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Respiratory subtype of Relapsing Polychondritis (RP) frequently presents as difficult asthma: a descriptive study of respiratory involvement in RP with 13 patients from a single UK centre

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Introduction Relapsing Polychondritis (RP) is a rare multisystem vasculitis characterised by recurrent cartilage inflammation. Respiratory involvement, of which tracheobronchomalacia (TBM) is the commonest form, is difficult to treat and is linked to increased mortality. We describe 13 patients with respiratory involvement. Methods This is a retrospective study of all the patients with RP at University Hospitals Coventry and Warwickshire NHS Trust (UHCW), a secondary care provider for ∼500 000. Only patients with respiratory involvement were included in this study. Results We identified 13 patients who fulfilled the inclusion criteria. Most patients were identified from the “difficult asthma” clinic. TBM was seen in 11 patients, whilst 2 patients had pleural effusions which resolved with immunosuppression and 1 patient had small airways disease. CT scans (inspiratory and expiratory) and bronchoscopy findings were useful in diagnosing TBM. Pulmonary function testing revealed significant expiratory flow abnormalities. All patients were treated with corticosteroids/disease modifying anti rheumatic drugs (DMARDs) and some were given Cyclophosphamide or biological agents although the response to Cyclophosphamide (1 out of 4) or biologicals (2 out of 4) was modest in this cohort. Ambulatory continuous positive airway pressure (CPAP) ventilation was successful in 4 patients. Conclusions RP may be overlooked in “difficult asthma” clinics with patients having TBM (not asthma) and other features of RP. Awareness of this condition is crucial to enable early diagnosis and interventions to reduce the risk of life threatening airway collapse. A number of patients respond well to DMARDs and are able to minimise corticosteroid use.
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Original article
Respiratory subtype of Relapsing Polychondritis
(RP) frequently presents as difficult asthma: a
descriptive study of respiratory involvement in RP
with 13 patients from a single UK centre
Shirish Dubey, Colin Gelder, Grace Pink, Asad Ali, Christopher Taylor, Joanna Shakespeare, Susan
Townsend, Patrick Murphy, Nicholas Hart, David D'Cruz
Please cite this article as: Dubey S, Gelder C, Pink G, et al. Respiratory subtype of Relapsing
Polychondritis (RP) frequently presents as difficult asthma: a descriptive study of respiratory
involvement in RP with 13 patients from a single UK centre. ERJ Open Res 2021; in press
(https://doi.org/10.1183/23120541.00170-2020).
This manuscript has recently been accepted for publication in the ERJ Open Research. It is published
here in its accepted form prior to copyediting and typesetting by our production team. After these
production processes are complete and the authors have approved the resulting proofs, the article will
move to the latest issue of the ERJOR online.
Copyright ©ERS 2021. This article is open access and distributed under the terms of the
Creative Commons Attribution Non-Commercial Licence 4.0.
Respiratory subtype of Relapsing Polychondritis (RP) frequently presents
as difficult asthma: a descriptive study of respiratory involvement in RP
with 13 patients from a single UK centre
Authors:
Dr Shirish Dubey MBBS, FRCP, FRCPI, M.Med.Ed
Consultant Rheumatologist, Nuffield Orthopaedic Centre, Oxford University
Hospitals NHS Trust, Windmill Road, Oxford OX3 7LD
and
University Hospital Coventry and Warwickshire NHS Trust, Coventry CV2 2DX
Email: s.dubey@nhs.net
Dr Colin Gelder
Consultant Respiratory Physician (retired), University Hospital Coventry and
Warwickshire NHS Trust, Coventry CV2 2DX.
Dr Grace Pink
Fellow in Respiratory Medicine, University Hospital Coventry and Warwickshire
NHS Trust, Coventry CV2 2DX.
Dr Asad Ali
Consultant Respiratory Physician, University Hospital Coventry and
Warwickshire NHS Trust, Coventry CV2 2DX.
Dr Christopher Taylor
Consultant Respiratory Physician, Heart of England NHS Foundation Trust,
Birmingham. B9 5SS.
Mrs Joanna Shakespeare MSc, BSc.
Clinical Scientist, Department of Respiratory and Sleep Sciences, University
Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX
Mrs Susan Townsend
Respiratory Clinical Nurse Specialist, Department of Respiratory and Sleep
Sciences, University Hospitals Coventry and Warwickshire NHS Trust, Coventry,
CV2 2DX
Dr Patrick Murphy
Consultant Respiratory Physician, The Lane Fox Unit, St Thomas’ Hospital
London SE1 7EH
Professor Nicholas Hart MB BS BSc PhD MRCP FFICM
Professor of Respiratory & Critical Care Medicine, Clinical Director Sleep,
Respiratory and Critical Care, Guy's and St Thomas' NHS Foundation Trust,
London SE1 7EH
Professor David D’Cruz MD, FRCP.
Consultant Rheumatologist, Louise Coote Lupus Unit, Guy’s Hospital, London SE1
9RT
Corresponding author: Dr Shirish Dubey.
All authors have contributed to the study design and write up. SD, GP, CD,
AA, JS and ST have helped with data collection and data analysis.
Conflict of information and disclosure forms attached for all authors.
The article fulfils all requirements of the Strobe checklist.
Introduction
Relapsing polychondritis (RP) was described by Pearson et al. in 1960 [1] as a rare
multisystem disease characterised by recurrent episodes of inflammation and
subsequent degeneration of cartilage and connective tissue throughout the body. RP
most commonly affects the respiratory tract, nose, ears and joints [1-4]. McAdam et al
described 6 classical features of relapsing polychondritis, namely bilateral auricular
chondritis, nasal chondritis, respiratory tract chondritis, seronegative inflammatory
arthritis, ocular inflammation and audiovestibular damage [3]. McAdam’s diagnostic
criteria needed 3 out of 6 of the aforementioned clinical features for confirmation of
diagnosis. Additional diagnostic criteria were developed by Damiani and Michet
[2,5]. Both these groups have developed A and B criteria with Damiani criteria
keeping all 6 primary clinical features as A criteria and additionally including
histological confirmation as a B criterion and response to corticosteroids or Dapsone
as a C criterion. 3 A criteria or 1 A and B, or 2 A with C are needed for diagnosis.
Michet criteria include nasal, auricular and laryngotracheal cartilage inflammation as
A criteria with the rest as B criteria, and 2 A or 1 A and 2 B criteria are needed for
diagnosis.
Respiratory tract chondritis is thought to affect up to 50% of patients during the
course of their disease [2,3,6] and remains the primary cause of mortality in RP [3].
Patients often experience airway symptoms such as dyspnoea, cough, chest
discomfort, hoarseness, stridor [7] and even complete aphonia in some cases [4] due
to inflammatory oedema of the larynx, trachea and bronchi. The underlying chronic
cartilage inflammation in the tracheobronchial tree leads to tracheomalacia [8]; or
tracheobronchomalacia (TBM) when this extends to one or both primary bronchi.
Both phenomena can result in exaggerated airway narrowing during expiration and
widening during inspiration [9-11], demonstrable in pulmonary function tests and
computerised tomography (CT) scans of the chest. Unless early diagnosis and
appropriate medical or surgical interventions are in place, the progressive cartilage
destruction in the airways due to recurrent cartilaginous inflammation may ultimately
result in life-threatening airway obstruction and dynamic airway collapse [12]. RP can
involve the eyes, neurological system, heart and blood vessels and there is an
association with HLA DR4 allele [13]. Respiratory problems can be particularly
difficult to treat, and very little data exist to guide us with regards to optimal
screening and assessment modalities for tracheomalacia or tracheobronchomalacia
(TBM). Management of these patients continues to remain a challenge and the
diagnostic delay can often result in significant damage, which necessitates long term
mechanical support through stents or pneumatic support through continuous positive
airway pressure (CPAP) [14, 15]. Despite best treatment, patients are often left with
substantial life changing disability.
We describe a series of patients with RP all of whom had respiratory involvement.
Most had presented to respiratory clinics or had been admitted to hospital with severe
shortness of breath. All patients attended University Hospital Coventry and
Warwickshire NHS Trust which is based in Coventry in West Midlands in UK, and is
a secondary care provider for a population of around 500,000. This case series
describes the respiratory manifestations and aims to increase the awareness of RP in
patients presenting with respiratory symptoms, particularly in individuals who appear
to have oral corticosteroid dependent asthma.
Materials and Methods
We reviewed the medical records of thirteen patients with relapsing polychondritis;
all of whom had respiratory involvement. Patients were identified through the
respiratory and rheumatology clinics at a single centre between 2013 and 2018 and
patients were often seen together in a combined clinic. The diagnosis of RP was made
clinically using the clinical diagnostic criteria [2,3,5]. Disease activity was assessed
using Relapsing Polychondritis Disease Activity Index (RPDAI) which includes
scoring on each organ that can be affected by RP as well as C-Reactive Protein (CRP)
[16]. There are 28 different items with scores ranging from 1 to 24. Respiratory
chondritis scores 14 without and 24 with respiratory failure and is the highest scoring
item in RPDAI. Patients’ demographic characteristics, clinical features, diagnostic
test results and therapeutic interventions were noted. The database was set up in 2016
and details of patients were updated regularly. Ethical approval was obtained from
Research and Development office within our Trust; approval number GF 0267.
Statistics are predominantly descriptive, and MS Excel programme was used to
assimilate the data.
Results
We identified 13 patients with relapsing polychondritis, all of these patients had
respiratory involvement. We did not need to exclude any patients due to lack of
respiratory involvement. Most of these patients (10 out of 13) were identified in
‘difficult asthma’ clinics with 2 being diagnosed following an inpatient admission
with acute shortness of breath and 1 diagnosed from a rheumatology clinic. The
demographics are described in table 1. Male to female ratio was 1:3 with 3 males and
9 females. The median age of the patients was 65 (range 28 to 76) years. Most
patients had other co-morbidities with diabetes being the commonest in 5 patients and
hypertension seen in 4 patients. Other auto-immune disorders were diagnosed in 7 of
these patients. Psoriasis and hypothyroidism were noted in 2 patients each. One
patient had overlap with Behcet’s disease (mouth and genital ulcers with inflamed
cartilage - MAGIC syndrome), another had ankylosing spondylitis. [Table 1, figures
1-5]
We found that 8 patients (62%) had bilateral auricular chondritis and nasal chondritis,
whilst 10 patients (77%) had seronegative polyarthropathy with 2 patients (15%)
having ocular inflammation and 5 patients (38%) had audiovestibular damage [Figure
6]. All patients had good response to oral Prednisolone and fulfilled criteria for
diagnosis of RP (Damiani). Most patients (10 out of 13) were picked up from the
difficult asthma clinics. All patients had wheeze and persistent cough and hence a
diagnostic label of asthma, but it was the presence of monophonic wheeze, presence
of inspiratory stridor in 2 patients, barking nature of cough in 2 patients and lack of
classical reversibility and response to steroids that led to the suspicion of underlying
more complex airway issues and possible expiratory airway collapsibility. Patients
with good response to oral prednisolone demonstrated return of their signs and
worsening of other symptoms with dosage reduction below 20mg daily leading to
further suspicion about the underlying diagnosis. Dynamic CT (inspiratory and
expiratory) images were obtained along with flexible bronchoscopy. Bronchoscopy
was performed in 4 patients. Mild sedation using intravenous midazolam and local
analgesia with 2% lignocaine was instilled. Patients were able to co-operate and
forcibly exhale. Views were taken from the proximal and distal trachea, right and left
main bronchi and segmental bronchi during inspiration and forced expiration. 50% or
more reduction in the cross sectional area of the airway during the dynamic
bronchoscopy and CT were used as the diagnostic cut off for the diagnosis of TBM.
Two of our patients demonstrated smooth thickening of the airway wall and luminal
narrowing of the distal trachea and main bronchi and one demonstrated symmetrical
stenosis of the large airways, whereas the remaining had >50% reduction of the
airway luminal area with crescentic appearance of the airway due to flattening of
airway walls during expiration.
Although other features such as bilateral auricular chondritis or nasal chondritis had
been present in 8 patients, they had rarely complained about these symptoms to their
clinicians as other symptoms, particularly severe breathlessness were their primary
concern. Eliciting these symptoms required direct questioning. One patient had
classical nasal bridge collapse which they previously told several clinicians (via
interpreters) was the result of childhood trauma, although on detailed questioning
there was in fact no history of trauma. Seronegative inflammatory arthritis was a
presenting feature in 2 patients (predominantly large joints), and had been noted in 10
patients.
Laboratory testing showed anaemia in seven patients and raised inflammatory
markers including CRP or erythrocyte sedimentation rate in 6 patients. As a number
of patients were on long term corticosteroids for ‘difficult asthma’, it was difficult to
get accurate trends of inflammatory markers prior to treatment. None of the patients
had evidence of eosinophilia at any point. Rheumatoid factor, anti-cyclic citrullinated
antibodies, antinuclear antibodies, anti-double stranded DNA antibodies and
neutrophil cytoplasmic antibodies were all negative, although one patient had
antiphospholipid antibodies. Chest radiographs were normal in 11 patients, 2 had
shown features of pleural effusions and these were confirmed on CT scans later. None
of the patients had any other features to suggest ANCA associated vasculitis.
In 12 out of 13 patients, flow-volume loops demonstrated flattening of either
inspiratory or expiratory curves, or both. Flattening of the expiratory limbs in flow-
volume loops was prevalent in most, suggesting large airway collapsibility during
expiration. [Figures 7,8]. There was no evidence of reversibility with beta 2 agonists
in 11 patients, whilst 1 patient with small airway disease showed reversibility with
likely co-existent asthma.
Treatment: Corticosteroids were used in all patients, and disease modifying anti
rheumatic drugs (DMARDs) such as Methotrexate 15 to 25 mg weekly (6 patients),
Azathioprine 1-2.5 mg/kg/d (2 patients) and Mycophenolate mofetil 1-2 grams daily
(2 patients) were successful in reducing disease activity (Table 2). One patient
developed hypogammaglobulinemia which was thought to be secondary to
immunosuppression and was treated with replacement IV Immunoglobulin (IVIG) as
she was having recurrent infections (predominantly chest infections). Prednisolone
was usually started at 1 mg/kg/day orally in patients with respiratory failure and 0.5
mg/kg/day in patients without respiratory failure with gradual tapering every 2-4
weeks initially. Dose reduction was achieved in all cases but 4 patients struggled to
wean Prednisolone dose down below 10 mg. In 2 patients, we only used <20 mg
Prednisolone, higher doses were not needed. IV Cyclophosphamide was used in 4
cases, but was thought to be unsuccessful in 3 of these on the basis of lack of
symptomatic benefit. Cyclophosphamide was only used after failure of conventional
DMARDs and was used primarily for TBM. Patients with severe airway collapse
>90% of airway area with disabling symptoms were considered for large airway
stenting alongside medical therapies. Successful stenting was performed in 3 patients;
in one other patient the stent had to be removed as it was exacerbating infections and
another due to continuous coughing. Six patients with moderately severe airway
compromise (75%-90%) and significant breathlessness on exertion were receiving
intermittent ambulatory CPAP, 2 discontinued due to lack of tolerance. NIV was used
with maximum inspiratory pressure (IPAP) of 24 and expiratory pressures (EPAP) of
10cm H2O whilst CPAP pressures were between 10 and 13 cm H2O. Overnight sleep
studies excluded significant sleep disordered breathing in these patients. Within this
cohort, 7 patients have had recurrent admissions for ‘flare of asthma’ prior to the
diagnosis with 3 of these not requiring further inpatient admissions once
immunosuppression was instituted. [Table 2 here]
Biological DMARDs were tried in 4 patients with anti-TNF therapies being
successful in 1 and unsuccessful in 3 patients (two due to inefficacy, another due to
allergic reactions to both Etanercept and Adalimumab). Of the 3 patients who failed
anti-TNF therapy, 2 were tried on other agents, with one patient responding well to
Abatacept whilst another patient was started on Secukinumab for ankylosing
spondylitis and had good response for spinal disease, but no change in RPDAI. Eight
patients are still under regular follow-up (FU) and have been under FU for more than
5 years since diagnosis, one has been lost to follow up and 4 patients have died. In
two of these cases, primary cause of death was chest infection, in the other two, it was
unrelated causes, one from complications of myelodysplasia.
Discussion
A number of studies have described small numbers of patients with respiratory
features and some have shown airway involvement to be the leading cause of death in
RP [1,3,6,15,17]. TBM has been reported in literature in up to 50% of patients with
RP. Our series saw TBM as the commonest presentation of RP, although it is quite
likely that a number of patients with less serious problems might not have been
appropriately diagnosed given the rarity of this condition. A French series reported
142 patients with RP who formed three distinct patterns haematological, respiratory
and ‘mild’ phenotypes [18]. Within the respiratory phenotype which formed 22.5% of
their series, auricular involvement was less common, something we have seen as well.
Similar to our series, they found that these patients received more intensive
treatment, were prone to infections, and were frequently admitted to the ICU.
Our series provides more detail about the respiratory sub-type of RP with specific
focus on presentation and management. We did not need to exclude any patients with
RP due to lack of respiratory involvement. Given its rarity, it is likely that there are
other patients with less serious manifestations that have not reached rheumatology or
respiratory clinics and have not been given the diagnosis yet. The majority of these
patients were originally thought to have oral corticosteroid dependant asthma, and
once TBM was suspected or diagnosed, physicians started searching for and finding
other features of RP. Patients had not complained about the other manifestations such
as chronic auricular chondritis or nasal chondritis as the symptom of breathlessness
predominated.
Physical treatments of TBM with stenting and CPAP are well recognised [6-9,17,19],
however, there is very little information in literature about pharmacological treatment
of TBM through immunosuppression. This is important as TBM can be the only
manifestation of RP [20]. In our series, most patients had responded well to
pharmacological therapy, although some needed stent insertion to support the
bronchial tree. Stenting also had mixed results and it is unclear as to whether there are
specific features that would indicate use of stents in preference to drug therapy.
Stenting is most likely to be useful after optimal control of active disease (to stabilise
damaged section of the tracheobronchial tree once medical treatment has controlled
active inflammation). Complications following stenting are relatively common with
one study showing 49/58 patients having a complication commonest of which are
stent migration, infection and partial obstruction [21]. Aggressive early management
can be difficult to achieve when the patient has been symptomatic for so many years
and airway damage has accumulated before the diagnosis is made. Intermittent
ambulatory continuous positive airway pressure has been described previously with
variable results [22-24]; our group has previously described successful use of CPAP
in TBM. Such long term use of portable NIV combined with overnight CPAP has not
been reported to our knowledge. We have seen good symptomatic improvement and
long term stability with CPAP used in this fashion together with medical treatments.
Clinical and symptomatic evaluation, dynamic (inspiratory and expiratory) CT scans
and flexible bronchoscopy were critical in establishing the diagnosis of TBM which is
consistent with reports from literature [8-10]. Other features of RP were identified
clinically although recent reports suggest Positron Emission Tomography (PET CT)
might be an additional resource for defining the severity and extent of disease [25].
PET CT has other potential advantages as it can a) differentiate damage from active
inflammation, and b) provide information about large vessel vasculitis and other
organs that are not easy to assess clinically. We have not used this modality in our
patients, and this can be evaluated in future studies.
The prevalence of relapsing polychondritis in Coventry appears to be at least 26 per
million on the basis that we have 13 patients locally within our catchment area of
around 500,000. If these prevalence data were true for the rest of UK as well, one
would expect roughly 1500 additional patients! It is difficult to estimate the true
prevalence for a rare condition, and the literature has offered very wide estimates
(between 3.5 per million to 23 per million). Hungarian data suggest similar numbers
(23 per million) to the numbers estimated here based on 233 cases from a population
of 10 million [26]. Incidence in that study was around 3.5 per million patient years.
Incidence of RP in a UK study was 0.71 per million patient years and prevalence was
estimated at 9 per million [27]. In Rochester (Minnesota), the incidence of RP was
estimated at 3.5 per million [4]. Given the rarity of the condition and difficulty in
diagnosis, it is not a surprise that there is such wide variation. This study provides
new impetus to looking for specific features of RP which may have a major influence
on incidence and prevalence estimates.
There are no controlled clinical trials in this area (as is the case for a number of rare
diseases), and it may be possible to set up trials in this area if the prevalence is
significantly higher than was previously thought. There is a need to increase
awareness of this disease amongst all the specialties that are likely to come across
these patients. Optimal management of these patients continues to remain a challenge.
The exact pathogenesis is not clearly understood. Various immune processes that
have been described include reduction of immunoregulatory cells, antibodies
attacking cartilage tissue elements like type-II, type-IX, and type-XI collagen and
matrilin1, changes in cytokine profiles, deposition of immune complexes, and
insufficient tissue regeneration [28-34]. This makes it quite challenging when
choosing drugs for refractory patients. Within our cohort, we observed some
responses to DMARDs with Methotrexate, Azathioprine and Mycophenolate being
successful. In fact, in one patient we were able to completely stop corticosteroids and
have not needed to go back to corticosteroids for more than 2 years. Responses to
biological agents and intravenous (IV) Cyclophosphamide have been modest in this
cohort this may be due to delay in diagnosis which can sometimes be a number of
years. Also, we have not routinely used IV Cyclophosphamide for induction, but
tended to use it when other agents have failed. Disease activity and damage scores
have been developed [16, 35] and are of use in documenting response to treatment;
and also serve as a reminder of the various manifestations of this rare illness. Multiple
biological agents have been tried, but due to the rarity of the condition, there are no
randomised controlled trials in this field. A French national study looking at biologics
in RP did not demonstrate any clear trends that would help guide use of biological
agents [36].
Limitations
This is a retrospective review and studies of this sort are subject to systemic biases
which are applicable to this study. Prevalence data are affected by referral pathways
and other biases which would be applicable to this study. Also patients presenting
with respiratory symptoms were selected so this is a referral bias. There is also likely
to be left censorship bias as some patients who may have died or were lost to follow-
up would not have been included.
Conclusions
Relapsing Polychondritis, although rare, with prevalent respiratory involvement may
be the cause of significant morbidity and mortality. Patients may be misdiagnosed
with other respiratory diseases in particular being labelled as difficult asthma.
There is an important need to recognise and diagnose relapsing polychondritis, as
there are specific treatment options including DMARDs that these patients are likely
to benefit from. Awareness of this condition is crucial to enable early diagnosis and
clinical interventions to reduce the risk of life threatening airway collapse.
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polychondritis. Joint Bone Spine. 2019;86:363-368.
36. Moulis G, Pugnet G, Costedoat-Chalumeau N, et al. Efficacy and safety of
biologics in relapsing polychondritis: a French national multicentre study. Annals of
the Rheumatic Diseases 2018;77:1172-1178.
Table 1: Clinical features of patients with Relapsing polychondritis.
Patient
Sex
Age
Co-morbidities
NC
SP
OI
AD
Response to
corticosteroids
TBM
proven
1
M
65
T2DM, hypothyroid,
psoriasis
Y
N
Y
N
Y
Y
2
F
70
Memory loss
Y
Y
N
N
Y
Y
3
F
50
T2DM
Y
Y
N
Y
Y
Y
4
F
53
Hypothyroid,
fibromyalgia, HTN,
Behcet's, obesity
Y
Y
N
N
Y
Y
5
F
76
Previous TB,
immunodeficiency,
HTN, T2DM, OA
N
Y
N
Y
Y
Y
6
F
74
HTN, Angina, AF,
T2DM, anti-
phospholipid Abs
Y
Y
N
N
Y
Y
7
F
76
Emphysema
N
N
N
N
Y
Y
8
F
70
HTN, obesity, acoustic
neuroma,
hyperlipidaemia
N
Y
N
N
Y
Y
9
F
78
T2DM, obesity, MI,
AF, CKD, dementia,
asthma
Y
Y
N
Y
Y
Y
10
M
31
Hypoadrenalism,
bronchiectasis
Y
Y
N
N
Y
Y
11
F
52
obesity, COPD,
anklyosing spodylitis,
psoriasis
Y
Y
N
Y
Y
N
12
M
79
Myelodysplasia,
Follicular lymphoma,
Osteoporosis.
N
N
Y
N
Y
N
13
M
78
T2DM, IHD, CKD,
myositis
N
Y
N
Y
Y
Y
BAC: Bilateral auricular chondritis, NC: Nasal chondritis, RTC: Respiratory tract chondritis,
SP: seronegative polyarthritis, OI: Ocular inflammation, AD: Audiovestibular damage.
T2DM: Type 2 Diabetes mellitus, HTN: Hypertension, TB: Tuberculosis, OA: Ost eoarthritis,
AF: Atrial fibrillation, MI : Myocardial infarction, CKD : Chronic kidney disease, COPD:
Chronic obstructive pulmonary disease.
Table 2: Pharmacological and non pharmacological treatment for patients with RP
Patient
Sex
Age
CPAP
IS Drugs
Corticosteroid
dose
Previous Drugs
Baseline
RPDAI
1
M
65
N
MTX
-
Pred
37
2
F
70
N
MMF, Infliximab
Pred 5mg
SSZ
27
3
F
50
DNT
MTX
-
Pred
45
4
F
53
Y
MMF, MTX
Pred 10 mg
AZA,
Cyclophosphamide,
ADA and ETN
47
5
F
76
Y
SSZ, HCQ, ABT,
IVIG
Pred 7.5 mg
MTX, ETN,
leflunomide, AZA
44
6
F
74
Y
MTX, AZA
Pred 10 mg
Cyclophosphamide
43
7
F
76
Y
Cyclophosphamide
Pred 10 mg
MTX
27
8
F
70
N
AZA
Pred 5 mg
-
15
9
F
78
DNT
Pred 5 mg
MTX, AZA, HCQ
24
10
M
31
N
HCT
20/10/10
-
33
11
F
52
N
Secukinumab
Pred 10 mg
MTX, ETN, HCQ,
Cyclophosphamide,
ADA
38
12
M
79
N
Pred 5 mg
-
35
13
M
78
Y
MTX
Pred 5 mg
AZA
40
IS: Immunosuppressant drugs, MTX: Methotrexate, MMF: Mycophenolate mofetil, SSZ: Sulfasalazine, HCQ:
Hydroxychloroquine, ADA: Adalimumab, AZA: Azathioprine, ABT: Abatacept; IVIG: Intravenous
immunoglobulin, ETN: Etanercept, Pred: Prednisolone, HCT: Hydrocortisone, RPDAI: Relapsing
Polychondritis Activity Index.
FIGURES
Figure 1:
A: Admission CT scan showing near complete collapse of trachea in a patient that was subsequently diagnosed with RP.
B: Repeat CT after IV corticosteroids with inspiratory and expiratory films showing significant improvement of tracheal narrowing (expiratory
phase CT).
Figure 2:
A: Another patient with admission CT chest showing near complete collapse of trachea and pleural effusions
B: Repeat CT after treatment with high dose corticosteroids with improvement in trachea and resolution of pleural effusions.
Figure 3: Another patient with collapse of trachea.
Figure 4
A: Another patient with presentation CT showing significant narrowing of trachea
B: Post treatment imaging showing improvement in dimensions of trachea.
Figure 5: Pre-treatment tracheal collapse in another patient
Figure 6: Patient images demonstrating auricular chondritis with inflammation of the external ear with sparing of non-cartilaginous part.
Figure 7: Flow volume loop of patient 4 showing flattening of the expiratory limb and inspiratory limb to a lesser extent
Figure 8: Flow-volume curve of patient 6 showing flattening of the expiratory limb and inspiratory limb to a lesser extent.
... The patient started glucocorticoids and methotrexate with complete resolution of the clinical manifestation. The second one is a 52-year-old female diagnosed with ankylosing spondylitis overlapping RP complicated by respiratory tract chondritis [93]. The patient, after failure of methotrexate, cyclophosphamide, entanercept and adalimumab, was treated with secukinumab, resulting in improvement only in spinal disease, without any change in RP manifestations. ...
Article
Introduction: Relapsing polychondritis (RP) is a rare systemic inflammatory disease of unknown etiology, primarily affecting cartilaginous tissue and proteoglycan-rich structures. Clinical manifestations vary from mild symptoms to occasional organ or life-threatening complications. Treatment can be challenging and is mostly based on experience or case reports/series. Areas covered: There is growing literature investigating the role of biologics in the management of RP. TNFα antagonists, abatacept, tocilizumab, rituximab, anakinra and tofacitinib have been prescribed in several RP patients, mainly as second-line treatment, after conventional immunosuppressive agents' failure. Expert opinion: : Glucocorticoids represent the gold standard treatment of RP. Conventional immunosuppressants should be administered in refractory patients or when a glucocorticoid-sparing effect is needed. Biologic therapy should be used after failure of conventional treatments or in severe manifestations. TNFα inhibitors are the most prescribed biologic agent, with partial or complete response in several cases; but loss of efficacy may occur over time. Infliximab and adalimumab should be preferred among TNFα antagonists. Abatacept and tocilizumab proved to be effective as second-line biologic agents, but frequent infections are reported with the former. Data on anakinra and rituximab are controversial, therefore they are not recommended as first-line biologic drugs. The use of JAK inhibitors is still anecdotal.
... The average time from onset to diagnosis has been reported to be 2.9 years, and approximately one-third of patients are reported to have visited more than five doctors before diagnosis [7]. Further, RP can be misdiagnosed as bronchial asthma [8]. There are several case reports where the patients had already developed tracheobronchomalacia at the time of the diagnosis of RP [9,10]. ...
Article
Full-text available
We describe the case of a 60-year-old Japanese man with relapsing polychondritis (RP). The patient was referred to Hamanomachi Hospital due to mild elevation of C-reactive protein and mild anemia on medical checkup without any symptoms. Body CT imaging showed thickened tracheal and bronchial walls with no active lesions in the lung. Precise physical examination revealed swelling in both ears. Bronchoscopy revealed redness and swelling of the tracheal and bronchial mucosa in the membranous lesion. Histologic examination of the bronchial biopsy showed inflammatory cell infiltration in the sub-mucosa with no vasculitis. Serum anti-type 2 collagen antibodies were found to be positive (33.9 EU/mL). Corticosteroid treatment improved his tracheochondritis. It is challenging to diagnose RP in the early stage due to its rarity and nonspecific symptoms. Airway involvement in RP is irreversible and the major cause of morbidity and mortality; hence, early recognition of airway involvement and treatment is warranted.
... The diagnosis of RP with TBM is often misdiagnosed as asthma (10). Once patients with RP have persistent cough, shortness of breath, and dyspnea, the possibility of TBM needs to be considered first. ...
Article
Full-text available
Relapsing polychondritis is an immune disorder of unknown etiology involving multiple systems that is characterized by persistent inflammation and destruction of cartilage, including the ears, nose, costal, joint, and airways. Airway involvement caused by relapsing polychondritis is common, and tracheobronchomalacia is the most serious complication, which is life-threatening. Currently, the exact mechanism of relapsing polychondritis with tracheobronchomalacia is unknown. Although glucocorticoids and immunosuppressive agents are administered, failures often occur. Currently, bronchoscopy-guided intervention therapy used in tracheobronchomalacia caused by chronic obstructive pulmonary disease or other etiology has gradually increased, but bronchoscopy-guided intervention therapy with extracorporeal membrane oxygenation assist used in tracheobronchomalacia caused by relapsing polychondritis has not been reported. Here, we report a case of relapsing polychondritis with severe tracheobronchomalacia. Although drug therapy was provided and airway stent implantation was performed, the tracheal stenosis was further aggravated. Because conventional anesthesia and mechanical ventilation cannot meet the needs of bronchoscopy-guided intervention therapy or guarantee sufficient safety. The intervention treatment was performed with the support of extracorporeal membrane oxygenation, which was successfully completed without obvious complications. The symptoms were significantly improved, and the patient was discharged uneventfully.
Chapter
Relapsing polychondritis is a severe systemic immune-mediated disease characterized by an episodic and progressive inflammatory condition with progressive destruction of cartilaginous structures. The multiple clinical presentations and episodic nature of relapsing polychondritis cause a significant diagnosis delay. The most common initial clinical picture is chondritis of the ears associated with pain, erythema, and edema, followed by chondritis of the nose. Chondritis of chondro-costal joints and upper airways, scleritis and episcleritis, arthralgia, and various mucocutaneous lesions can subsequently occur. Repeated inflammation can lead to the destruction of the cartilage and deformity of the nose, ears and respiratory tract. Tracheobronchomalacia and ascending aorta involvement are the most feared complications. The current diagnosis of relapsing polychondritis is clinical, based on Michet et al. criteria. Anti-inflammatory drugs, colchicine or dapsone, along with low-dose glucocorticoid therapy, is preferred for mild disease. Corticosteroids combined with an immunosuppressive or immunomodulatory agent may reduce the frequency and severity of relapses in severe cases.
Article
Full-text available
Objectives: Relapsing polychondritis is a rare, multi-systemic and inflammatory condition of unknown origin. We currently lack a core set of measures to assess and follow damage in patients suffering from this condition. Our primary aim was to derive a disease-specific damage measuring tool for relapsing polychondritis, the Relapsing Polychondritis Damage Index (RPDAM). Methods: We performed an international 4-round multicenter Delphi study during which experts were asked to rate the relevance of potential damage items for relapsing polychondritis (141 items were obtained from a literature review and 12 from expert suggestion), using a Likert scale. The selection of items for each subsequent round was based on the median rating of each item. Results: Twenty-four experts from 11 nationalities participated in round 1 and 22 in rounds 2, 3 and 4. From the initial 153 potential damage items, 44 items were selected during round 1, 30 items during round 2 and 16 during round 3. During round 4, we refined the index to a total of 17 items referring to ear nose and throat, eye, respiratory, cardiovascular and hematological systems as well as to treatment-related specific damage items. Conclusion: Physicians involved in the care of relapsing polychondritis patients are currently lacking standardized tools for patient assessment. We have developed by international consensus a scoring system to assess damage in patients with relapsing polychondritis. The RPDAM may contribute to improve the care of patients suffering from this rare condition as well as to standardize data collection for future clinical trials.
Article
Full-text available
Objective: Relapsing polychondritis (RP) is a rare autoimmune inflammatory disease that attacks mainly cartilaginous structures or causes serious damage in proteoglycan-rich structures (the eyes, heart, blood vessels, inner ear). This study shows results regarding the epidemiology, progression, and associations of this highly variable disease by collecting all cases from a 124-million-person-year Central European nationwide cohort. Methods: We used the Hungarian Health Care Database to identify all persons with possible RP infection. We followed patients who had International Classification of Diseases 10th edition code M94.1 at least once in their inpatient or outpatient records between January 1, 2002 and December 31, 2013 in Hungary. We classified these patients into disease severity groups by their drug consumption patterns between January 1, 2010 and December 31, 2013. We analyzed the regional distribution of RP incidences as well. Overall maps of comorbidity are presented with network layouts. Results: We identified 256 patients with RP among cumulatively 11.5 million registered inhabitants. We classified these patients into four severity classes as "extremely mild" (n=144), "mild" (n=22), "moderate" (n=41), and "severe" (n=4). Two additional groups were defined for patients without available drug data as "suspected only" (n=23) and "confirmed but unknown treatment" (n=22). The age and sex distributions of patients were similar to worldwide statistics. Indeed, the overall survival was good (95% confidence interval for 5 years was 83.6%-92.9% and for 10 years was 75.0%-88.3% which corresponds to the overall survival of the general population in Hungary), and the associations with other autoimmune disorders were high (56%) in Hungary. Almost any disease can occur with RP; however, the symptoms of chromosomal abnormalities are only incidental. Spondylosis can be a sign of the activation of RP, while Sjögren syndrome is the most frequent autoimmune association. Regional distribution of incidences suggests arsenic drinking water and sunlight exposure as possible triggering factors. Conclusion: The good survival rate of RP in Hungary is probably associated with the early diagnosis of the disease.
Article
Full-text available
Relapsing polychondritis is a rare disease characterized by cartilage inflammation. Our aim was to estimate the incidence, prevalence and mortality of relapsing polychondritis and describe the clinical features of relapsing polychondritis in a large population. All participants diagnosed with relapsing polychondritis were sampled from the Clinical Practice Research Datalink. Prevalence and incidence rates for 1990-2012 were estimated. Relative mortality rates were estimated in a time-to-event framework using reference UK life tables. A questionnaire validation study assessed diagnostic accuracy. There were 117 participants with relapsing polychondritis ever recorded. Fifty (82%) of 61 cases were validated by a physician and unconfirmed cases were excluded. The analysis included 106 participants (42 men, 64 women) diagnosed with relapsing polychondritis. The mean age (range) at diagnosis in men was 55 (range 17-81) years and in women 51 (range 11-79) years. The median interval from first symptom to diagnosis was 1.9 years. The incidence of relapsing polychondritis between 1990 and 2012 was 0.71 (95% CI 0.55, 0.91) per million population per year. There were 19 deaths from any cause. There were 16 observed deaths eligible for survival analysis and 7.4 deaths expected for the UK population of the same age, sex and period. The standardized mortality ratio was 2.16 (95% CI 1.24, 3.51), P < 0.01. Respiratory disease, cardiac conditions and cancer were the most frequent causes of death. The incidence of relapsing polychondritis may be lower than previously estimated, and diagnostic misclassification and delay are common. Mortality in relapsing polychondritis is more than twice that of the general population. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Article
Objective: To evaluate 18F-fluorodeoxyglucose (FDG) PET/CT in the assessment of disease activity, extent of the disease and response to therapy in relapsing polychondritis. Methods: Twenty-five patients (9 men, 16 women) with a mean age of 38.2 years (s.d. 13.7; range 18-62), diagnosed to have relapsing polychondritis according to Damiani and Levine's modification of McAdam's criteria, who underwent PET/CT examination were included. Ten patients underwent a second PET/CT examination after therapy or during follow-up. Clinical symptoms and auxiliary examination findings were recorded. PET/CT findings were reviewed and correlated with the clinical symptoms. Results: The major symptoms were aural pain (n = 21), nasal pain (n = 10), stridor (n = 5), cough (n = 9), fever (n = 8) and laryngeal tenderness (n = 8). The initial PET/CT was positive in 23/25 patients. PET/CT revealed involvement of auricular (n = 14), nasal (n = 8), laryngeal (n = 7), tracheobronchial (n = 6) and Eustachian (n = 3) cartilages with a mean maximum standardized uptake value (SUVmax) of 4.1 (s.d. 2.5; range 1.7-12.7). Fair correlation of aural/nasal pain/stridor with FDG avidity of cartilage involvement on PET/CT was noted. The key finding was detection of asymptomatic large airway involvement in seven patients (28%). Re-examination PET in 10 patients revealed complete therapeutic response (n = 5), partial response (n = 1), stable disease (n = 1), progressive disease (n = 1) and disease recurrence (n = 2). Conclusion: FDG PET/CT is a useful tool for the assessment of the disease activity and extent. It identified activity in clinically inaccessible sites that are of clinical significance. It is also useful in assessing treatment response and finding relapse.
Article
Objectives To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP). Methods We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response. Results This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non-biologic disease-modifying antirheumatic drugs. Conclusions This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections.
Conference Paper
Excessive dynamic airway collapse (EDAC) and tracheobronchomalacia (TBM) occur due to weakening of the walls of the central airways leading to airway collapse on expiration. Positive airway pressure provides a pneumatic stent maintaining airway patency. CPAP is used to prevent airway collapse during sleep, but could also facilitate improved exercise capacity in this patient group. The aim of this study was to investigate the effect of ambulatory continuous positive airway pressure (CPAP) on neural respiratory drive and exercise capacity. Patients with CT or bronchoscopic evidence of EDAC or TBM underwent baseline testing and 6 min walk test (6MWT). Physiological testing was performed with patients self-ventilating and on CPAP at 4, 7 and 10 cm H2O to identify optimal ambulatory CPAP pressure. Patients then underwent repeat 6MWT on sham or active CPAP in a random order. Neural respiratory drive index (NRDI) was assessed by surface electromyography of the parasternal intercostals (EMGpara%max χ respiratory rate) while self-ventilating and on CPAP. We studied 20 (9 male), ambulatory adult patients with EDAC and/or TBM: mean ±SD age 60±13 years, height 1.67±0.86 m, and BMI 34.1±6.6 kg/m². The NRDI was 356±182 AU while self-ventilating and reduced when CPAP was applied (231±122 AU; p<0.001). The 6MWT while on optimal CPAP was increased comparing to self-ventilation and sham CPAP (296±112 m vs 264±120 m vs 252±125 m, respectively; p<0.001) (figure 1). The treatment effect between sham and optimal CPAP was 31±39 m (95% CI: 13 to 50 m). While on optimal CPAP, 12 patients increased their 6MWT more than 30 m compared to self-ventilation (responders). Comparing responders with non-responders, differences were identified for NRDI (−167±110 AU vs. −63±90 AU, respectively; p=0.039) and 6MWT while self-ventilating (203±94 m vs. 336±133 m, respectively; p=0.022). In conclusion, CPAP reduces neural respiratory drive and increases exercise capacity in patients with EDAC/TBM. Furthermore, the degree of functional limitation and off-loading of the respiratory muscles on CPAP can identify those likely to have a reduction in neural respiratory drive and enhanced exercise tolerance. • Download figure • Open in new tab • Download powerpoint Abstract S134 Figure 1 The 6MWT while on optimal CPAP was increased comparing to self-ventilation and sham CPAP.
Article
Relapsing polychondritis (RP) is a rare disease characterized by recurrent inflammation and destruction of the cartilaginous structures. Tracheobronchial chondritis is a dreaded complication of RP. We wish to report a case of RP of the trachea and bronchi which was treated with nasal continuous positive airway pressure.