The management of pulmonary small vessel vasculitides

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The management of pulmonary small vessel
vasculitides

• Dr. Aditya Jindal
• www.jindalchest.com
  

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• 55 years female
• Cough with hemoptysis x 1month
• Sputum AFB ve

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• EBB/TBLB/BAL-granulomatuous inflammtion with
  neutrophilic infiltration
• cANCA ve

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• 59 y female
• Hoarseness of voice x 1m
• Fever x 1 m
• Weight loss/ cough
• Sputum AFB ve
• TBLB/ BAL non specific inflammation
• cANCA strongly ve

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• First patient
• Given Cyclophosphamide steroid pulse
• Initial recovery
• Developed relapse after 4 months and died
• Second patient
• Given steroid pulse with methotrexate
• Doing well with almost complete resolution of
  lesions

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• The vasculitides are a set of related disorders
  characterized by blood vessel inflammation
  leading to tissue or end-organ injury
• Differentiated from other vascular disorders by
  the presence of inflammation of the vessel wall
  as compared to bland vasculopathy

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Frankel SK, Jayne D. The Pulmonary Vasculitides.
Clin Chest Med 31 (2010) 519536
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(No Transcript)
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Frankel SK, Jayne D. The Pulmonary Vasculitides.
Clin Chest Med 31 (2010) 519536
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Clinical criteria for GPA, E-GPA, and MPA
Arman et al. Int J Nephrol Renovasc Dis. 2018
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Management
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1. Not much difference between different types of
   vasculitis
2. Most trials of GPA, treatment extrapolated to
   other types
3. Divided into remission-induction and maintenance
   phases
4. Treatment stratified according to severity

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Mukhtyar C etal. EULAR recommendations for the
management of primary small and medium vessel
vasculitis. Ann Rheum Dis 200968310317.
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• Remission induction

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Frankel SK, Jayne D. The Pulmonary Vasculitides.
Clin Chest Med 31 (2010) 519536
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• A. Localised disease
• Refers to isolated upper or lower airway disease
  and a complete absence of other end organ
  involvement or constitutional symptoms
• Managed with topical therapy, corticosteroids,
  and/or a single moderate potency cytotoxic agent
  such as methotrexate or azathioprine

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• B. Early generalized disease
• Presence of constitutional symptoms and active
  vasculitis but without any specific threat to
  organ function
• Standard therapy ? Azathiprine/ Methotrexate/
  Cylophosphamide steroids
• C. Generalized active disease
• Presence of constitutional symptoms and
  threatened organ function caused by vasculitic
  activity
• Standard therapy ? Cylophosphamide steroids

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• D. Severe disease
• Presence or threat of immediate organ failure
  and/or death
• Rapidly progressive glomerulonephritis and renal
  failure (creatinine gt5.7 mg/dL)
• Alveolar hemorrhage associated with respiratory
  failure
• Cardiomyopathy with heart failure
• Life-threatening arrhythmias
• Central nervous system disease
• Gastrointestinal disease with bowel schemia or
  life-threatening hemorrhage
• Standard treatment ? Plasma exchange i/v
  cyclophophamide steroids

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Induction Trials in AAV
Lee et al. Pediatric Rheumatology. 2019
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• Oral cyclophosphamide plus steroids ? standard
  therapy since the 1970s
• CYCLOPS (Daily Oral Versus Pulse Cyclophosphamide
  for Renal Vasculitis) trial
• 149 patients with newly diagnosed generalized
  active AAV (GPA or MPA) were randomized to pulse
  intravenous cyclophosphamide (15 mg/kg every 2
  weeks x first 3 doses, then every 3 weeks for
  next 3 -6 doses) or daily oral cyclophosphamide
  (2 mg/kg/d) plus prednisolone

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• No difference in time to remission or proportion
  of patients who achieved remission (88.1 vs
  87.7 at 9 months) or survival or renal function
• Pulse group had a lower rate of leukopenia and
  received a lower total cumulative dose of
  cyclophosphamide
• de Groot K, Harper L, Jayne DR, et al. Pulse
  versus daily oral cyclophosphamide for induction
  of remission in antineutrophil cytoplasmic
  antibody-associated vasculitis a randomized
  trial. Ann Intern Med 2009150670

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• NORAM (Non-Renal Alternative with Methotrexate)
  trial
• Compared methotrexate with cyclophosphamide for
  the induction of remission in early disease
• 95 patients (89 with GPA and 6 with MPA)
• MTx dose ? 15 mg /week escalating to 20 25
  mg/week
• Time to remission (5 m vs 3 m)
• Relapse rate (74 vs 42) favored
  cyclophosphamide
• Methotrexate was better tolerated and had less
  side affects
• de Groot K, Rasmussen N, Bacon PA, et al.
  Randomized trial of cyclophosphamide versus
  methotrexate for induction of remission in early
  systemic antineutrophil cytoplasmic
  antibody-associated vasculitis. Arthritis Rheum
  2005522461

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• Mycophenolate mofetil (MMF)
• 3 RCTS
• First compared MMF 2g/day to ivCYC
• 35 participants (34 GPA, 1 MPA)
• Exclusions
• severe renal failure
• life-threatening organ manifestations (lung
  haemorrhage, central nervous system involvement)
• 14 of 18 patients (77.8) treated with MMF and 8
  of 17 patients (47.1) receiving CYC had complete
  remission
• Second MMF 1- 1.5 g/d vs CYC monthly pulses
• 41 patients (all MPA)
• Complete remission achieved in 63.6 of the CVYC
  group and 78.9 of the MMF group

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• Third - MYCYC (MMF versus CYC for remission
  induction of AAV)
• MMF (2-3 g/d) vs iv CYC
• Complete remission in 67 in MMF group vs 61 in
  CYC group
• relapses occurred significantly more frequently
  with MMF (33) compared to ivCYC (19)
• Hu W, Liu C, Xie H, Chen H, Liu Z, Li L.
  Mycophenolate mofetil versus cyclophosphamide for
  inducing remission of ANCA vasculitis with
  moderate renal involvement. Nephrology, dialysis,
  transplantation official publication of the
  European Dialysis and Transplant Association -
  European Renal Association. 2008 Apr
  23(4)1307-1312.
• Han F, Liu G, Zhang X, Li X, He Q, He X, et al.
  Effects of mycophenolate mofetil combined with
  corticosteroids for induction therapy of
  microscopic polyangiitis. American journal of
  nephrology. 2011 33(2)185-192.
• Jones RB, Hiemstra TF, Ballarin J, Blockmans DE,
  Brogan P, Bruchfeld A, et al. Mycophenolate
  mofetil versus cyclophosphamide for remission
  induction in ANCA-associated vasculitis a
  randomised, non-inferiority trial. Ann Rheum Dis.
  201978(3)399405

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• Methotrexate / MMF (indications)
• in the absence of renal involvement
• Nasal and paranasal disease without bony
  involvement (erosion) or cartilage collapse or
  olfactory dysfunction or deafness
• Skin involvement without ulceration
• Myositis (skeletal muscle only)
• Non-cavitating pulmonary nodules/infiltrate
  without haemoptysis
• When cyclophosphamide or rituximab are not
  available or contraindicated or patient choice

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• Methotrexate / MMF contraindications
• Meningeal involvement
• Retro-orbital disease
• Cardiac involvement
• Mesenteric involvement
• Acute-onset mononeuritis multiplex
• Pulmonary haemorrhage of any severity

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• MEPEX (Plasma Exchange or High-Dosage
  Methylprednisolone as Adjunctive Therapy for
  Severe Renal Vasculitis)
• EUVAS sponsored randomised controlled trial
• 137 patients with a new diagnosis of AAV and a
  serum creatinine level greater than 500 mmol/L
  (5.7 mg/dL) were included
• All patients received standard therapy with oral
  cyclophosphamide and oral prednisolone and were
  then randomized to either 7 plasma exchanges or
  3000 mg of intravenous methylprednisolone
• Primary end point ? ESRD or death at 3 m

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• At 3m ? 69 of patients treated with plasma
  exchange were alive and independent of dialysis
  compared with only 49 in the methylprednisolone
  group
• No significant benefit on long term follow up
  (composite end point of ESRD and death)
• Jayne DRW, Gaskin G, Rasmussen N, et al.
  Randomised trial of plasma exchange or high dose
  methyl prednisolone as adjunctive therapy for
  severe renal vasculitis. J Am Soc Nephrol 2007
  182180
• Walsh M, Casian A, Flossmann O, Westman K,
  Hoglund P, Pusey C, et al. Long-term follow-up of
  patients with severe ANCA-associated vasculitis
  comparing plasma exchange to intravenous
  methylprednisolone treatment is unclear. Kidney
  international. 2013 Aug 84(2)397-402
• A 20 patient case series showed the efficacy of
  this treatment strategy in alveolar hemorrhage
  also
• Klemmer PJ, Chalermskulrat W, Reif MS, et al.
  Plasmapheresis therapy for diffuse alveolar
  hemorrhage in patients with small vessel
  vasculitis. Am J Kidney Dis 2003421149

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• PEXIVAS (Plasma exchange and glucocorticoid
  dosing in the treatment of ANCA-associated
  vasculitis)
• 704 patients with 7 year follow up
• Compared Plasma exchange with no plasma exchange
• Also standard dose with reduced dose steroids
  (lt60)
• Composite end point of ESRD and death
• 289 (41) PR3-ANCA, 209 (59) MPO-ANCA
• 691 (98) with renal involvement 191 (27) with
  alveolar hemorrhage
• 109 (15) patients received rituximab and 595
  (85) received cyclophosphamide

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• Primary outcome 31 in no plasma exchange group
  and 28 in plasma exchange group
• Primary outcome in 28 in reduced steroid group
  and 26 in standard dose group
• Less infections in reduced steroid group
• www.pexivas.bham.ac.uk, http//clinicaltrials.gov/
  ct2/show/NCT00987389
• Walsh M, Merkel PA, Jayne D. The Effects of
  Plasma Exchange and Reduced-Dose Glucocorticoids
  during Remission-Induction for Treatment of
  Severe ANCA-Associated Vasculitis
  abstract. Arthritis Rheumatol. 2018 70 (suppl
  10).

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• Rituximab
• Targets the CD20 antigen on the surface of B
  cells and clears circulating B cells from the
  circulation
• RAVE (Rituximab in ANCA-Associated Vasculitis)
  trial
• Multicenter, randomized, double-blind,
  double-dummy, noninferiority trial, 197 patients
• Compared rituximab with po CYC followed by AZA
  for the induction of complete remission by 6
  months in patients with severe ANCA-associated
  vasculitis
• 64 of the patients achieved complete remission
  compared to 53 in the cyclophosphamide control
  arm

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• More efficacious than the cyclophosphamide-based
  regimen for inducing remission of relapsing
  disease 34 of 51 patients in the rituximab group
  (67) as compared with 21 of 50 patients in the
  control group (42) (P 0.01)
• As effective as cyclophosphamide in the treatment
  of patients with major renal disease or alveolar
  hemorrhage
• No significant differences between the treatment
  groups with respect to rates of adverse events
• Remission rates lower than other trials (earlier
  discontinuation of steroids)
• Long term follow up In severe AAV without organ
  failure RTX better at maintaining remission
  after 18 m
• Stone JH, Merkel PA, Spiera R et al. Rituximab
  versus cyclophosphamide for ANCA-associated
  vasculitis. N Engl J Med 2010 36322132

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• RITUXVAS (rituximab versus cyclophosphamide in
  ANCA associated vasculitis) trial
• 44 patients with newly diagnosed ANCA-associated
  vasculitis and renal involvement were randomly
  assigned, in a 31 ratio, to a standard
  glucocorticoid regimen plus
• either rituximab at a dose of 375 mg/sqm/week for
  4 weeks, with two intravenous cyclophosphamide
  pulses (33 patients, the rituximab group)
• or intravenous cyclophosphamide for 3 to 6 months
  followed by azathioprine (11 patients, the
  control group)
• More severe disease than RAVE trial
• 76 patients in the rituximab group and 82
  patients in the control group had a sustained
  remission (P 0.68)

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• Severe adverse events occurred in 14 patients in
  the rituximab group (42) and 4 patients in the
  control group (36) (P 0.77)
• Rituximab-based regimen was not superior to
  standard intravenous cyclophosphamide for severe
  ANCA-associated vasculitis
• Sustained-remission rates were high in both
  groups
• Rituximab-based regimen was not associated with
  reductions in early severe adverse events
• Jones RB, Tervaert JW,Hauser T et al. Rituximab
  versus cyclophosphamide in ANCA-associated renal
  vasculitis. N Engl J Med 2010 36321120

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• E. Refractory disease
• Disease that does not respond to conventional
  accepted therapy
• Investigational or unproven therapies are used
• Infliximab - chimeric IgGk monoclonal antibody
  against soluble and membrane-bound TNF
• Has given positive benefit in small trials

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• b. Anti thymocyte globulin
• Studied in the EUVAS sponsored SOLUTION trial
• 15 patients received ATG for refractory
  vasculitis
• Partial disease remission was induced in 9/15 and
  complete disease remission in 4/15
• 2 patients died after drug administration
• 1 of pulmonary hemorrhage
• 1 of infection
• Serum sickness and nonfatal infections were among
  the notable complications
• Schmitt WH etal. Treatment of refractory
  Wegener's granulomatosis with antithymocyte
  globulin (ATG) an open study in 15 patients.
  Kidney Int. 2004 Apr65(4)1440-8

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• Intravenous immunoglobulin (IVIg)
• Studied in small clinical trials
• Effect is generally short-lived
• Most appropriate in acute situations where
  conventional therapy is contraindicated
  especially if severe infection is present
• WEGENT (Wegeners Granulomatosis-Entretien) trial
• 32 induction-refractory (24 WG and 8 MPA)
  patients were treated with oral CYC in 20
  patients, combined with infliximab in 1
• 15 (75) achieved remission or low disease
  activity state, 3 subsequently died of
  uncontrolled disease and 2 entered remission
  using several other agents including biological
  agents
• Seror R, Pagnoux C, Ruivard M, et al. Treatment
  strategies and outcome of induction-refractory
  Wegeners granulomatosis or microscopic
  polyangiitis analysis of 32 patients with
  first-line induction-refractory disease in the
  WEGENT trial. Ann Rheum Dis 20106921252130
• Alemtuzumab
• Deoxyspergualin

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• Remission maintenance

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Maintenance Trials in AAV
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Lee et al. Pediatric Rheumatology. 2019
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• CYCAZAREM (Cyclophosphamide versus Azathioprine
  for Remission in Generalized Vasculitis) trial
• EUVAS sponsored randomised controlled trial
• Patients were initially treated with oral
  cyclophosphamide and oral prednisolone for
  induction
• They were then randomised to
• Either oral cylophosphamide for 12 m followed by
  azathioprine
• Or directly to azathioprine
• No difference in relapse rates (15.5 in the AZA
  group and 13.7 in the CYC group) P 0.65 95
  confidence interval (CI) -9.9 to13.0 up to the
  end of the study at 18 months after treatment
  outset
• Jayne D, Rasmussen N, Andrassy K, et al. A
  randomized trial of maintenance therapy for
  vasculitis associated with antineutrophil
  cytoplasmic autoantibodies. N Engl J Med 2003
  34936.

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• IMPROVE (International Mycophenolate Mofetil to
  Reduce Outbreaks of Vasculitides) trial
• EUVAS sponsored Open-label randomized controlled
  trial
• Directly compared mycophenolate mofetil with
  azathioprine for the maintenance of remission in
  renal vasculitis
• 156 patients were assigned to azathioprine (n80)
  or mycophenolate mofetil (n76) and followed up
  for a median of 39 months

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• Relapses were more common in the mycophenolate
  mofetil group (42/76 patients) compared with the
  azathioprine group (30/80 patients), with an
  unadjusted hazard ratio (HR) for mycophenolate
  mofetil of 1.69 (95 confidence interval CI,
  1.06-2.70 P.03)
• Severe adverse events did not differ
  significantly between groups
• Hiemstra TF, Walsh M, Mahr A, et al European
  Vasculitis Study Group (EUVAS). Mycophenolate
  mofetil vs azathioprine for remission maintenance
  in antineutrophil cytoplasmic antibody-associated
  vasculitis a randomized controlled trial. JAMA
  2010304(21)23812388

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• WEGENT trial
• MTX vs AZA
• 126 participants with AAV (GPA 96 and MPA 30)
• Patients randomised to either MTX or AZA after
  pulse CYC (6 doses)
• Given for 2 years and withdrawn
• 24 months after randomisation, relapse-free
  survival rates were 71.8 in the AZA group and
  74.5 in the MTX group
• The hazard ratio for the risk of relapse among
  MTX vs AZA was 0.92 (95 CI, 0.52 to 1.65 P
  0.78)
• Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard
  M, Ducroix JP, et al. Azathioprine or
  methotrexate maintenance for ANCA-associated
  vasculitis. N Engl J Med. 2008

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• MAINRITSAN trial
• 115 participants with AAV (87 GPA, 23 MPA and
  five with renal limited vasculitis)
• Compared RTX to AZA
• RTX given as 500 mg infusion at 0 and 2 weeks
  followed by 6, 12 and 18 m
• fewer major relapses at 28 months in the RTX
  group compared with the AZA group (5 versus 29)
• Long term follow up of 60 m showed superiority of
  RTX with greater rates of relapse-free and
  overall survival
• Guillevin L, Pagnoux C, Karras A, Khouatra C,
  Aumaitre O, Cohen P, et al. Rituximab versus
  azathioprine for maintenance in ANCA-associated
  vasculitis. N Engl J Med. 2014371

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• MAINRITSAN 2 trial
• Compared an individually tailored RTX regimen
  with fixed-schedule regimen
• Tailored-infusion arm received RTX at
  randomization and received repeat infusions based
  on lymphocyte counts and ANCA titers until 18 m
• Fix-scheduled arm received the same regimen from
  the original MAINRITSAN trial
• No significant difference between the number of
  relapses but the tailored infusion arm received
  fewer number of infusions
• Charles P, Terrier B, Perrodeau E, Cohen P,
  Faguer S, Huart A, et al. Comparison of
  individually tailored versus fixed-schedule
  rituximab regimen to maintain ANCA-associated
  vasculitis remission results of a multicentre,
  randomised controlled, phase III trial
  (MAINRITSAN2). Ann Rheum Dis. 2018

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(No Transcript)
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Yates M, Watts RA, Bajema IM, et al. Ann Rheum
Dis 2016
49

• Additional points
• Dosage and schedule of cyclophosphamide
• 15 mg/kg (maximum 1.2 g) iv infusion every 2
  weeks for first three doses f/b every 3 weeks for
  next 3 6 doses
• Dose adjustment can be made based on creatinine
  levels
• Oral prednisolone or prednisone at 1 mg/kg/day is
  started alongside and maintained for 1 month, and
  should not be reduced to less than 15 mg/day for
  the first 3 months ?then tapered to a maintenance
  dose of 10 mg/day or less during remission
• When a rapid effect is needed, intravenous pulsed
  methylprednisolone may be used in addition to the
  oral prednisolone as part of remission induction
  therapy

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Protocol target prednisolone dosages
Yates M, Watts RA, Bajema IM, et al. Ann Rheum
Dis 2016
51

• The addition of trimethoprim/sulphamethoxazole
  (800/160 mg twice daily) to standard remission
  maintenance can reduce the risk of relapse in WG
• Prophylaxis against Pneumocystis jiroveci in all
  patients being treated with cyclophosphamide
  with trimethoprim/sulphamethoxazole (800/160 mg
  on alternate days or 400/80 mg daily) is
  recommended

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• Thromboembolic disease in the setting of AAV
• The Wegeners Clinical Occurrence of Thrombosis
  (WeCLOT) study identified that the incidence of
  thromboembolic disease in patients with WG was
  7.0 per 100 person-years, which is the same rate
  of venous thromboembolic (VTE) disease as for
  patients with a known prior history of VTE
• Clinicians should consider patients with AAV to
  be at higher risk for VTE
• Merkel PA, Lo GH, Holbrook JT, et al. Brief
  communication high incidence of venous
  thrombotic events among patients with Wegener
  granulomatosis the Wegeners Clinical Occurrence
  of Thrombosis (WeCLOT) Study. Ann Intern Med
  2005 142620

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Yates M, Watts RA, Bajema IM, et al. Ann Rheum
Dis 2016
54

• Alveolar hemorrhage(AH)
• Defined as bilateral alveolar infiltrates on
  radiological imaging without an alternative
  explanation plus at least one of the following
• Hemoptysis
• Increased carbon monoxide diffusing capacity
• Bronchoscopic evidence of hemorrhage
• Unexplained drop in hemoglobin
• Casian A, Jayne D. Management of Alveolar
  Hemorrhage in Lung Vasculitides. Semin Respir
  Crit Care Med 201132335345
• Vasculitis was the third most common cause of AH
  requiring intensive care support (19 of
  patients), after thrombocytopenia (27) and
  sepsis (22)
• Rabe C, Appenrodt B, Hoff C, et al. Severe
  respiratory failure due to diffuse alveolar
  hemorrhage clinical characteristics and outcome
  of intensive care. J Crit Care 201025(2) 230235

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• The majority (80) of these vasculitis cases with
  AH are due to ANCA associated vasculitis (AAV)

Papiris SA, Manali ED, Kalomenidis I, Kapotsis
GE, Karakatsani A, Roussos C. Bench-to-bedside
review pulmonary-renal syndromesan update for
the intensivist.. Crit Care 200711(3)213
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• AH is the most common respiratory manifestation
  of AAV, occurring in 24
• Casian A, Jayne D. Management of Alveolar
  Hemorrhage in Lung Vasculitides. Semin Respir
  Crit Care Med 201132335345
• AH appears similar in the PR3-ANCA and MPO ANCA
  groups with regard to clinical features and
  severity of respiratory failure
• Mild AH is more common (in 24 to 28 of AAV)
• 28 of patients may retrospectively report
  previous symptoms suggestive of AH for gt12 months
  before diagnosis

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• Cyclophosphamide/rituximab glucocorticoids /-
  Plasma exchange
• Recombinant, activated factor VII ? useful in
  case reports in life threatening, uncontrollable
  AH
• Henke D, Falk RJ, Gabriel DA. Successful
  treatment of diffuse alveolar hemorrhage with
  activated factor VII. Ann Intern Med
  2004140(6)493494
• Heslet L, Nielsen JD, Levi M, Sengeløv H,
  Johansson PI. Successful pulmonary administration
  of activated recombinant factor VII in diffuse
  alveolar hemorrhage. Crit Care 200610(6)R177
• Extracorporeal membrane oxygenation (ECMO)

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Diagnosis -investigations -severity
Localised
Early systemic
Generalised
Severe
Refractory
Induction
Standard Steroids CYC
Ritux Steroids rituximab
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Remission achieved
Maintenance
Standard Steroids AZA/ MTX
Rituximab Steroids RTX
Tailored
Scheduled
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At the end

• The prognosis of the pulmonary small vessel
  vasculitides has improved markedly in the last
  few years provided timely diagnosis is made and
  adequate treatment instituted
• Important to follow a structured clinical
  assessment and treatment protocol
• Long term follow up is required
• Lots of new developments in the field

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• THANK YOU