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\begin{document}

\title{The Liverpool Experience: The Role of Immunosuppression in treating
Vasculitic Subglottic Stenosis}



\author[1]{Matthew Zammit}%
\author[1]{Vedika  Dhunnoo}%
\author[1]{Andrew Kinshuck}%
\author[1]{Sarah  Hardy}%
\author[1]{Janice  Harper}%
\author[1]{Alessandroo Panarese}%
\author[1]{Christopher Webb}%
\affil[1]{Liverpool University Hospitals NHS Foundation Trust}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Five Key Points * Subglottic stenosis (SGS) is the commonest
tracheobronchial manifestation of granulomatosis with polyangiitis
(GPA), with early recognition and treatment key to preventing its
vasculitic progression and fibrosis. * Previous studies have shown SGS
to be the first feature of GPA in 4\% of cases. It is not uncommon to
see negative biochemical (10\% ANCA negative) and negative histological
biopsies (77\% of head and neck specimens are negative). * Our
management strategy emphasized rapid SGS-GPA treatment with limited
surgical manipulation of the airway and systemic immunosuppression (IS)
to prevent evolution of SGS \& concurrent systemic vasculitic relapse. *
In our study early multi-disciplinary team involvement to deliver
induction IS in the presence of active SGS-GPA led to a procedure free
interval (PFI) of 31.3 months. This is a significant increase compared
to other published studies. * Nineteen percent (4/21) of the cohort did
not require any surgical input following induction IS.%
\end{abstract}%



\sloppy


\emph{Five Key Points}

Subglottic stenosis (SGS) is the commonest tracheobronchial
manifestation of granulomatosis with polyangiitis (GPA), with early
recognition and treatment key to preventing its vasculitic progression
and fibrosis.

Previous studies have shown SGS to be the first feature of GPA in 4\% of
cases. It is not uncommon to see negative biochemical (10\% ANCA
negative) and negative histological biopsies (77\% of head and neck
specimens are negative).

Our management strategy emphasized rapid SGS-GPA treatment with limited
surgical manipulation of the airway and systemic immunosuppression (IS)
to prevent evolution of SGS \& concurrent systemic vasculitic relapse.

In our study early multi-disciplinary team involvement to deliver
induction IS in the presence of active SGS-GPA led to a procedure free
interval (PFI) of 31.3 months. This is a significant increase compared
to other published studies.

Nineteen percent (4/21) of the cohort did not require any surgical input
following induction IS.

\textbf{MeSH Keywords:} laryngostenosis, acquired subglottic stenosis,
Granulomatosis with Polyangiitis, immunosuppressants, Antineutrophil
Cytoplasmic Antibodies

\emph{Main Manuscript (Blinded for Review)}

\textbf{Introduction}

Subglottic stenosis (SGS) is the commonest manifestation of
tracheobronchial disease in granulomatosis with polyangiitis (GPA)
(8-23\% cases).\textsuperscript{1} The progression of the inflammatory
ring and fibrosis below the true vocal cords in GPA is dictated by the
number of relapses and vasculitic insult sustained. Early recognition
and management is imperative in limiting SGS in GPA (SGS-GPA), with
otolaryngologists often the first clinician to encounter the
disease.\textsuperscript{2}

Management of SGS-GPA can be challenging as delayed treatment may cause
respiratory compromise, whilst aggressive surgery may trigger a systemic
inflammatory response and associated vasculitic
complications.\textsuperscript{3}There are currently no guidelines for
SGS-GPA management. Several different surgical techniques described in
the literature,\textsuperscript{3} including subglottic dilatation with
pulmonary balloons, bougie, rigid bronchoscopy, laser and use of
intra-lesional steroid injections. \textsuperscript{3,5} However, the
impact of systemic immunosuppression (IS) on SGS-GPA management and
deferring surgery has not been widely explored.

Our department adopted a combined medical and surgical approach,
consisting of subglottic dilatations with systemic steroids given at
induction of anaesthesia and systemic IS in the peri-operative period.
IS was administered with the view of suppressing any current or
potential inflammatory response from surgery.

\textbf{Objectives}

We analysed the impact of IS on surgical procedure rates, by comparing
our operative rates with other case studies. Patient and disease
co-variables' impact on operative rates were also reviewed.

\textbf{Method}

\textbf{Ethical Considerations}

The study does not represent research, confirmed with the Health
Research Authority tool. It was registered as a service evaluation
project with the Liverpool University Hospitals NHS Foundation Trust's
audit department. The STROBE guideline was used for this manuscript.

\textbf{Study Design \& Participants}

This was a retrospective single-cohort study, consisting of SGS-GPA
patients treated and followed-up between 1st January 2000 to 2nd
November 2020. Diagnosis of GPA was considered on the background of
clinical, radiological and histological findings. \textsuperscript{}

\textbf{Setting: Departmental treatment of SGS-GPA}

Patients were included in this study from the joint ENT and vasculitis
multi-disciplinary team (MDT) database. The MDT consists of
otolaryngologists with sub-specialty expertise in vasculitis,
multi-organ vasculitis consultants and a vasculitis advanced nurse
practitioner. Those with suspected or confirmed vasculitis were reviewed
for ENT involvement in the joint vasculitis clinic. Patients with
significant SGS involvement were consented for airway assessment under
general anaesthesia (laryngotracheobronhcoscopy) with/without biopsy and
dilatation.

At surgery, high dose intravenous steroid (commonly 500mg - 1g
methylprednisolone) was administered at induction of general
anaesthesia. The subglottis was dilatated to its normal caliber using
either pulmonary balloons (Boston Scientific\textsuperscript{TM}) or
serial dilatation with bougie.

A multi-organ vasculitis team review was arranged on diagnosis of
SGS-GPA.

Patients with a new diagnosis of active SGS-GPA inflammation received
induction IS with steroids and Cyclophosphamide or Rituximab. Target
date for the start of induction IS was a couple of months prior to
surgery where possible, however diagnostic delays and patients with
severe symptoms requiring urgent intervention delayed initiation of
induction IS in certain instances. Induction IS was administered in
accordance with European guidelines concerning Anti-Neutrophil
Cytoplasmic Antibodies (ANCA) associated vasculitis.\textsuperscript{6}

Symptom review and nasendoscopy was undertaken on follow-up to assess
for SGS progression. Patients in remission or exhibiting fibrotic
non-active SGS-GPA received maintenance IS, usually consisting of either
Azathioprine or Rituximab maintenance therapy.

\textbf{Data Sources}

Patient demographics, GPA organ involvement, induction IS utilised,
investigations, surgical interventions and follow-up data were extracted
from the Trust's electronic records system.

The severity of stenosis was classified using the Cotton-Myer (C-M)
classification system; an average subglottic diameter taken as 14mm and
17mm for females and males respectively.\textsuperscript{4}

Relapses were defined as active inflammatory recurrence in the airway or
recurrent SGS requiring further treatment, whilst remission was
considered when a patent airway was maintained and no inflammatory
recurrence seen.

\textbf{Data Analysis}

Data was analysed using `R' software v4.0.5 for Mac IOS. A frailty model
(using Cox proportional-hazards regression) was performed to obtain the
procedure-free interval (PFI) with IS use. Co-variables reviewed
included patient gender, ANCA status, GPA-associated disease
progression, type of surgical procedure and C-M grade.

The mean PFI was calculated for comparisons with our cohort \&
stipulated SGS-GPA studies. This was based on the number of surgical
procedures per patient divided by the stipulated average follow-up
period.

\textbf{Results}

\textbf{SGS-GPA Cohort \& Characteristics}

There were twenty-seven patients managed for SGS-GPA in the joint ENT
vasculitis clinic between the 1\textsuperscript{st} of January 2000 to
2\textsuperscript{nd} November 2020. Six patients were excluded from our
analysis: two were surgically managed outside the region with no
management records available and four patients were referred with GPA
late into their disease progression, undergoing multiple surgical
dilatations with no induction IS.

The average age at diagnosis was 51.1 years (range 21-67), with a female
majority (15F:6M). SGS was the initial presentation of GPA in four
patients. Other affected sites by GPA in the cohort are summarised in
table 1.

\textbf{SGS-GPA Investigations}

Flexible nasendoscopy \& pulmonary function tests were performed in all
patients pre-operatively. The average C-M grade on presentation was 1.9
(range 1-3). Computed tomography (CT) or magnetic resonance imaging
(MRI) was performed in 18 patients (86\%).

ANCA was detected in 12 patients (57\%), with the remaining 9 patients
treated as ANCA-negative vasculitis. SGS biopsies were taken in 13
patients (62\%); the majority showing non-specific inflammation/
fibrosis (11/13), whilst two specimens (2/13) demonstrating GPA through
necrosis with focal granulomatosis.

\textbf{Management \& Follow-up of SGS-GPA}

All 21 patients underwent IS on SGS diagnosis; four (19\%) required
solely medical therapy, with the majority requiring surgical dilatation
(81\%). Figure 1 displays the individual management pathways of the
cohort.

Following dilatation and induction IS all patients remained on
maintenance oral IS. Eighteen patients (90\%) went into remission, with
no further active inflammation reported. Two patients experienced
relapse with recurrent SGS during their follow-up period requiring
further IS (figure 1 -- patients 9 \&19).

A total of twenty-nine SGS dilatations (24 bougie \& 5 balloon
dilatations) were performed. Four of the patients required emergency
tracheostomy (patient 9 required a tracheostomy on two separate
occasions). All patients were successfully decannulated.

Intralesional steroid (40mg methylprednisolone) was utilised in the four
balloon dilatations, with intravenous corticosteroid administered in all
procedures. Post-operative complications were experienced following one
balloon dilatation procedure (hospitalisation for pneumonia) and one
tracheostomy (pneumothorax). No complications were recorded for bougie
dilatations.

The cohort (21 patients) was followed up for a mean period of 59.8
months (range 15.7-201.5 months). One patient died from urosepsis
(unrelated to GPA progression).

When calculating the mean PFI; 17 patients underwent 34 procedures were
followed up for an average of 66.5 months. The mean PFI was denoted to
be a procedure every 31.3 months (range of 5.4- 201.5 months). Figure 2
represents the regression model attained (72\% concordance). None of the
covariables reviewed showed any statistically significant impact on PFI.

\textbf{Discussions}

There are no diagnostic criteria for ANCA-associated vasculitis
(AAV).\textsuperscript{2} Investigative accuracy has been limited in
AAV; 77\% of head and neck biopsies are non-diagnostic and 10\% of AAV
patients being ANCA negative. The latter is accentuated in localised GPA
disease such as SGS.\textsuperscript{2}

This is echoed in our cohort with 9 ANCA-negative cases and only 23\% of
biopsies confirming GPA. Considering the low yield of diagnostic tests,
we recommend regular clinical assessments for signs of systemic
involvement and early MDT input where systemic features of GPA are
recognised.

Our medical strategy for SGS-GPA has shown that induction IS for active
SGS-disease improves the PFI and decreasing need for more invasive
surgery.\textsuperscript{7} Comparing with other studies utilizing a
surgically centered approach (table 2),\textsuperscript{3,8-10} our PFI
was notably better, with 19\% of the cohort not requiring surgery. This
demonstrates a 65\% increase when comparing against the mean PFI of the
quoted studies at 19.0 months (this was calculated with individual mean
PFIs given different weighting based on the study's cohort
size).\textsuperscript{3,8-10}

Four patients required a tracheostomy for emergency airway management.
Ideally all SGS-GPA patients should be managed with an emergency airway
dilatation where possible rather than an emergency tracheostomy.
However, with the joint ENT vasculitis being a regional service,
emergency airway dilatation procedures are not always available in the
peripheral hospitals. Nevertheless, the tracheostomy rate in this study
(19\%) was lower than that quoted in the literature
(41-52\%),\textsuperscript{3} with all patients decannulated promptly.

The benefit of IS is further stated when assessing the four patients
excluded from our study due to extensive SGS-GPA and late referral for
MDT management: undergoing a combined 54 dilatational procedures,
translating to a 6-fold increase in surgeries required in the absence of
induction IS. This enforces the message of early MDT management with
induction IS.

The regression model estimated an improved mean PFI of 48 months,
reflecting a more accurate representation of the mean PFI obtained our
patients' individual rates at 42.8 months. Unfortunately, the impact of
the other covariables could not be adequately analysed, due to small
sample size obtained.

\textbf{Conclusions}

A high index of vasculitic suspicion in SGS should be maintained,
despite the potential for negative biochemical and histological
findings.\textsuperscript{2}

Early multidisciplinary input for SGS-GPA with induction IS has reduced
the need for surgery: increasing the PFI by 65\% when compared to the
literature and reducing morbidity otherwise sustained from
tracheostomies and other complex surgical interventions.

\textbf{References}

\begin{enumerate}
\tightlist
\item
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\item
  Coates ML, Martinez Del Pero M. Updates in antineutrophil cytoplasmic
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\item
  Nouraei SAR, Obholzer R, Ind PW, Salama AD, Pusey CD, Porter F, et al.
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\item
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\item
  Horta-Baas G, Hernández-Cabrera MF, Catana R, Pérez-Cristóbal M,
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\item
  Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, et al.
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\item
  Hunter RW, Welsh N, Farrah TE, Gallacher PJ, Dhaun N. ANCA associated
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\item
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\end{enumerate}

\emph{Table \& Figure Captions}

\textbf{Table 1: GPA Disease Progression in SGS-GPA Patients}

\emph{Abbreviations} ; SGS: Subglottic Stenosis, GPA: Granulomatosis
with Polyangiitis

\textbf{Table 2: Comparison of Procedure Efficacy}

\emph{Abbreviations} ; SGS: Subglottic Stenosis, GPA: Granulomatosis
with Polyangiitis, No.: Number, Trach: Tracheostomies, PFI:
Procedure-free Interval, M: Medical Therapy, ILSI: Intra-Lesional
Steroid Injection, D: Dilatation, LASER: Light Amplification by the
Stimulated Emission of Radiation, LTR: Laryngo-Tracheal Reconstruction/
Resection, MC: Topical Mitomycin C).

\textbf{Figure 1: SGS-GPA Patient Management Timeline}

\emph{Abbreviations} ; SGS: Subglottic Stenosis, GPA: Granulomatosis
with Polyangiitis, IS: Immunosuppression

\textbf{Figure 2: Frailty Model illustrating Procedure-free interval
estimate and its respective confidence intervals}

\emph{Abbreviations} ; SGS: Subglottic Stenosis, GPA: Granulomatosis
with Polyangiitis, PFI: Procedure-free Interval

\emph{Marker indicating the mean PFI estimated (48 months)}\selectlanguage{english}
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