimia at 6 months. All patients were sustained virological responders. The safety was satisfactory as no serious adverse events were noted.

“Here we report on the results of using direct-acting HCV drugs without pegylated interferon and ribavirin for the treatment of vasculitides,” Saadoun said. “This is the first study using these new regimens where we compare the efficacy and safety if older regimens used in a previous cohort with the new regimens.”

Saadoun said the kinetics of complete remission of vasculitis were “fast” with the novel direct-acting HCV regimen. “We saw up to a 50% complete response after 3 months of therapy, and 100% after 6 months of therapy,” he said. “Regarding the virologic response, within 4 weeks there was no detectable HCV RNA.”

An important statistic is the proportion of patients who receive immunosuppressive drugs, according to Saadoun. “In the sofosbuvir and daclatasvir arm, less than 5% of patients were receiving steroids or rituximab compared to 40% in the older regimens,” he said. “Plus, there were no serious side effects with sofosbuvir and daclatasvir.”

The group concluded this is an efficient, fast-acting and safe regimen. Saadoun said as future regimens emerge, the need for immunosuppressants will be further reduced. “We recommend that physicians go ahead and start HCV therapy first in order to resolve a patient’s vasculitis,” he said. “We can avoid a lot of rituximab and steroids using this method.”

For Grayson, there was an additional take-home message. “Basically, a lot of the research we are seeing lately is geared toward determining if we can get away with less steroid use and still keep them from relapsing,” he said. “How do we keep them in remission?”

Lymphoma and CNS Vasculitis

Carlo Salvarani, MD, of Arcispedale Santa Maria Nuova-IRCCS in Reggio Emilia, Italy, and colleagues assessed the frequency of lymphoma in patients treated for vasculitis and lymphoma at the Mayo Clinic in Rochester, Minn. between 1982 and 2014. The study included 168 patients, 10 of whom had both primary CNS vasculitis and lymphoma. Investigators aimed to determine the parameters of patients with both conditions and compared them to patients with primary CNS vasculitis without lymphoma. For the most part, clinical manifestations of vasculitis were similar among the 10 patients with lymphoma and vasculitis as well as among the 158 patients without lymphoma.

Cognitive dysfunction occurred in 80% of patients with lymphoma vs. 53% of the comparison group. Also, visual field defects were less frequent in the lymphoma group (0% vs. 19%), as was the incidence of intracranial hemorrhage (0% vs. 10%). Patients in the lymphoma group were more likely to demonstrate meningeal gadolinium enhancing lesions on MRI (50% vs 19%). A higher rate of poor outcomes was reported in the lymphoma group.

“Most clinical characteristics of [primary CNS vasculitis] PCNSV were similar in those with or without lymphoma, however, patients with lymphoma had a more severe cerebral vasculitis with increased neurological disability and mortality,” the researchers concluded.

“Vasculitis can be a complication of lymphoproliferative diseases,” Salvarani said in an interview with Healio Rheumatology. “When we looked at patients with primary CNS vasculitis and lymphoma, we were able to define 10 patients with both conditions. In seven of those patients, the diagnosis was simultaneous, which we believe means both vasculitis and lymphoma manifestations came simultaneously.”

For Salvarani, the key was that patients with lymphoma had more cerebral vasculitis with increased cerebral disability and mortality than patients who did not have lymphoma. “People treating lymphoma should be aware of these manifestations,” he said. “Patients may have associated vasculitides and more severe complications.”

Behçet’s Disease and Other Rarer Vasculitides

Christopher Sjöwall, MD, of the Department of Clinical and Experimental Medicine Rheumatology/AIR at Linköping University in Sweden, and colleagues aimed to describe the clinical characteristics and epidemiology of hypocomplementemic urticarial vasculitis. All patients diagnosed with this condition in the districts surrounding Skåne University Hospital in Lund, Sweden from 2000 to 2015 were included in the analysis. Researchers identified 16 patients. They concluded the condition is “rare but not benign,” and renal and lung manifestations were severe in some cases.

“We provide an overview of the clinical characteristics and epidemiology of this condition,” Sjöwall said. “The strength of the study is we have a strong health care system with good coverage of patients, so we were able to looked for this condition through medical records and lab analysis.”

The incidence rate is about one per million individuals, according to Sjöwall. “Despite how rare this condition is, about one-third went into end-stage liver disease,” he said. “Some patients underwent lung transplantation. We want to highlight this condition and let physicians know they should be doing anti-CD1Q analysis.”

Fabiani and colleagues investigated the efficacy of adalimumab in a cohort of 40 selected patients with of Behçet’s disease-related uveitis. The multicenter, retrospective observational study included 66 eyes. Reduction of ocular inflammatory flares served as the primary endpoint, while improvement of best corrected visual acuity, reduction of macular thickness measured by optical coherence tomography (OCT) and reduction in the occurrence of vasculitis assessed by fluorescein angiography served as secondary endpoints. However, another important endpoint included an assessment of differences between patients treated with adalimumab monotherapy and those treated with adalimumab plus disease-modified antirheumatic drugs, along with patients initially treated with adalimumab compared to patients previously administered with other biologics.

They also investigated whether the study drug spared steroid use. A decrease from 200 flares per 100 patients per year to 8.5 flares per 100 patients per year was reported during the first 12 months of adalimumab therapy, according to the results. Best corrected visual acuity improved from 7.4 ± 2.9 at baseline to 8.5 ± 2.1. A mean reduction of central macular thickness of 27.27 ± 42.8 m was reported at the end of follow-up, according to OCT findings. Retinal vasculitis was reported in 22 patients at baseline, eight patients after 3 months and in one patient at 12-months follow-up. “[Adalimumab] is highly effective and safe for the treatment of [Behçet’s disease]-related uveitis, providing a long-term control of ocular inflammation,” the researchers concluded.

“Something we keep coming back to is that these therapies are effective but not curative,” Grayson said.

Olives and colleagues described a case of in-hospital spontaneous intraperitoneal hemorrhage, which can be a severe complication of cocaine-related ANCA vasculitis. They suggested ANCA vasculitis is frequently reported in association with levamisole-adulterated cocaine use. “Catastrophic in-hospital hemorrhage due to ANCA vasculitis and vascular necrosis, though previously unreported, may occur with ongoing cocaine use,” they wrote.

“We have recently started seeing a drug-induced vasculitis that looks like ANCA,” Grayson said. “We have figured out that one of the big problems we have been having is that cocaine is contaminated with levamisole leading to a condition that looks similar to ANCA vasculitis. If you stop using the drug, the disease goes away. This needs to be on the radar of clinicians.”

• References:
• Charles P, et al. Abstract #16L. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Fabiani C, et al. Clin Rheumatol. 2017;doi:10.1007/s10067-016-3480-x.
• Olives TD, et al. J Addict Med. 2017;doi:10.1097/ADM.0000000000000290.
• Ray E, et al. Abstract #2951. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Saadoun D, et al. Abstract #17L. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Salvarani C, et al. Abstract #2957. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Saygin D, et al. Abstracts #18L and #2952. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.
• Sjöwall C, et al. Abstract #2958. Presented at: American College of Rheumatology Annual Meeting; Nov. 11-16, 2016; Washington.

• For more information:
• Pierre Charles, MD, can be reached at 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; email: pierre.charles@imm.fr.
• Peter Grayson, MD, can be reached at 1 AMS Cir., Bethesda, MD 20892; email: peter.grayson@nih.gov.
• Rula A. Hajj-Ali, MD, FACP, can be reached at 9500 Euclid Ave., Cleveland, OH 44195; email: hajjalr@ccf.org.
• Elisabeth Ray, MD, can be reached at 9500 Euclid Ave., Cleveland, OH 44195.
• David Saadoun, MD, can be reached at CHU Paris-GH La Pitié Salpêtrière-Charles Foix – Hôpital Pitié-Salpêtrière 47-83 boulevard de l’Hôpital, 75013 Paris, France; email: david.saadoun@aphp.fr.
• Carlo Salvarani, MD, can be reached at Viale Risorgimento, 80, 42123 Reggio Emilia RE, Italy; email: salvarani.carlo@asmn.re.it.
• Christopher Sjöwall, MD, PhD, can be reached at Rheumatology Unit University Hospital SE-581 85, Linköping, Sweden; e-mail: chrsj@imk.liu.se.

Disclosures: Grayson, Hajj-Ali, Ray, Salvarani and Sjöwall report no relevant financial disclosures. Charles reports he has no associations with Hoffmann-LaRoche Inc. Saadoun reports he has associations with AbbVie, Gilead, GlaxoSmithKline, Medimmune, Roche and Servier.