Acr 2018 PDF

American College of Rheumatology (ACR)
Vasculitis Guideline—ANCA-Associated Vasculitis
Project Plan – July 2018
PARTICIPANTS
Core Oversight Team John Stone, MD, MPH

Sharon Chung, MD, MAS (Principal Sangeeta Sule, MD, PhD
Investigator/Voting Panel Leader) Robert Sundel, MD, BA
Gary Hoffman, MD (Content Expert) Ann Warner, MD
Carol Langford, MD (Content Expert)
Mehrdad Maz, MD (Content Expert) Expert Panel
Antoine Sreih, MD (Content Expert) Ora Gewurz-Singer, MD
Reem Mustafa, M.B.B.S., PhD, MPH (Literature Rula Hajj-Ali, MD
Review Leader) Eric Matteson, MD, MPH
Gordon Guyatt, MD (GRADE Expert) Robert Spiera, MD
Linda Wagner-Weiner, MD
Literature Review Team Ken Warrington, MD
Kevin Byram, MD
Anisha Dua, MD, MPH Patient Panel
Nedaa Husainat, MD TBD
Karen E. James, MD, M.S.C.E
Mohamad Kalot, MD ACR Staff
Yih Chang Chen Lin, MD Robin Lane
Catherine Najem, MD Amy S. Turner
Amit Shah, MD, MPH Regina Parker
Jason Springer, MD, MS
Marat Turgunbaev, MD, MPH
Alexandra Villa-Forte, MD, MPH
Voting Panel
Amy Archer, MD, PhD
Doyt Conn, MD
Peter C. Grayson, MD, M.Sc.
Maria Ibarra, MD
Susan Kim, MD
Peter Merkel, MD, MPH
Rennie Rhee, MD
Phil Seo, MD, MHS
1
1
2 ORGANIZATIONAL LEADERSHIP AND SUPPORT
3
4 This project of the American College of Rheumatology (ACR) has the broad objective of developing an
5 evidence-based clinical practice guideline related to the treatment and management of systemic
6 vasculitis.
7
8 BACKGROUND
9
10 The ACR has previously not developed guidelines for the management of systemic vasculitis. The
11 diagnosis, treatment, and monitoring of these diseases can be challenging given their rarity and the
12 paucity of large, randomized clinical trials to guide therapy for some vasculitic diseases. Therefore, the
13 ACR convened the Vasculitis Guideline core leadership team to develop evidence-based guidelines for
14 the management of systemic vasculitis. The group was encouraged to scope broadly, without mandate
15 to cover a specific type of vasculitis. It was recognized that one set of guidelines could not cover the
16 entire spectrum of vasculitic diseases, and that vasculitides not addressed in this initial effort could be
17 covered in future guidelines.
18 At the group’s first in-person meeting in June 2017, the Core Oversight Team, Voting Panel, and Expert
19 Panel discussed the scope that should be covered in this initial guideline effort. The 2012 Revised
20 International Chapel Hill Consensus Conference Nomenclature (1) was used as the basis for categorizing
21 the vasculitides to be considered. For this initial effort, the vasculitides in the major categories—large,
22 medium, and small vessel vasculitis—were prioritized given their prevalence compared to other
23 categories of vasculitis. After discussion, the group members elected to first focus on large and medium
24 vessel vasculitides, due to the scope of the project, need for clinical guidelines for these diseases and
25 the available evidence upon which these guidelines could be based. The project plan presenting the
26 committee’s work on large and medium vessel vasculitis was presented to the rheumatology community
27 in March 2018. After development of that project plan, the committee began the current effort to
28 develop guidelines for small vessel vasculitis. At this time, guidelines are being developed for anti-
29 neutrophil cytoplasmic antibody (ANCA)-associated vasculitis due to the relative prevalence and
30 availability of literature and therapeutic options. We recognize that management guidelines for other
31 types of small vessel vasculitis such as IgA vasculitis, cryoglobulinemic vasculitis, hypocomplementic
32 urticarial vasculitis, and anti-glomerular basement membrane disease are also needed. Development of
33 guidelines for these vasculitides may be addressed at a later time.
34 Using the Chapel Hill Consensus Conference nomenclature, the ANCA-associated vasculitides included in
35 this effort are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic
2
36 granulomatosis with polyangiitis (EGPA). Renal limited ANCA-associated vasculitis is not being addressed
37 specifically in this effort, but studies of renal limited ANCA-associated vasculitis will be included in the
38 literature review. Many questions presented in this project plan consider GPA and MPA together. We
39 recognize that these are different diseases for which disease specific management approaches exist,
40 particularly for GPA. However, we have grouped these two diseases together for many treatment
41 questions since pivotal trials have enrolled and presented results for these diseases together, and data
42 may be limited regarding the treatment outcomes for these diseases individually. The Vasculitis
43 Guideline group intends for these guidelines to be applicable to both adults and children affected by
44 these diseases. Thus, the group is comprised of both adult and pediatric rheumatologists, and the
45 questions addressed in this guideline apply to both adults and children.
46
47 OBJECTIVES
48
49 The objective of this project is to develop recommendations informing the use of laboratory testing,
50 pharmacologic treatments, and non-pharmacologic interventions for the management of ANCA-
51 associated vasculitis: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and
52 eosinophilic granulomatosis with polyangiitis (EGPA).
53
54 Specifically, we aim to:
55
56 1. Develop recommendations for the use of laboratory and imaging studies that inform the
57 management of ANCA-associated vasculitis.
58 2. Develop recommendations for the use of glucocorticoids, non-glucocorticoid and biologic
59 immunosuppressive agents, and non-pharmacologic interventions for the management of
60 ANCA-associated vasculitis based on considerations of both efficacy and safety.
61
62 METHODS
63
64 Identification of Studies
65
66 Literature search strategies, based on PICO questions (Population/patients, Intervention, Comparator,
67 and Outcomes; see Appendix A) will be developed by the principal investigators, systematic literature
68 review leader, and a research librarian, with input from the Core Team. The search strategies will be
69 peer reviewed by another medical librarian using Peer Review of Electronic Search Strategies (PRESS)
70 (2). Searches will be performed in OVID Medline (1946 +), Embase (1974 +), the Cochrane Library, and
71 PubMed (mid-1960s +).
3
72
73 The search strategies will be developed using the controlled vocabulary or thesauri language for each
74 database: Medical Subject Headings (MeSH) for OVID Medline, PubMed and Cochrane Library; and
75 Emtree terms for Embase. Text words will also be used in OVID Medline, PubMed, and Embase, and
76 keyword/title/abstract words in the Cochrane Library.
77
78 Search Limits
79
80 Only English language articles will be retrieved.
81
82 Grey Literature
83
84 The websites of appropriate agencies, such as the Agency for Healthcare Research and Quality (AHRQ),
85 will be searched for peer-reviewed reports not indexed by electronic databases.
86
87 Literature Search Update
88
89 Literature searches will be updated just before the voting panel meeting to ensure completeness.
90
91 Inclusion/Exclusion Criteria
92
93 See PICO questions (Appendix A), which outline the defined patient population, interventions,
94 comparators and outcomes.
95
96 Management of Studies and Data
97
98 References and abstracts will be imported into bibliographic management software (Reference
99 Manager) (3), duplicates removed, and exported to Distiller SR, a web-based systematic review manager
100 (4). Screening and data abstraction forms will be created in Distiller SR. Search results will be divided
101 among reviewers, and two reviewers will screen each title/abstract, with disagreements at the
102 title/abstract screening stage defaulting to inclusion for full manuscript review. Following the same dual
103 review process, disagreements at the full manuscript screening stage will be discussed and adjudicated
104 by the literature review leadership, if necessary.
105
106
107
108
4
109 Phases
110
111 1. A search for randomized controlled trials and observational studies about interventions aimed
112 at the pharmacologic treatments and non-pharmacologic interventions for the management of
113 ANCA-associated vasculitis (GPA, MPA, and EGPA) will be performed to determine existing
114 studies covering outcomes of interest. Studies of renal limited ANCA-associated vasculitis will
115 not be excluded. Subsequently, identified studies will be assessed using the RevMan (5) and
116 GRADE Pro tools (6).
117 2. Chosen studies will be assessed for risk of bias using modified versions of the Cochrane Risk of
118 Bias tool (7) and the Newcastle-Ottawa Scale (8).
119 3. Additionally, recently published systematic reviews covering outcomes of interest will also be
120 sought and used for reference cross-checking.
121
122 GRADE Methodology
123
124 GRADE methodology (9) will be used in this project to grade available evidence and facilitate
125 development of recommendations. The certainty in the evidence (also known as ‘quality’ of evidence)
126 will be graded as high, moderate, low or very low. The strength of recommendations will be graded as
127 strong or conditional. The strength of recommendations will not depend solely on the certainty in the
128 evidence, but also on patient preferences and values, and the weight between benefits and harms. A
129 series of articles that describe the GRADE methodology can be found on the GRADE working group’s
130 website: www.gradeworkinggroup.org.
131
132 Analysis and Synthesis
133
134 The literature review team will analyze and synthesize data from included studies that address the PICO
135 questions. An evidence profile, including a GRADE Summary of Findings table, will be prepared for each
136 PICO question using Review Manager (RevMan) (3) and GRADEprofiler (GRADEpro) software (6). The
137 Summary of Findings table contains the benefits and harms for each outcome across studies, the
138 assumed and corresponding risk for comparators and interventions (95% CI), the absolute risk and
139 relative effect (95% CI), the number of participants/number of studies, and the certainty in the evidence
140 for each critical and important outcome (i.e., high, moderate, low or very low).
141
142 The evidence profile documents the overall certainty in the evidence for each critical and important
143 outcome across studies and summarizes the rationale of the GRADE criteria for downgrading (risk of
144 bias, inconsistency, indirectness, imprecision and publication bias), or upgrading the certainty in a body
5
145 of evidence (large magnitude of effect, dose-response gradient, and all plausible confounding that
146 would reduce a demonstrated effect).
147
148 Development of Recommendation Statements
149
150 PICO questions will be revised into drafted recommendation statements. Using the GRADE Evidence
151 Profiles and Summaries of Findings tables, the voting panel, consisting of eight adult rheumatologists,
152 four pediatric rheumatologists, and patient representatives, will consider the drafted recommendation
153 statements in two stages. The first assessment will be done individually, and the results will be
154 anonymous; this vote will only be used to determine where consensus might or might not already exist
155 and develop the voting panel meeting agenda. At the face-to-face voting panel meeting, chaired by the
156 principal investigator, the panelists will discuss the evidence in the context of their clinical experience
157 and expertise to arrive at consensus on the final recommendations. The voting panel meeting
158 discussions will be supported by the literature review leader, the GRADE expert, and selected members
159 of the literature review team, who will attend the meeting to provide details about the evidence, as
160 requested. Voting panel discussions and decisions will be informed by a separately convened patient
161 panel, which will meet in the days before the voting panel meeting, to provide unique patient
162 perspectives on the drafted recommendations based on their experiences and the available literature.
163
164 PLANNED APPENDICES (AT MINIMUM)
165
166 A. Final literature search strategies
167 B. GRADE evidence profiles and summary of findings tables for each PICO question
168
169 AUTHORSHIP
170
171 Authorship of the guideline will include: principal investigator, Dr. Sharon Chung, as the lead author and
172 voting panel leader; Dr. Reem Mustafa, literature review leader; Drs. Gary Hoffman, Carol Langford,
173 Mehrdad Maz, and Antoine Sreih, content experts; and Dr. Gordon Guyatt, GRADE expert. Members of
174 the literature review team and voting panel will also be authors. The PI will determine final authorship,
175 dependent on the efforts made by individuals throughout the guideline development process, using
176 international authorship standards as guidance.
177
178
179
180
181
6
182 DISCLOSURES/CONFLICTS OF INTEREST

183
184 The ACR’s disclosure and COI policies for guideline development will be followed for this project. These
185 can be found in the ACR Guideline Manual on this page of the ACR web site, under Policies &
186 Procedures. See Appendix B for participant disclosures.
187
188 REFERENCES
189
190 1. Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International
191 Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65:1-11.
192 2. Sampson M, McGowan J, Lefebvre C, Moher D, Grimshaw J. PRESS: Peer Review of Electronic
193 Search Strategies. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2008.
194 3. Review Manager [software]. Oxford (UK): Cochrane Collaboration; 2013.
195 http://ims.cochrane.org/revman
196 4. DistillerSR. Ottawa, Canada: Evidence Partners; 2013. http://systematic-review.net/
197 5. Reference Manager [software]. Thomson Reuters; 2013. http://www.refman.com/
198 6. GRADEprofiler [software]. Oxford (UK): Cochrane Collaboration; 2013.
199 http://ims.cochrane.org/revman/gradepro
200 7. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions
201 Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available:
202 http://handbook.cochrane.org.
203 8. Wells GA, Shea B, O'Connell D, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS)
204 for assessing the quality of nonrandomised studies in meta-analyses. 2010. Available:
205 http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
206 9. GRADE guidelines - best practices using the GRADE framework. 2013. Available:
207 http://www.gradeworkinggroup.org/publications/JCE2011.htm
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208 APPENDIX A – PICO Questions
209
210 EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (EGPA; CHURG-STRAUSS)
211 Definitions:
212
213 A. Disease states
214 1. Active disease: new, persistent, or worsening clinical signs and/or symptoms attributed
215 to eosinophilic granulomatosis with polyangiitis (Churg-Strauss; EGPA) and not related
216 to prior damage
217 2. Severe disease: vasculitis with life/organ-threatening manifestations (e.g.,
218 glomerulonephritis, mononeuritis multiplex, diffuse alveolar hemorrhage, cardiac
219 involvement, mesenteric ischemia, limb/digit ischemia)
220 3. Non-severe disease: vasculitis or non-vasculitis symptoms without life/organ-
221 threatening manifestations (e.g. rhino-sinusitis, asthma, mild systemic symptoms,
222 uncomplicated cutaneous disease, mild inflammatory arthritis)
223 4. Remission: absence of apparent clinical signs or symptoms attributed to EGPA on or off
224 of immunosuppressive therapy
225 5. Refractory: persistent active disease (excluding rhinosinusitis and asthma) despite an
226 appropriate course of immunosuppressive therapy
227 6. Relapse: recurrence of active disease following a period of remission
228
229 B. Therapy
230 1. Pulse intravenous glucocorticoids:
231 • Adults: methylprednisolone 500-1000 mg given intravenously for 3-5 days or
232 equivalent
233 • Children: methylprednisolone 30 mg/kg/day (maximum 1000 mg/day) for 3-5
234 days or equivalent
235 2. High dose oral glucocorticoids:
236 • Adults: prednisone 1 mg/kg/day (generally up to 80 mg/day) or equivalent
237 • Children: prednisone 1-2 mg/kg/day (generally up to 60 mg/day) or equivalent
238 3. Moderate dose oral glucocorticoids:
239 • Adults: prednisone 0.25-0.5 mg/kg/day (generally between 10-40 mg/day) or
240 equivalent
241 • Children: prednisone ~0.5 mg/kg/day (generally 10-30 mg/day) or equivalent
8
242 4. Low dose oral glucocorticoids:

243 • Adults: prednisone ≤ 10 mg/day or equivalent
244 • Children: prednisone ≤ 0.2 mg/kg/day (maximum 10 mg/day) or equivalent
245 5. Remission induction therapy:
246 • Cyclophosphamide (CYC)
247 o Oral: up to 2 mg/kg/day
248 o IV: 15 mg/kg q2 weeks x 3 doses, followed by 15 mg/kg q3 weeks for at least
249 3 doses
250 • Rituximab (RTX): 375 mg/m2 IV week x 4 doses or 1000 mg IV on days 1 and 15
251 • Mepolizumab: 300 mg subcutaneous every 4 weeks
252 6. Remission maintenance therapy:
253 • Azathioprine (AZA): up to 2 mg/kg/day
254 • Methotrexate (MTX): up to 25 mg/week subcutaneous or po
255 • Rituximab (RTX): 500 mg IV q6 months or 1 gm IV q4 months
256 • Mycophenolate mofetil (MMF): up to 1500 mg po bid
257 o Mycophenolic acid and mycophenolate sulfate also used
258 • Mepolizumab: 300 mg subcutaneous every 4 weeks
259 • Omalizumab: 300-600 mg subcutaneous every 2-4 weeks
260
261 7. Pneumocystis prophylaxis: SMZ/TMP, dapsone, atovaquone, aerosolized pentamidine
262
263 C. Disease assessments
264 1. Clinical monitoring: Assessing for clinical signs and symptoms of active disease and
265 obtaining clinical labs including inflammatory markers, immunoglobulin E (IgE) levels
266 and eosinophil count
267 2. ANCA: immunofluorescence testing for c-ANCA/p-ANCA and ELISA testing for MPO and
268 PR3 antibodies
269 3. Routine laboratory monitoring: complete blood count, comprehensive metabolic panel,
270 urinalysis with microscopy, erythrocyte sedimentation rate, C-reactive protein
271 4. Cardiac imaging: transthoracic echocardiogram or cardiac MRI
272
273 D. Disease-related outcomes
274 1. Activity as determined by the Birmingham Vasculitis Activity Score (BVAS), BVAS/WG, or
275 study-specific disease activity assessment
276 2. Damage as determined by the Vasculitis Damage Index (VDI), ANCA-Vasculitis Damage
277 Index (AVID) or study-specific disease damage measure
9
278 3. Clinical symptoms and organ damage attributable to disease

279 4. Relapse
280 5. Death
281 6. Patient-Reported Outcomes
282 a. SF36 (Short Form Health Survey), EQ-5D (EuroQol), or CHQ (Child Health
283 Questionnaire)
284 b. If above not available: Patient Global Assessment, PROMIS, RAPID3, or MDHAQ
285
286 E. Treatment-related adverse events
287 1. Serious adverse events
288 2. Infection
289 3. Malignancy
290 4. Glucocorticoid Toxicity Index
291 5. Any toxicity leading to drug dose reduction or treatment discontinuation
292 6. Complications of surgical procedures
293
294 PICO Questions:
295 Diagnostic/prognostic tools

296
297 Role of FFS:
298 1. In patients with EGPA, what is the impact of using the Five Factor Score vs. intuitive
299 assessment of patient’s status to guide therapy on disease-related outcomes and treatment-
300 related adverse events?
301 Cardiac imaging:
302 2. In patients with EGPA, what is the impact of performing cardiac imaging at time of diagnosis
303 and yearly vs. not performing cardiac imaging on disease-related outcomes and treatment-
305
306 Treatment: Remission Induction
307
308 Pulse vs. high dose prednisone:
309 3. In patients with active severe EGPA, what is the impact of using pulse intravenous vs. high-
310 dose oral glucocorticoids on disease-related outcomes and treatment-related adverse
311 events?
312
313
10
314 Rituximab vs. CYC:

315 4. In patients with active severe EGPA, what is the impact of using rituximab vs.
316 cyclophosphamide for remission induction on disease-related outcomes and treatment-
318 4a. How does the impact vary by ANCA status?
319 Role of mepolizumab:
320 5. In patients with active severe EGPA, what is the impact of using mepolizumab plus
321 glucocorticoids vs. glucocorticoids alone on disease-related outcomes and treatment-
323 6. In patients with active severe EGPA, what is the impact of using mepolizumab vs. rituximab
324 for remission induction on disease-related outcomes and treatment-related adverse events?
325 7. In patients with active severe EGPA, what is the impact of using mepolixumab vs.
326 cyclophosphamide for remission induction in disease-related outcomes and treatment-
328 Non-severe disease:
329 8. In patients with active non-severe EGPA, what is the impact of initiating treatment with
330 azathioprine + glucocorticoids vs. methotrexate + glucocorticoids on disease-related
331 outcomes and treatment-related adverse events?
333 azathioprine+ glucocorticoids vs. MMF+ glucocorticoids on disease-related outcomes and
334 treatment-related adverse events?
336 methotrexate + glucocorticoids vs. MMF + glucocorticoids on disease-related outcomes and
339 methotrexate/azathioprine/MMF + glucocorticoids vs. rituximab + glucocorticoids on
340 disease-related outcomes and treatment-related adverse events?
342 methotrexate/azathioprine/MMF + glucocorticoids vs. cyclophosphamide + glucocorticoids
343 on disease-related outcomes and treatment-related adverse events?
345 methotrexate/azathioprine/MMF + glucocorticoids vs. glucocorticoids alone on disease-
346 related outcomes and treatment-related adverse events?
347
348
349
350
11
351 Treatment: Remission Maintenance

352
353 CYC, MTX/AZA, RTX, MMF:
354 14. In patients with severe EGPA who have entered remission, what is the impact of using
355 methotrexate vs. azathioprine for remission maintenance on disease-related outcomes and
358 methotrexate vs. MMF for remission maintenance on disease-related outcomes and
361 azathioprine vs. MMF for remission maintenance on disease-related outcomes and
364 rituximab vs. methotrexate/azathioprine/MMF for remission maintenance on disease-
366 18. In patients with severe EGPA who have entered remission with mepolizumab therapy, what
367 is the impact of using methotrexate/azathioprine/MMF vs. continuing mepolizumab for
368 remission maintenance on disease-related outcomes and treatment-related adverse events?
369 Duration of remission maintenance therapy:
370 19. In patients with severe EGPA on remission maintenance therapy not using prednisone, what
371 is the impact of continuing remission maintenance therapy for > 18 months vs. stopping
372 remission maintenance therapy at or prior to 18 months on disease related outcomes and
373 treatment related adverse events?
374 20. In patients with severe EGPA on remission maintenance therapy and prednisone, what is the
375 impact of continuing remission maintenance therapy for > 18 months with prednisone vs.
376 stopping remission maintenance therapy at or prior to 18 months and continuing
377 prednisone on disease related outcomes and treatment-related adverse events?
378 21. In patients with severe EGPA on remission maintenance therapy, what is the impact of using
379 oral glucocorticoids for 6 months versus more than 6 months on disease-related outcomes
380 and treatment-related adverse events?
381
382 Treatment: Refractory/Smoldering Disease
383
384 Refractory disease:
385 22. In patients with severe EGPA who have not entered remission with cyclophosphamide or
386 rituximab therapy, what is the impact of adding mepolizumab vs. continued
12
387 rituximab/cyclophosphamide therapy on disease-related outcomes and treatment-related

388 adverse events?
389
390 Treatment: Relapse
391
392 Severe Relapse:
393 23. In patients with EGPA who have relapsed with severe disease manifestations after prior
394 remission induction with cyclophosphamide or rituximab and on either non-rituximab
395 maintenance therapy or no maintenance therapy, what is the impact of using the same
396 agent vs. switching to the other agent for remission re-induction on disease-related
398 Non-severe relapse with asthma and sino-nasal disease only:
399 24. In patients with EGPA who have relapsed with non-severe disease manifestations (asthma
400 and/or sino-nasal disease) while on methotrexate/azathioprine/MMF, what is the impact of
401 adding mepolizumab versus switching to another agent on disease-related outcomes and
403 25. In patients with EGPA and high IgE levels who have relapsed with non-severe disease
404 manifestations (asthma and/or sino-nasal disease) while on
405 methotrexate/azathioprine/MMF, what is the impact of adding omalizumab versus
406 switching to another agent on disease-related outcomes and treatment-related adverse
407 events?
408 26. In patients with EGPA who have relapsed with non-severe disease manifestations (asthma
409 and/or sino-nasal disease) while on low dose glucocorticoids and no other therapy, what is
410 the impact of increasing the dose of glucocorticoids versus adding
411 methotrexate/azathioprine/MMF/mepolizumab on disease-related outcomes and
413
414 Other
415
416 Role of continued prednisone use:
417 27. In patients with EGPA in remission and currently only on prednisone, what is the impact of
418 continuing with low dose prednisone long-term (e.g., > 18 months) vs. stopping low dose
419 prednisone on disease-related outcomes and treatment related adverse events?
420 28. In patients with EGPA in remission on remission maintenance therapy and prednisone, what
421 is the impact of continuing low dose prednisone long-term (e.g., > 18 months) vs. stopping
422 low dose prednisone and continuing remission maintenance therapy on disease-related
423 outcomes and treatment related adverse events?
13
424 Role of nasal rinses:

425 29. In patients with sino-nasal involvement in EGPA, what is the impact of using nasal rinses vs.
426 not using nasal rinses on disease related outcomes and treatment-related adverse events?
427 Pneumocystis prophylaxis:
428 30. In patients with EGPA on cyclophosphamide or rituximab, what is the impact of using
429 Pneumocystis prophylaxis vs. not using Pneumocystis prophylaxis on Pneumocystis infection
431 Role of leukotriene inhibitors:
432 31. In patients with newly diagnosed EGPA and on leukotriene inhibitors, what is the impact of
433 discontinuing leukotriene inhibitors versus continuing leukotriene inhibitors on disease-
435 32. In patients with EGPA and active asthma and/or sino-nasal disease what is the impact of
436 adding leukotriene inhibitors versus not adding leukotriene inhibitors on disease-related
438
439
440 GRANULOMATOSIS WITH POLYANGIITIS (GPA) and MICROSCOPIC POLYANGIITIS (MPA)

441
442 Definitions:
443
444 A. Disease states
445 1. Severe disease: vasculitis with life/organ-threatening manifestations (e.g., alveolar
446 hemorrhage, rapidly progressive glomerulonephritis)
447 2. Non-severe disease: vasculitis without life/organ-threatening manifestations (e.g. sinusitis)
448 3. Active disease: new, persistent, or worsening clinical signs and/or symptoms attributed to
449 GPA/MPA and not related to prior damage
450 4. Remission: absence of clinical signs or symptoms attributed to GPA/MPA, on or off of
451 immunosuppressive therapy
452 5. Refractory: persistent active disease despite an appropriate course of immunosuppressive
453 therapy
454 6. Relapse: recurrence of active disease following a period of remission
455
456 B. Therapy
457 1. Pulse intravenous glucocorticoids:
458 • Adults: methylprednisolone 500-1000 mg given intravenously for 3-5 days or
459 equivalent
14
460 • Children: methylprednisolone 30 mg/kg/day (maximum 1000 mg/day) for 3-5

461 days or equivalent
462 2. High dose oral glucocorticoids:
463 • Adults: prednisone 1 mg/kg/day (generally up to 80 mg/day) or equivalent
464 • Children: prednisone 1-2 mg/kg/day (generally up to 60 mg/day) or equivalent
465 3. Moderate dose oral glucocorticoids:
466 • Adults: prednisone 0.25-0.5 mg/kg/day (generally between 10-40 mg/day) or
467 equivalent
468 • Children: prednisone ~0.5 mg/kg/day (generally 10-30 mg/day) or equivalent
469 4. Low dose oral glucocorticoids:
470 • Adults: prednisone ≤ 10 mg/day or equivalent
471 • Children: prednisone ≤ 0.2 mg/kg/day (maximum 10 mg/day) or equivalent
472 5. Remission induction therapy:
473 • Cyclophosphamide (CYC)
474 o Oral: up to 2 mg/kg/day
475 o IV: 15 mg/kg q2 weeks x 3 doses, followed by 15 mg/kg q3 weeks for at least
476 3 doses
477 • Rituximab (RTX): 375 mg/m2 IV a week x 4 doses or 1000 mg IV on days 1 and 15
478 • Methotrexate (MTX): up to 25 mg/week po or subq
479 6. Remission maintenance therapy:
480 • Azathioprine (AZA): up to 2 mg/kg/day
481 • Methotrexate (MTX): up to 25 mg/week subq or po
482 • Rituximab (RTX): 500 mg IV q6 months or 1 gm IV q4 months
483 • Mycophenolate mofetil (MMF): up to 1500 mg po bid
484 o Mycophenolic acid and mycophenolate sulfate also used
485 • Leflunomide (LEF): up to 30 mg/day
486 • Sulfamethoxazole/trimethoprim (SMZ/TMP): up to 1 DS tablet po bid
487 7. Pneumocystis prophylaxis: low dose SMZ/TMP, dapsone, atovaquone, aerosolized
488 pentamidine
489
490
491 C. Disease assessments
492 1. Clinical monitoring: Assessing for clinical signs and symptoms of active disease and
493 obtaining clinical labs including inflammatory markers
494 2. ANCA: immunofluorescence testing for c-ANCA/p-ANCA and ELISA testing for MPO and PR3
495 antibodies
15
496 3. Routine laboratory monitoring: Complete blood count, Comprehensive metabolic panel,
497 Urinalysis with microscopy, Erythrocyte sedimentation rate, C-reactive protein
498 4. Non-invasive imaging: volumetric chest CT
499
500 D. Disease-related outcomes
501 1. Activity as determined by the Birmingham Vasculitis Activity Score (BVAS), Birmingham
502 Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG), or other study-specific
503 disease activity assessment
504 2. Damage as determined by the ANCA-Vasculitis Index of Damage (AVID), Vasculitis Damage
505 Index (VDI) or other study-specific disease damage measure
506 3. Clinical symptoms and organ damage attributable to disease
507 4. Relapse (up to 24 months of follow-up)
508 5. Death
509 6. Patient-Reported Outcomes
510 a. SF36 (Short Form Health Survey), EQ-5D (Euroqol), or CHQ (Child Health
511 Questionnaire)
512 b. If above not available: Patient Global Assessment, PROMIS, RAPID3, or MDHAQ
513
514 E. Treatment-related adverse events
515 1. Serious adverse events
516 2. Infection
517 3. Malignancy
518 4. Any toxicity leading to drug dose adjustment or treatment discontinuation
519 5. Complications of surgical procedures
520
521 PICO Questions (GPA/MPA = GPA or MPA):
522 Diagnostic Testing

523
524 Role of following ANCA titers in assessing disease activity:
525 1. In patients with GPA/MPA, what is the impact of obtaining ANCA levels/titers at fixed intervals
526 vs. not obtaining ANCA levels/titers on disease-related outcomes and treatment-related adverse
527 events?
528
529 Treatment: Remission Induction
530
531 Prednisone dosing:
16
532 2. In patients with active severe GPA/MPA, what is the impact of using pulse intravenous vs. high-
533 dose oral glucocorticoids for remission induction on disease-related outcomes and treatment-
535 3. In patients with active severe GPA/MPA, what is the impact of using high-dose vs. moderate
536 dose oral glucocorticoids for remission induction on disease-related outcomes and treatment-
538 Rituximab vs. CYC:
539 4. In patients with active severe GPA/MPA, what is the impact of using rituximab vs.
540 cyclophosphamide for remission induction on disease-related outcomes and treatment-related
541 adverse events?
542 4a. How does the impact differ between those who are ANCA positive vs. ANCA
543 negative?
544 IV vs. po CYC:
545 5. In patients with active severe GPA/MPA, what is the impact of using IV CYC vs. po CYC for
546 remission induction on disease-related outcomes and treatment-related adverse events?
547 Different rituximab regimens:
548 6. In patients with active severe GPA/MPA, what is the impact of initiating treatment with
549 rituximab 1000 mg IV days 1 and 15 vs. rituximab 375 mg/m2 qweek x 4 weeks on disease-
551 Avacopan:
552 7. In patients with active severe GPA/MPA, what is the impact of using avacopan +
553 cyclophosphamide/rituximab vs. cyclophosphamide/rituximab + glucocorticoids on disease-
555 Non-severe disease:
556 8. In patients with active non-severe GPA, what is the impact of initiating treatment with
557 azathioprine + glucocorticoids vs. methotrexate + glucocorticoids on disease-related outcomes
560 azathioprine+ glucocorticoids vs. MMF+ glucocorticoids on disease-related outcomes and
563 methotrexate + glucocorticoids vs. MMF + glucocorticoids on disease-related outcomes and
566 glucocorticoids + SMZ/TMP vs. glucocorticoids + methotrexate or azathioprine on disease
17
569 methotrexate or azathioprine vs. rituximab on disease-related outcomes and treatment-related
570 adverse events?
572 methotrexate or azathioprine vs. cyclophosphamide on disease-related outcomes and
575 methotrexate or azathioprine vs. glucocorticoids on disease-related outcomes and treatment-
577
578 Treatment: Remission Maintenance
579
580 CYC, MTX/AZA, RTX, MMF, LEF:
581 15. In patients with severe GPA/MPA who have entered remission with cyclophosphamide therapy,
582 what is the impact of using methotrexate or azathioprine vs. continuing cyclophosphamide for
583 remission maintenance on disease-related outcomes and treatment-related adverse events?
584 16. In patients with severe GPA/MPA who have entered remission, what is the impact of using
585 methotrexate vs. azathioprine for remission maintenance on disease-related outcomes and
587 17. In patients with severe GPA/MPA who have entered remission with cyclophosphamide therapy,
588 what is the impact of using rituximab vs. methotrexate or azathioprine for remission
589 maintenance on disease-related outcomes and treatment-related adverse events?
590 18. In patients with severe GPA/MPA who have entered remission with rituximab therapy, what is
591 the impact of using rituximab vs. methotrexate or azathioprine for remission maintenance on
592 disease-related outcomes and treatment-related adverse events?
593 19. In patients with severe GPA/MPA who have entered remission with cyclophosphamide or
594 rituximab therapy, what is the impact of using MMF for remission maintenance vs.
595 methotrexate or azathioprine on disease-related outcomes or treatment-related adverse
596 events?
597 20. In patients with severe GPA or MPA who have entered remission with cyclophosphamide or
598 rituximab therapy, what is the impact of using leflunomide for remission maintenance vs.
599 methotrexate or azathioprine on disease-related outcomes or treatment-related adverse
600 events?
601
602
603
604
18
605 SMZ/TMP (sulfamethoxazole/trimethoprim):

606 21. In patients with non-severe GPA who have entered remission, what is the impact of using
607 SMZ/TMP vs. methotrexate or azathioprine for remission maintenance on disease-related
609 22. In patients with severe GPA who have entered remission, what is the impact of using SMZ/TMP
610 vs. methotrexate or azathioprine for remission maintenance on disease-related outcomes or
612 CD19/ANCA titers with rituximab remission maintenance:
613 23. In patients with GPA/MPA on rituximab for remission maintenance therapy, what is the impact
614 of using CD19 counts to guide re-dosing of rituximab vs. scheduled re-dosing of rituximab on
615 disease-related outcomes or treatment-related adverse events?
616 24. In patients with GPA/MPA on rituximab for remission maintenance therapy, what is the impact
617 of using ANCA titers to guide re-dosing of rituximab vs. scheduled re-dosing of rituximab on
618 disease-related outcomes or treatment-related adverse events?
619 Duration of remission maintenance therapy:
620 25. In a patient with severe GPA/MPA using remission maintenance therapy, what is the impact of
621 continuing remission maintenance therapy for > 18 months vs. stopping remission maintenance
622 therapy at or prior to 18 months on disease related outcomes and treatment related adverse
623 events?
624 25a. How does this impact change in the presence of concomitant prednisone?
625 26. In patients with severe GPA/MPA starting remission maintenance therapy that includes
626 prednisone, what is the impact of treatment with prednisone for 6 months or less vs. 6-18
627 months vs. longer than 18 months during remission maintenance on disease-related outcomes
629
630 Treatment: Relapse
631
632 Therapy for remission induction following remission and relapse:
633 27. In patients with GPA/MPA who have relapsed with severe disease manifestations after prior
634 remission induction with cyclophosphamide or rituximab and on either non-rituximab
635 maintenance therapy or no maintenance therapy, what is the impact of using the same agent vs.
636 switching to the other agent for remission induction on disease-related outcomes and
638 Relapse treatment if on rituximab:
639 28. In patients with GPA/MPA who have relapsed with severe disease manifestations while on
640 rituximab for remission maintenance, what is the impact of continuing rituximab at a higher
19
641 dose vs. switching to cyclophosphamide for remission induction on disease-related outcomes
642 and treatment-related adverse effects?
643 Other
644
645 Role of continued prednisone use:
646 29. In patients with GPA/MPA in remission and currently only on prednisone, what is the impact of
647 continuing with low dose prednisone long-term (e.g., > 18 months) vs. stopping low dose
648 prednisone on disease-related outcomes and treatment related adverse events?
649 Role of plasma exchange in severe disease:
650 30. In patients with GPA/MPA with active glomerulonephritis, what is the impact of adding plasma
651 exchange to cyclophosphamide or rituximab vs. not adding plasma exchange on disease-related
653 31. In patients with GPA/MPA with active alveolar hemorrhage, what is the impact of adding plasma
654 exchange to cyclophosphamide or rituximab vs. not adding plasma exchange on disease-related
656 Role of nasal rinses/topical nasal therapy:
657 32. In patients with sino-nasal involvement in GPA, what is the impact of using nasal rinses vs. not
658 using nasal rinses on disease related outcomes and treatment-related adverse events?
659 33. In patients with sino-nasal involvement in GPA, what is the impact of using nasal antibiotics vs.
660 not using nasal antibiotics on disease related outcomes and treatment-related adverse events?
661 34. In patients with chronic sino-nasal disease and mucosal damage, what is the impact of topical
662 nasal lubricants (e.g., oils, ointments, or hyaluronic acid spray) on disease-related outcomes and
664 35. In patients with chronic sino-nasal disease and mucosal inflammation, what is the impact of
665 topical corticosteroid therapies on disease-related outcomes and treatment-related adverse
666 events?
667 Role of immunosuppression for subglottic and/or endobronchial stenosis:
668 36. In patients with GPA and subglottic and/or endobronchial stenosis, what is the impact of
669 treatment with immunosuppression vs. surgical dilation with intralesional glucocorticoid
670 injection on disease-related outcomes and treatment related adverse events?
671 Role of immunosuppression for orbital pseudotumor and mass lesions:
672 37. In patients with GPA and orbital pseudotumor, what is the impact of treatment with
673 immunosuppression vs. surgical removal of pseudotumor tissue on disease-related outcomes,
674 ocular symptoms (e.g. ocular/orbital pain, diplopia, and vision loss) and treatment-related
675 adverse events?
676 38. In patients with GPA and mass lesions aside from orbital pseudotumor (e.g., lung, brain, parotid
677 gland, kidney, prostate gland), what is the impact of treatment with immunosuppression vs.
20
678 surgical removal of the mass lesion on disease-related outcomes and treatment-related adverse
679 events?
680 Pneumocystis prophylaxis
681 39. In patients with GPA/MPA on cyclophosphamide or rituximab, what is the impact of using
682 Pneumocystis prophylaxis vs. not using Pneumocystis prophylaxis on the development of
683 Pneumocystis pneumonia and treatment-related adverse events?
684 Infection prophylaxis
685 40. In patients with GPA/MPA on remission maintenance therapy with rituximab who have
686 hypogammaglobulinemia (e.g., IgG< 3 g/L), what is the impact of IVIG supplementation vs. no
687 IVIG supplementation on the development of infections and treatment-related adverse events?
688 Cosmetic surgery
689 41. In patients with GPA/MPA in remission and nasal bridge collapse/nasal fistulas, what is the
690 impact of cosmetic surgery vs. no surgery on disease-related outcomes and treatment-related
691 adverse events?
692 Kidney transplant in ESRD
693 42. In patients with GPA/MPA in remission and chronic kidney disease stage V, what is the impact of
694 renal transplantation vs. no renal transplantation on disease-related outcomes and treatment-
696 Duration of anticoagulation in patients with GPA/MPA and venous thromboembolism
697 43. In patients with GPA/MPA and venous thromboembolism what is the impact of anticoagulation
698 for 6 months vs. anticoagulation for 6-18 months vs. anticoagulation > 18 months on the
699 development of recurrent venous thromboembolic events and treatment-related side effects?
700
21
APPENDIX B – Participant Disclosures
In order for the College to most effectively further its mission and to otherwise maintain its excellent reputation in the medical community and with the public, it is important that confidence in the College’s integrity be maintained. The cornerstone of the ACR’s Disclosure Policy is disclosure of actual and potential conflicts so that they can be evaluated by the College in order to
avoid undue influence of potential conflicts. The purpose of the ACR’s Disclosure Policy is identification of relationships which may pose actual or potential conflicts. These actual or potential conflicts can then be evaluated by the College so that adjustments can be made that will avoid any undue influence. This policy is based on the principle that, in many cases, full disclosure of the
actual or potentially conflicting relationship will of itself suffice to protect the integrity of the College and its interests.
Sources of Personal Income (salary information from primary Investments to Include Medical Industry
Participants Role Primary Employer employer is not required): Research Grants/Contracts and Nonmedical Industry Organizational Benefit Activities with Other Organizations
University of California, San
Sharon Chung Core Team/PI Francisco N/A NIH; UCSF; UCSF School of Medicine N/A N/A N/A
The Vasculitis Foundation; Philadelphia
Rheumatism Society; The Vasculitis
Clinical Research Consortium; The
PCORI; NIH/NIAMS; NIH/NHLBI; Genentech- Vasculitis Patient Powered Research
Antoine G. Sreih Core Team/Content Expert The University of Pennsylvania Krogg and Partners; Rupert Case Management ; Naxion Investigator-Initiated Clinical Trial Alexion N/A Network
NIH; FDA; Genentech; Genentech, NIH;
Carol Langford Core Team/Content Expert Cleveland Clinic McGraw Hill GlaxoSmith Kline; Bristol-Myers Squibb N/A N/A N/A
Mehrdad Maz Core Team/Content Expert Kansas University N/A Glaxo-Smith-Kline N/A N/A N/A
Gary Hoffman Core Team/Content Expert Self employed N/A Philanthropy (study) N/A N/A N/A
Gordon Guyatt Core Team/GRADE Expert McMaster University N/A N/A N/A N/A N/A
American College of Physicians; US

GRADE Netwrok; Canadian Society of
Nephrology; The Institute for Clinical
Reem Mustafa Core Team/Lit Review Lead University of Kansas Medical Center N/A PCORI (2); American Society of Hematology N/A N/A and Economic Review (ICEF)
Gary Firestein ACR Board of Directors Liaison UCSD Astra Zeneca; Eli Lilly; Elsevier; Roche Arthritis Foundation; NIH; Janssen; Gilead; RRF Ignyta; Sialix N/A N/A
NIH;
Janssen/Amgen/Roche//Mesoblast/Novartis;
Pfizer; Novartis, Roche/Bristol-Myers-
Eric Matteson Expert Panel Mayo Clinic College of Medicine Up To Date Squibb/Genentech//Pfizer N/A Pfizer Vasculitis Foundation
Kenneth J. Warrington Expert Panel Mayo Clinic American College of Physicians GSK; Eli Lilly N/A N/A N/A
Abbott Pharmaceuticals; UCB
Pharmaceuticals; Bristol-Myers Squibb
Company ; Alliance for Lupus Research; Pfizer Lupus Society of Illinois; Pediatric
Linda Wagner-Weiner Expert Panel The University of Chicago American Academy of Pediatrics Pharmaceuticals N/A N/A Rheumatology Journal
univ. of Pennsylvania; Clev. Clinic Foundation;
Ora Gewurz-Singer Expert Panel University of Michigan N/A Univ. of Oxford N/A N/A N/A
Roche Genetech; Corbus; Chemocentryx;
Robert Spiera Expert Panel Hospital for Special Surgery Roche-Genetech; GSK Cytori; GSK N/A N/A N/A
Rula Hajj-Ali Expert Panel Cleveland Clinic Novartis; Abbvie N/A N/A N/A N/A
Northwestern
Amy Archer Voting Panel Medicine/Northwestern University N/A N/A N/A Vasculitis Foundation Vasculitis Foundation
Ann Warner Voting Panel Self Employed Best Doctors N/A N/A N/A N/A
John H. Stone Voting Panel Massachusetts General Hospital Roche/Genentech Roche; Genentech N/A N/A N/A
NIH: NIAMS, NCATS, NHLBI; FDA; PCORI; BMS,
Various Academic Institutions; Actelion; BMS; Genentech/Roche; GSK; ChemoCentryx; PrincipiaBio, InflaRx, Boston Celegene, ChemoCentryx, Genentech/Roche,
Peter A. Merkel Voting Panel University of Pennsylvania Pharmaceuticals GSK; Kypha N/A N/A N/A
Peter Grayson Voting Panel National Institute of Health N/A N/A N/A N/A N/A
Phil Seo Voting Panel Johns Hopkins University Daniel Lee English, Esq.; Genentech; GSK; UptoDate; Oxford University Press NIAMS N/A Centocor N/A
Rheumatology Research Foundation; Vasculitis
Rennie Rhee Voting Panel University of Pennsylvania N/A Foundation; Gilead Sciencies N/A N/A N/A
Robert Sundel Voting Panel Boston Children's Hospital UpToDate; Paul Hastings (Law Firm); Conway, Homer & Chin-Caplan, P.C.; Medical Education Resources; Misc Legal Firms Pfizer Bristol Myers Squibb; BIB (Biotech ETF); XLV (Medical ETF) N/A N/A
Susan Kim Voting Panel UCSF Benioff Children's Hospital N/A CARRA N/A N/A CARRA
Sangeeta Sule Voting Panel Johns Hopkins University Springer Healthcare Medicine Matters Rheumatology N/A N/A N/A Lupus Foundation DC/MD/VA Chapter
Maria Ibarra Voting Panel Children's Mercy Hospital N/A N/A N/A N/A N/A
Lisa Imundo Voting Panel Columbia University N/A Sobi; Pfizer; PROPEL; PASCAL N/A N/A Athritis Foundation; AAP; ABP
Doyt Conn Voting Panel Emory University N/A N/A N/A N/A N/A

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American College of Rheumatology (ACR)

Vasculitis Guideline—ANCA-Associated Vasculitis

Project Plan – July 2018

Core Oversight Team John Stone, MD, MPH

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182 DISCLOSURES/CONFLICTS OF INTEREST

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208 APPENDIX A – PICO Questions

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242 4. Low dose oral glucocorticoids:

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278 3. Clinical symptoms and organ damage attributable to disease

295 Diagnostic/prognostic tools

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314 Rituximab vs. CYC:

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351 Treatment: Remission Maintenance

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387 rituximab/cyclophosphamide therapy on disease-related outcomes and treatment-related

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424 Role of nasal rinses:

440 GRANULOMATOSIS WITH POLYANGIITIS (GPA) and MICROSCOPIC POLYANGIITIS (MPA)

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460 • Children: methylprednisolone 30 mg/kg/day (maximum 1000 mg/day) for 3-5

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522 Diagnostic Testing

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605 SMZ/TMP (sulfamethoxazole/trimethoprim):

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American College of Physicians; US

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