Report
Relapsing polychondritis, an underestimated dermatological urgency: case report and literature review ~ aranda1,3, MD , Sergio Mora4, MD , Daniel Cuestas1,2, MD , Elkin Pen nica Patin ~ o1, MD , and Carolina Cortes1,3, MD , Ingrid Galvis4,5, MD , Mo 1,3 Oscar Velasquez , MD
1
Dermatology Service, Samaritana University Hospital - ESE, 2Dermatology Program, El Bosque University, 3 Dermatology Program, National University of Colombia, 4Rheumatology Service, Samaritana University Hospital - ESE, , and 5Radiology Program, La Bogota Sabana University, Chia, Coloumbia Correspondence Daniel Cuestas, MD Dermatology Service, University Hospital of , Colombia, the Samaritana ESE, Bogota Carrera 8 No. 0-29 Sur, Dermatology Program, El Bosque University., Av. Cra 9 No. 131A 02, Bogota Colombia E-mail: [email protected]
Abstract Background Relapsing polychondritis is an autoimmune multisystemic disease with primary chondral involvement. Its high mortality and morbidity make it a real clinical challenge. Case description A 32-year-old woman with a history of relapsing polychondritis, refractory to multiple treatments, with multisystem compromise, imminent risk of death due to severe tracheobronchial damage and difficult ventilatory support, and successful treatment with infliximab. Discussion and evaluation Several treatments have been described in the literature, such as nonsteroidal anti-inflammatory drugs, corticosteroids, dapsone, azathioprine, cyclosporine, cyclophosphamide, and methotrexate. However, the cases refractory to conventional therapy may lead to chronicity, irreversibility, and death. As a result, a third-line therapy could improve the prognosis of these patients. Conclusions Biological therapy is a good option for disease control and quality of life improvement. In addition, the physician should consider these treatments to avoid the chronicity and risk of death of these patients.
Funding: None Conflict of interest: None doi: 10.1111/ijd.13755
Background
(2:1 to 4:1) between the 4th to 5th decade of life, although it can also affect the pediatric population.1,4,9–11
Relapsing polychondritis (RPC) is an autoimmune multisystemic
The onset of the disease and the clinical characteristics may
disease with recurrent inflammation of three types of cartilage:
be different between each patient, being a clinical challenge that
hyaline, elastic, and fibrous. However, it possibly involves
allows a late diagnosis, resulting in cartilage destruction, great
another system, such as the ear, nose, airway, eyes, blood ves-
morbidity, and mortality. Also, the treatment is not established, and there are no algorithms for the management of it, which
sels, heart, and skin.1–5 RPC was first described by Wartenhorst6 in 1923, but Pearson and colleagues,7 in 1960, described its recurrence. Years later, the diagnostic criteria were proposed
causes confusion in the medical field. However, owing to the
in 1976 by McAdam1 empirically, and these persist today. Dami-
tional immunosuppressants, the advent of biological therapy
ani and Levine8 proposed a modification of these criteria: for
represents a hopeful third line of management.1,9–15
resistance to corticosteroids and therapeutic failure with conven-
the diagnosis, (i) all patients had to have at least three or more McAdam diagnostic criteria, the histologic confirmation is not necessary; (ii) one or more of McAdam’s signs with histologic confirmation; (iii) chondritis in two or more different anatomic locations with response to steroids and/or dapsone treatment. The epidemiological data show an incidence of approximately
Case report A 32-year-old Colombian woman with 5 years of self-limited and recurrent episodes of erythema, edema, and auricular pain accompanied by rhinorrhea, dysphonia, and odynophagia con-
0.71, 2.0, and 3.5 per million from population studies in the Uni-
sulted several health centers that were treated with unknown
ted Kingdom, Hungary, and Minnesota, USA, respectively,2,9,10
antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs).
with a slight predominance in Caucasian women than in men
The patient improved modestly but without a clear diagnosis. In
ª 2017 The International Society of Dermatology
International Journal of Dermatology 2017
1
2
Report
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
the course of time, her clinical condition declined, and the patient began to lose her hearing by sensorineural deafness. At the first
Treatment with prednisolone 1 mg/kg/day, methotrexate 25 mg/week, and azathioprine 200 mg/day was considered,
hospital visit, she was in regular general conditions but without
but after 3 months of follow-up, the patient’s clinical condition
respiratory distress. Physical examination revealed a bilateral
worsened.
conjunctival injection without impairment of visual acuity, an
decreased visual acuity by posterior uveitis, and laryngotra-
important chondral commitment by a “saddle nose” deformity,
cheal chondral inflammation with progressive respiratory dis-
cauliflower ears, (Fig. 1a, b, c) tortuous external auditory ducts,
tress, so the mechanical ventilation was necessary with
and global costochondritis, mainly manubriosternal and stern-
tracheotomy because orotracheal intubation was not possible
oclavicular chondritis. In addition, large and small joints were affected by arthritis, the proximal interphalangeal joints, the
and even after the procedure, the patient continued with great respiratory distress, requiring ventilatory supervision in the
metacarpophalangeal joints, the left elbow, the shoulder, and the
intensive care unit. The complementary exams showed a
right knee were the most prominent. There was no involvement
chest x-ray without consolidation but with basal atelectasis of
of the lobules of the ears, skin manifestations, signs of renal
the left lower lobe, the arterial blood gases suggested a non-
damage (macroscopic hematuria) or neurological abnormal find-
compensated respiratory acidosis. We considered performing
ings (encephalitis or sensorimotor polyneuropathy). The car-
a computed tomography (CT) with additional three-dimensional
diopulmonary
physical
reconstruction (Fig. 3a, b, c) which showed stenosis in the
examination showed no signs of valve, myocardial, or pericardial dysfunction.
subglottic trachea, the main bronchi, and the carina; all these were distal to the tracheotomy, which explained the difficulty
auscultation
and
global
She
presented
increased
joint
pain,
fever,
The main suspected diagnosis was RPC; McAdam criteria
of orotracheal intubation and persistent respiratory distress
were applied with a total of 6 points, the first two modified crite-
despite the tracheotomy. The transthoracic doppler echocar-
ria were obtained, and an ear biopsy was performed (Fig. 2a,
diogram was normal.
b) which confirmed the diagnosis. The initial RPDAI (RPC Dis-
According to the imminent risk of death, the onset of biologi-
ease Activity Index)16 was 89 points with the erythrocyte sedi-
cal therapy was necessary. Three options for biological therapy
mentation rate (ESR) 20 mm/h and C-reactive protein (CRP)
in our hospital were available: tocilizumab (TCZ), infliximab
25 mg/dl; the other laboratory tests were negative (Table 1).
(IFX), and etanercept (ETA); however, TCZ and ETA were
(a)
(b)
(c)
Figure 1 Relapsing polychondritis findings. Lateral and front views of the nose with “saddle nose” deformity (back arrow) (a and b). Side view of the ear with “cauliflower” deformity (c)
(a)
(b)
Figure 2 Histopathological findings. Auricular biopsy with hematoxylin-eosin staining at 9100 (a) and 940 (b). Note the small circular foci of cartilage surrounded by an important inflammatory infiltrate of plasma cells, lymphocytes, neutrophils, and eosinophils (b) (black arrows). Chondral damage has resulted in fibrous tracts and cartilage loss (white arrows) International Journal of Dermatology 2017
ª 2017 The International Society of Dermatology
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
Report
Table 1 Summarizes the results of the complementary tests before and after the treatment
Complementary Test Liver Profile Aspartate and alanine, aminotransferase, ɤ-glutamyl transferase, alkaline phosphatase, bilirubin test Kidney profile Creatinine, ureic nitrogen, urinalysis, ionogram, 24-hour urine protein test, microscopic hematuria. Hematological profile Complete blood count, extended peripheral blood, bone marrow biopsy, protein electrophoresis Immunologic Profile Rheumatoid factor, anti-citrullinated protein antibodies, antinuclear antibodies, anti-dsDNA antibodies, extractable nuclear antigens, APS profile, antineutrophil cytoplasmic antibodies Infectious profile VDRL, FTS-ABS, hepatotrope viral tests, human immunodeficiency virus antibody, tuberculin skin test, cytomegalovirus Another biochemical profile Troponin, glycated hemoglobin Activity markers Erythrocyte sedimentation rate (ESR) C-reactive protein (CRP). RPC disease activity index
Before treatment
After Treatment with infliximab - Follow-up 6 months
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
20 mm/h 25 mg/dl 89
5 mm/h 10 mg/dl 47
ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; APS, antiphospholipid syndrome; VDRL, venereal disease research laboratory; FTA-ABS, fluorescent treponemal antibody-absorption; -, unremarkable. Note the improvement of activity markers and RPDAI after the treatment with infliximab.
(a)
(b)
(c)
Figure 3 CT with intravenous contrast medium in trachea level. Note the circumferential tracheal wall thickening before the tracheostomy (a). Three-dimensional reconstruction of trachea using computed tomography imaging after the tracheostomy. The tracheostomy cannula is well positioned (black arrows). Distal to the cannula, there are several irregular narrowings of the trachea, main bronchi, and carina (white arrows). The diameter of the airway is recovered at the level of the segmental bronchi (b, c)
unavailable at that time, and IFX was the only solution to
not require ventilatory support and was withdrawn (Fig. 4), and
resolve the imminent death from respiratory collapse. The
the echocardiographic follow-up in the eighth week ruled out
doses of IFX were 5 mg/kg given at weeks 0, 2, 6, and 8. After
any abnormality. The same dose was then administered
the second dose, a rapid improvement in respiratory, chondral, and polyarticular compromise was found; inflammation and
monthly, and six months later, the patient remains in remission. Unfortunately, chondral nasal and ear damage, secondary hear-
peripheral joint pain decreased. The tracheal stenosis improved
ing loss, and joint damage are irreversible despite final RPDAI
with a more extended endoluminal diameter, which allowed a
score of 47 points with ESR 5 mm/h and CRP 10 mg/dl. To
better ventilatory pattern. At week 4 of follow-up, the patient did
date, the patient has had no adverse effects (see Table 1).
ª 2017 The International Society of Dermatology
International Journal of Dermatology 2017
3
4
Report
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
monocyte/macrophage system. Once activated, the macrophage produces IL-8, which attracts neutrophils to damage the cartilage with greater exposure of epitopes; cell signaling involves the activation of T and B cells with subsequent production of antibodies (IgG, IgA, IgM) and formation of immune complexes which could explain the vasculitis and glomerulonephritis in these patients.23–27
Figure 4 CT with intravenous contrast medium in trachea level after the treatment with infliximab. Note the decrease in thickness and the circumference of the tracheal wall
Discussion Etiology and pathophysiology The etiology of RPC remains unknown, and though there are several theories, the most current correspond to the genetic predisposition inculcated to the region Ir of human leukocyte antigen (HLA) class II, responsible for the expression of the disease in rodents and primates immunized with native type II or XI cartilage collagen.17 Another association is with HLA DR4/ DQ8 in antigen presenting cells and CD4T helper positive lymphocytes at lesion sites.18 Some evidence suggests that each type of cartilage and its respective antigens have shared epitopes of collagen type II, IX, and XI, and specific fractions of proteoglycan and matriline-1, all of which are components of the intracellular matrix of several tissues, including extrachondral involvement of the disease.17,19–22 In fact, the immunization of rats with matrilin-1 produces RPC-like syndrome. This could be correlated with a case series where the anti-matrilin 1 antibodies were presented in 69% of the cases of respiratory tract chondritis in patients with RPC; this increase in matrilin-1 antibodies resulted from the cartilage destruction.13,19–22 In addition, some cases suggest that events such as mechanical, chemical, infectious aggressions, and cancer directed toward cartilaginous structures may precipitate the onset of RPC in genetically susceptible patients.12,13,17,19–23 The cellular response appears to be mediated by cytokines expressed and stored by chondrocytes and CD4T helper such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF), all of which inhibit the activity of insulin-like growth factor, which is an essential factor for the anabolic function of the chondrocytes. It is possible that this explains the clinical improvement with some type of biological therapy. Other molecules involved are monocyte chemoattractant protein-1 and macrophage inflammatory proteins-1 beta, which activate the International Journal of Dermatology 2017
Clinical features and diagnosis The most frequent clinical manifestations are the chondral involvement of the nose and ears, being the deformities in “saddle nose” and “cauliflower the most characteristic sequels; the airway has a middle participation but is potentially fatal. In the cohort study by Dion et al.14 (N = 32/200), laryngotracheal symptoms occurred in 55% of the cases and were correlated with visible structural changes in up to 23%, and usually it requires invasive maneuvers with ventilatory support and extensive medication as in our case and other studies described.1–3,25,26,28,29 Chest radiography may reveal tracheal narrowing, consolidations, or atelectasis that are induced by airway obstruction, pulmonary edema, and calcification of tracheal or laryngeal cartilage.29–31 The CT scanning plays an important role for active inflammatory airway, and it helps to define the location and extent of the airway narrowing and wall thickening.30,31 However, tracheobronchial luminal narrowing is not specific to RPC, and other causes such as infection or amyloidosis should be considered.14,30,31 Fluorine-18 fluorodeoxyglucose plus PET/CT (positron emission tomography with multislice helical computed tomography) has been proven to be a useful radiological tool for assessing early organ involvement and determining the extent of inflammation before and after treatment.32 The main joint manifestations are arthralgias related to monooligoarticular arthritis of large and small joints. The studies of synovial fluid are negative, and the disease is adequately controlled with NSAIDs, in cases with low activity.1,2,9,14,15,28,29 Our case presented asymmetric polyarthralgias, so it was necessary to rule out other differential diagnoses such as connective tissue disease (CTD) or a myelodysplastic syndrome (MDS).14,28,29 The eye involvement is not a strange manifestation, being the scleritis and episcleritis are the earliest manifestations of RPC; however, posterior uveitis is the most severe ocular manifestation, as occurred in our patient, and these data are consistent with Dion J et al. cohort and Mayo Clinic study.2,30 The spectrum of cutaneous manifestations is very broad; three groups have been revealed, the first one related to RPC with MDS with a worse prognosis, the second related to vasculitis and CTD with RPC, and the third related only to RPC. In all groups, the most frequent manifestations were purpura and nodules (41%), followed by urticarial papules (32%), phlebitis (27%), and livedo reticularis (23%). In global terms, cutaneous manifestations were more related to MDS and vasculitis.5,12,14,24,26,28,29,36 In our patient, skin manifestations were not found (See Table 2).1–3,14,33–40 ª 2017 The International Society of Dermatology
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
Report
Table 2 Clinical features of relapsing polychondritis
Principal features
Present at disease onset (%)
Cumulative presence over disease course (%)
Dion J et al. Present at disease onset
Dion J et al. Present over disease course (%)
Other features
Ear involvement Auricular chondritis Reduced hearing Joint involvement Arthritis
43 7
89 40
41 –
89 27
Tinnitus, hypoacusia, and Meniere’s disease.
32
72
32
69
Chronic pain sternoclavicular, costochondral, and manubriosternal joints
Nose involvement Nasal chondritis Vestibular dysfunction Saddle nose Ocular inflammation Episcleritis Scleritis
21 4 11 18 – –
61 28 25 59 – –
22 – – 18 – –
63 – 15–10 56 – 8
Hypogeusia and secondary respiratory distress
Airway involvement Tracheal and bronchial stenosis
23 15
55 23
– –
– 22
Renal involvement Microhematuria Elevated creatinine
7 15 7
10 26 13
– – –
– – –
Skin involvement Vasculitis Isolated oral aphthosis Nodules on the limbs Purpura Sterile pustules Livedo reticularis Ulcerations Erythema elevatum diutinum
4–12 2 – – – – – – –
25–36 14 11 15 10 7 6 5 1
15 – – – – – – – –
29 50 – – – – – – –
Heart involvement Aortic regurgitation Mitral regurgitation Aortic valve Mitral valve Aortic aneurysm
– – – – –
10–12 7.7 1.8 1.6 4
– – – – –
27 17 12 – 10
Aortitis, pericarditis, coronary vasculitis, heart failure, heart block, IM, heart failure, and death
–
–
–
11 3.3
Hemiplegia, seizures, organic brain syndrome, dementia, myelitis, peripheral neuropathy, aseptic meningitis, lymphocytic meningoencephalitis, rhombencephalitis, limbic encephalitis
Nervous system involvement Cranial neuropathies of the second, sixth, seventh, and eighth nerves
Proptosis, uveitis, salmon patch conjunctival lesion and ulcerative keratitis Breathing distress and failure, malignancy, secondary infection, obstructive bronchiectasis and dynamic tracheal/bronchial collapse and death Mesangial expansion, IgA nephropathy, tubule interstitial nephritis and segmental necrotizing crescentic glomerulonephritis and death Complex aphthosis, bluish-red papules, purpura, pustules, nodules, superficial thrombophlebitis
Update and modified with permission from: McAdam L 1976; Michet CJ 1986; Marshall DA et al. 1992; Kent PD et al. 2004; Frances C 2001; Dion J 2016. The first and second columns represent the data derived from a large series of 337 patients. McAdam L 1976; Michet CJ. The third and fourth columns summarize the data obtained from 200 patients from Dion J. The fifth column synthesize the other clinical features of a large case series and reviews.
ª 2017 The International Society of Dermatology
International Journal of Dermatology 2017
5
6
Report
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
The histological findings help to guide the diagnosis in nonclassic cases. In the early stages, cartilage biopsy reveals a
the Fc (constant) domain is of human origin. It has been reported previously in other reviews by Kemta et al.40, which demon-
loss of basophil staining, mixed polymorphonuclear infiltrate in
strated rapid improvement in the signs of nasal, auricular, and
the dermis, and perivascular lymphohistiocytic infiltration. In
laryngotracheal chondritis and complications such as tracheal
later stages, there is loss of architecture, calcification areas,
thickening, dyspnea, dysphonia, obstructive ventilatory impair-
granulation tissue, and rearrangement of elastic fibers with
ment, and sensorineural deafness.40,41 Moreover, it was partially
fibrous tracts.23–25
effective to treat aortic involvement, aortitis, episcleritis, airway
Finally, in clinical practice, antibodies against type II collagen
scleritis, ulcerative keratitis, urticaria, cutaneous vasculitis, arthri-
and matriline-1 are not standardized because they have low sensitivity and specificity. Also, they may be produced in
tis, meningitis, encephalitis, and MAGIC syndrome (mouth and genital ulcers with RPC).41–47 The efficacy of IFX seems to last
rheumatoid arthritis, osteoarthritis of the hip and knee, seroneg-
over 9 months up to three and allows steroid-sparing.29 Further-
ative spondyloarthropathies, and CTD such as systemic lupus €gren’s syndrome. In erythematosus, systemic sclerosis, and Sjo
more, the IFX has been used in some cases of RPC with CTD
fact, it is not uncommon to find evidence of other autoimmuni-
case, the patient presented imminent risk of death, and this treat-
ties or MDS accompanying the RPC; for this reason, it is impor-
ment resulted in a remarkable improvement of laryngotracheal,
tant
exclude
bronchial, costochondral, and articular compromise. As a curious
them.1,2,15,26,28,29 CRP and ESR are the most common laboratory used to evaluate the activity disease. However, approxi-
fact, visual acuity improved over the second week of biological treatment, which did not respond so effectively to the topical cor-
mately more than 10% of patients have a normal CRP level
ticosteroid. ETA (50 mg/week), a fusion protein between a
even during flares of the disease.14,16,29
human IgG1 Fc tail and TNF receptor and ADA (40 mg/
Treatment and prognosis RPC does not have an established management algorithm; the treatments are guided on empirical experience and RPDAI.1–3,16,26 The first line of management are oral steroids, which are used as maintenance therapy, NSAIDs are used for pain control and inflammation in nonsevere forms of auricular or nasal chondritis and arthritis. Parenteral corticosteroids (methylprednisone 1 g/day) and dapsone (50 to 100 mg/day-25 mg increments every one to two weeks) may be helpful for extra chondral involvement. However, they should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency or history of allergy. Azathioprine (2 mg/kg/day for 2 weeks), cyclophosphamide (1 mg/kg/day for 2 weeks with 25 mg increments every 2 weeks), and cyclosporine (5 mg/kg/ day) are considered as second line therapy. These are used to obtain better control of corticosteroid-resistant, corticosteroidsparing effect or if the first line therapy has failed.4,14,15,26,29 The available information on the use of methotrexate is very limited, and the risk of hepatotoxicity associated with the use of azathioprine should be considered. Physicians using these agents should be familiar with the adverse effects of each one. The third line of management is the biological therapy, used in severe forms of disease when second line therapies have failed. The TNF-alpha antagonists are the most effective in RPC; a broad review by Mathian et al.29, reported that the main TNFalpha antagonist agents used are IFX, ETA, and adalimumab (ADA), of which the IFX has management evidence in different multisystem compromises. In our case, this was an additional reason to choose IFX between the different TNF-alpha antagonist and another type of biological therapy; IFX (3–10 mg/kg every 6–8 weeks) is a chimeric monoclonal antibody to TNFalpha, in which the fab (variable) domain is of murine origin and
chondral, eye, and skin involvement with livedo reticularis and
to
consider
complementary
test
to
and vasculitis overlap such as Takayasu arteritis.41–47 In our
m3 weeks) fully human IG1 antibody, showed similar efficacy for
International Journal of Dermatology 2017
Raynaud syndrome with skin necrosis; however, the clinical response with ADA was longer than the IFX.29,40,48 As for the other biological therapies, the IL-1 receptor antagonist, anakinra (100 mg/day), has been used after a lack of efficacy of anti-TNF agents, and the clinical spectrum is similar to them.49,50 Abatacept (750 mg/mo) has limited reports and is used when 3 anti-TNF agents plus anakinra have failed.51 TCZ (8 mg/kg/mo), an anti-IL-6 receptor blocker, is perhaps the most effective biological therapy for all, but its efficacy in airway involvement is the same as anti-TNF agents.29,40,52 In our case, TCZ is used in our hospital for patients with rheumatoid arthritis and other spondyloarthropathies associated with inflammatory bowel disease; however, it was not possible to use in our patients because it was not accessible. Finally, rituximab, a chimeric Mab against the protein CD20, which depletes B cells, has few reports with inconclusive results.53 In our hospital, it is quite difficult to obtain the other agents mentioned because of lack of health policies in our country.
Conclusion RPC is a progressive and potentially lethal autoimmune disease; the experience treatment is extremely limited with heterogeneous results because of the rarity of this disease and the varied clinical manifestations that do not allow to perform clinical trials for establishing evidence-based therapeutic recommendations. For this reason, the physician must be trained in the recognition of all clinical possibilities to not delay its treatment. We present a case of RPC in which an imminent death was avoided. This case represents the teamwork of the dermatology and rheumatology departments. ª 2017 The International Society of Dermatology
Cuestas et al.
Ethical standards and consent This case report was approved by the Institutional Ethical Com, mittee from Samaritana, University Hospital - ESE, Bogota Colombia. All techniques were performed according to the Helsinki declaration of 1975 and all modifications about it. In addition, informed consent was obtained from the patient for publication of this report and any accompanying images.
Acknowledgments Drs. Daniel Mauricio Cuestas and Ingrid Galvis want to extend ~ aranda, and a special thanks to Drs. Sergio Mora, Elkin Pen Carolina Cortes for their love of science. This study did not receive any type of funding.
Reference 1 McAdam LP, O’Hanlan MA, Bluestone R, et al. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore) 1976; 55: 193–215. 2 Kent PD, Michet CJ, Luthra HS. Relapsing polychondritis. Curr Opin Rheumatol 2004; 16: 56–61. 3 Rafeq S, Trentham D, Ernst A. Pulmonary manifestations of relapsing polychondritis. Clin Chest Med 2010; 31: 513–518. ~as C, et al. Relapsing 4 Quintana Duque M.A, Toro CE, Can polychondritis. A study of 19 cases in Colombia. Salud Uninorte. Barranquilla (Col.) 2007; 23: 1–8. 5 Tronquoy AF, Quatrebarbes J, Picard D, et al. Papular and annular fixed urticarial eruption: a characteristic skin manifestation in patients with relapsing polychondritis. J Am Acad Dermatol 2011; 65: 1161–1166. 6 Jaksch-Wartenhorst R. Polychondropathia. Wien Arch J Intern 1923; 6:93. 7 Pearson CM, Kline HM, Newcomer VD. Relapsing polychondritis. N Engl J Med 1960; 263: 51–58. 8 Damiani JM, Levine HM. Relapsing polychondritis: report of ten cases. Laryngoscope. 1979; 89: 929–946. th A, Pa ll N, Molna r K, et al. A nationwide study of the 9 Horva epidemiology of relapsing polychondritis. Clin Epidemiol 2016; 8: 211. 10 Hazra N, Dregan A, Charlton J, et al. Incidence and mortality of relapsing polychondritis in the UK: a population-based cohort study. Rheumatology (Oxford) 2015; 54: 2181. 11 Sacco O, Fregonese B, Oddone M, et al. Severe endobronchial obstruction in a girl with relapsing polychondritis: treatment with Nd YAG laser and endobronchial silicon stent. Eur Respir J 1997; 10: 494–496. 12 Smylie A, Malhotra N, Brassard A. Relapsing polychondritis: a review and guide for the dermatologist. Am J Clin Dermatol 2016; 18: 77–89. 13 Arnaud L, Mathian A, Haroche J, et al. Pathogenesis of relapsing polychondritis: a 2013 update. Autoimmun Rev 2014; 13: 90–95. ne D, et al. Relapsing 14 Dion J, Costedoat-Chalumeau N, Se polychondritis can be characterized by three different clinical phenotypes: analysis of a recent series of 142 patients. Arthritis Rheumatol 2016; 68: 2992. 15 Sharma A, Gnanapandithan K, Sharma K, et al. Relapsing polychondritis: a review. Clin Rheumatol 2013; 32: 1575–1583.
ª 2017 The International Society of Dermatology
Relapsing polychondritis, an dermatological urgency
Report
16 Arnaud L, Devilliers H, Peng SL, et al. The Relapsing Polychondritis Disease Activity Index: development of a disease activity score for relapsing polychondritis. Autoimmun Rev 2012; 12: 204–209. 17 Zeuner M, Straub RH, Rauh G, et al. Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients. J Rheumatol 1997; 24: 96. 18 Lamoureux JL, Buckner JH, David CS, et al. Mice expressing HLA-DQ6alpha8beta transgenes develop polychondritis spontaneously. Arthritis Res Ther 2006; 8: R134. 19 Buckner JH, Van Landeghen M, Kwok WW, et al. Identification of type II collagen peptide 261-273-specific T cell clones in a patient with relapsing polychondritis. Arthritis Rheum 2002; 46: 238. 20 Hansson AS, Johannesson M, Svensson L, et al. Relapsing polychondritis, induced in mice with matrilin 1, is an antibodyand complement-dependent disease. Am J Pathol 2004; 164: 959. re G, Hartmann DJ, Vignon E, et al. Antibodies to types 21 Charrie I, II, IX, and XI collagen in the serum of patients with rheumatic diseases. Arthritis Rheum 1988; 31: 325. 22 Hansson AS, Heinegard D, Piette JC, et al. The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis. Arthritis Rheum 2001; 44: 2402. 23 Lahmer T, Treiber M, Von WA, et al. Relapsing polychondritis: an autoimmune disease with many faces. Autoimmun Rev 2010; 9: 540–546. 24 Rapini R, Warner N. Relapsing polychondritis. Clin Dermatol 2006; 24: 482–48. 25 Chopra R, Chaudhary N, Kay J. Relapsing polychondritis. Rheum Dis Clin N Am 2013; 39: 263–276. 26 Vitale A, Sota J, Lopalco G, et al. Relapsing Polychondritis: an update on pathogenesis, clinical features, diagnostic tools, and therapeutic perspectives. Curr Rheumatol Rep 2015; 18: 1–12. 27 Stabler T, Piette JC, Chevalier X, et al. Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation. Arthritis Rheum 2004; 50: 3663. 28 Letko E, Zafirakis P, Baltatzis S, et al. Relapsing polychondritis: a clinical review. Semin Arthritis Rheum 2002; 31: 384–395. 29 Mathian A, Miyara M, Cohen F, et al. Relapsing polychondritis: a 2016 update on clinical features, diagnostic tools, treatment and biological drug use. Best Pract Res Clin Rheumatol 2016; 30: 316–333. 30 Zhou H, Su M, Li L. 18F-FDG PET/CT imaging of relapsing polychondritis. Medicine 2016; 95: 33. 31 Thaiss WM, Nikolaou K, Spengler W, et al. Imaging diagnosis in relapsing polychondritis and correlation with clinical and serological data. Skeletal Radiol 2016; 3: 339–346. 32 Yamashita H, Takahashi H, Kubota K, et al. Utility of fluorodeoxyglucose positron emission tomography/computed tomography for early diagnosis and evaluation of disease activity of relapsing polychondritis: a case series and literature review. Rheumatology 2014; 53: 1482–1490. 33 Chang-Miller A, Okamura M, Torres VE, et al. Renal involvement in relapsing polychondritis. Medicine (Baltimore) 1987; 66: 202. 34 Marshall DA, Jackson R, Rae AP, et al. Early aortic valve cusp rupture in relapsing polychondritis. Ann Rheum Dis 1992; 51: 413. 35 Buckley LM, Ades PA. Progressive aortic valve inflammation occurring despite apparent remission of relapsing polychondritis. Arthritis Rheum 1992; 35: 812.
International Journal of Dermatology 2017
7
8
Report
Relapsing polychondritis, an dermatological urgency
s C, el Rassi R, Laporte JL, et al. Dermatologic 36 France manifestations of relapsing polychondritis. A study of 200 cases at a single center. Medicine (Baltimore) 2001; 80: 173–179. 37 Longo L, Greco A, Rea A, et al. Relapsing polychondritis: a clinical update. Autoimmun Rev 2016; 15: 539–543. 38 Jun S, Hiroshi O, Yoshihisa Y, et al. Cutaneous manifestations of patients with relapsing polychondritis: an association with extracutaneous complications. Clin Rheumatol 2016; 35: 781. 39 Ormerod AD, Clark LJ. Relapsing polychondritis–treatment with cyclosporin A. Br J Dermatol 1992; 127: 300. 40 Kemta LF, Kraus VB, Chevalier X. Biologics in relapsing polychondritis: a literature review. Semin Arthritis Rheum 2012; 41: 712–719. 41 Mpofu S, Estrach C, Curtis J, et al. Treatment of respiratory complications in recalcitrant relapsing polychondritis with infliximab. Rheumatology 2003; 42: 1117–1118. 42 Cazabon S, Over K, Butcher J. The successful use of infliximab in resistant relapsing polychondritis and associated scleritis. Eye (Lond) 2005; 19: 222. 43 Ratzinger G, Kuen-Spiegl M, Sepp N. Successful treatment of recalcitrant relapsing polychondritis with monoclonal antibodies. J Eur Acad Dermatol Venereol 2009; 23: 474–475. 44 Carter JD. Treatment of relapsing polychondritis with a TNF antagonist. J Rheumatol 2005; 32: 1413. 45 Marie I, Lahaxe L, Josse S, et al. Sustained response to infliximab in a patient with relapsing polychondritis with aortic involvement. Rheumatology (Oxford) 2009; 48: 1328–1329.
International Journal of Dermatology 2017
Cuestas et al.
46 Saadoun D, Deslandre CJ, Allanore Y, et al. Sustained response to infliximab in 2 patients with refractory relapsing polychondritis. J Rheumatol 2003; 30: 1394–1395. 47 Soares de Barros AP, Nakamura NA, Santana Tde F, et al. Infliximab in relapsing polychondritis. Rev Bras Rheumatol 2010; 50: 211–221. 48 Moulis G, Sailler L, Pugnet G, et al. Biologics in relapsing polychondritis: a case series. Clin Exp Rheumatol 2013; 31: 937e9. 49 Vounotrypidis P, Sakellariou GT, Zisopoulos D, et al. Refractory relapsing polychondritis: rapid and sustained response in the treatment with an IL-1 receptor antagonist (anakinra). Rheumatol Oxf 2006; 45: 491e2. 50 Wendling D, Govindaraju S, Prati C, et al. Efficacy of anakinra in a patient with refractory relapsing polychondritis. Jt Bone Spine 2008; 75: 622e4. 51 Moulis G, Sailler L, Astudillo L, et al. Abatacept for relapsing polychondritis. Rheumatology (Oxford) 2010; 49: 1019. 52 Kawai M, Hagihara K, Hirano T, et al. Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis. Rheumatology (Oxford) 2009; 48: 318–319. 53 Leroux G, Costedoat-Chalumeau N, Brihaye B, et al. Treatment of relapsing polychondritis with rituximab: a retrospective study of nine patients. Arthritis Rheum 2009; 61: 577e82.
ª 2017 The International Society of Dermatology
Relapsing polychondritis, an underestimated dermatological urgency: case report and literature review ~ aranda1,3, MD , Sergio Mora4, MD , Daniel Cuestas1,2, MD , Elkin Pen nica Patin ~ o1, MD , and Carolina Cortes1,3, MD , Ingrid Galvis4,5, MD , Mo 1,3 Oscar Velasquez , MD
1
Dermatology Service, Samaritana University Hospital - ESE, 2Dermatology Program, El Bosque University, 3 Dermatology Program, National University of Colombia, 4Rheumatology Service, Samaritana University Hospital - ESE, , and 5Radiology Program, La Bogota Sabana University, Chia, Coloumbia Correspondence Daniel Cuestas, MD Dermatology Service, University Hospital of , Colombia, the Samaritana ESE, Bogota Carrera 8 No. 0-29 Sur, Dermatology Program, El Bosque University., Av. Cra 9 No. 131A 02, Bogota Colombia E-mail: [email protected]
Abstract Background Relapsing polychondritis is an autoimmune multisystemic disease with primary chondral involvement. Its high mortality and morbidity make it a real clinical challenge. Case description A 32-year-old woman with a history of relapsing polychondritis, refractory to multiple treatments, with multisystem compromise, imminent risk of death due to severe tracheobronchial damage and difficult ventilatory support, and successful treatment with infliximab. Discussion and evaluation Several treatments have been described in the literature, such as nonsteroidal anti-inflammatory drugs, corticosteroids, dapsone, azathioprine, cyclosporine, cyclophosphamide, and methotrexate. However, the cases refractory to conventional therapy may lead to chronicity, irreversibility, and death. As a result, a third-line therapy could improve the prognosis of these patients. Conclusions Biological therapy is a good option for disease control and quality of life improvement. In addition, the physician should consider these treatments to avoid the chronicity and risk of death of these patients.
Funding: None Conflict of interest: None doi: 10.1111/ijd.13755
Background
(2:1 to 4:1) between the 4th to 5th decade of life, although it can also affect the pediatric population.1,4,9–11
Relapsing polychondritis (RPC) is an autoimmune multisystemic
The onset of the disease and the clinical characteristics may
disease with recurrent inflammation of three types of cartilage:
be different between each patient, being a clinical challenge that
hyaline, elastic, and fibrous. However, it possibly involves
allows a late diagnosis, resulting in cartilage destruction, great
another system, such as the ear, nose, airway, eyes, blood ves-
morbidity, and mortality. Also, the treatment is not established, and there are no algorithms for the management of it, which
sels, heart, and skin.1–5 RPC was first described by Wartenhorst6 in 1923, but Pearson and colleagues,7 in 1960, described its recurrence. Years later, the diagnostic criteria were proposed
causes confusion in the medical field. However, owing to the
in 1976 by McAdam1 empirically, and these persist today. Dami-
tional immunosuppressants, the advent of biological therapy
ani and Levine8 proposed a modification of these criteria: for
represents a hopeful third line of management.1,9–15
resistance to corticosteroids and therapeutic failure with conven-
the diagnosis, (i) all patients had to have at least three or more McAdam diagnostic criteria, the histologic confirmation is not necessary; (ii) one or more of McAdam’s signs with histologic confirmation; (iii) chondritis in two or more different anatomic locations with response to steroids and/or dapsone treatment. The epidemiological data show an incidence of approximately
Case report A 32-year-old Colombian woman with 5 years of self-limited and recurrent episodes of erythema, edema, and auricular pain accompanied by rhinorrhea, dysphonia, and odynophagia con-
0.71, 2.0, and 3.5 per million from population studies in the Uni-
sulted several health centers that were treated with unknown
ted Kingdom, Hungary, and Minnesota, USA, respectively,2,9,10
antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs).
with a slight predominance in Caucasian women than in men
The patient improved modestly but without a clear diagnosis. In
ª 2017 The International Society of Dermatology
International Journal of Dermatology 2017
1
2
Report
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
the course of time, her clinical condition declined, and the patient began to lose her hearing by sensorineural deafness. At the first
Treatment with prednisolone 1 mg/kg/day, methotrexate 25 mg/week, and azathioprine 200 mg/day was considered,
hospital visit, she was in regular general conditions but without
but after 3 months of follow-up, the patient’s clinical condition
respiratory distress. Physical examination revealed a bilateral
worsened.
conjunctival injection without impairment of visual acuity, an
decreased visual acuity by posterior uveitis, and laryngotra-
important chondral commitment by a “saddle nose” deformity,
cheal chondral inflammation with progressive respiratory dis-
cauliflower ears, (Fig. 1a, b, c) tortuous external auditory ducts,
tress, so the mechanical ventilation was necessary with
and global costochondritis, mainly manubriosternal and stern-
tracheotomy because orotracheal intubation was not possible
oclavicular chondritis. In addition, large and small joints were affected by arthritis, the proximal interphalangeal joints, the
and even after the procedure, the patient continued with great respiratory distress, requiring ventilatory supervision in the
metacarpophalangeal joints, the left elbow, the shoulder, and the
intensive care unit. The complementary exams showed a
right knee were the most prominent. There was no involvement
chest x-ray without consolidation but with basal atelectasis of
of the lobules of the ears, skin manifestations, signs of renal
the left lower lobe, the arterial blood gases suggested a non-
damage (macroscopic hematuria) or neurological abnormal find-
compensated respiratory acidosis. We considered performing
ings (encephalitis or sensorimotor polyneuropathy). The car-
a computed tomography (CT) with additional three-dimensional
diopulmonary
physical
reconstruction (Fig. 3a, b, c) which showed stenosis in the
examination showed no signs of valve, myocardial, or pericardial dysfunction.
subglottic trachea, the main bronchi, and the carina; all these were distal to the tracheotomy, which explained the difficulty
auscultation
and
global
She
presented
increased
joint
pain,
fever,
The main suspected diagnosis was RPC; McAdam criteria
of orotracheal intubation and persistent respiratory distress
were applied with a total of 6 points, the first two modified crite-
despite the tracheotomy. The transthoracic doppler echocar-
ria were obtained, and an ear biopsy was performed (Fig. 2a,
diogram was normal.
b) which confirmed the diagnosis. The initial RPDAI (RPC Dis-
According to the imminent risk of death, the onset of biologi-
ease Activity Index)16 was 89 points with the erythrocyte sedi-
cal therapy was necessary. Three options for biological therapy
mentation rate (ESR) 20 mm/h and C-reactive protein (CRP)
in our hospital were available: tocilizumab (TCZ), infliximab
25 mg/dl; the other laboratory tests were negative (Table 1).
(IFX), and etanercept (ETA); however, TCZ and ETA were
(a)
(b)
(c)
Figure 1 Relapsing polychondritis findings. Lateral and front views of the nose with “saddle nose” deformity (back arrow) (a and b). Side view of the ear with “cauliflower” deformity (c)
(a)
(b)
Figure 2 Histopathological findings. Auricular biopsy with hematoxylin-eosin staining at 9100 (a) and 940 (b). Note the small circular foci of cartilage surrounded by an important inflammatory infiltrate of plasma cells, lymphocytes, neutrophils, and eosinophils (b) (black arrows). Chondral damage has resulted in fibrous tracts and cartilage loss (white arrows) International Journal of Dermatology 2017
ª 2017 The International Society of Dermatology
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
Report
Table 1 Summarizes the results of the complementary tests before and after the treatment
Complementary Test Liver Profile Aspartate and alanine, aminotransferase, ɤ-glutamyl transferase, alkaline phosphatase, bilirubin test Kidney profile Creatinine, ureic nitrogen, urinalysis, ionogram, 24-hour urine protein test, microscopic hematuria. Hematological profile Complete blood count, extended peripheral blood, bone marrow biopsy, protein electrophoresis Immunologic Profile Rheumatoid factor, anti-citrullinated protein antibodies, antinuclear antibodies, anti-dsDNA antibodies, extractable nuclear antigens, APS profile, antineutrophil cytoplasmic antibodies Infectious profile VDRL, FTS-ABS, hepatotrope viral tests, human immunodeficiency virus antibody, tuberculin skin test, cytomegalovirus Another biochemical profile Troponin, glycated hemoglobin Activity markers Erythrocyte sedimentation rate (ESR) C-reactive protein (CRP). RPC disease activity index
Before treatment
After Treatment with infliximab - Follow-up 6 months
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
(–)
20 mm/h 25 mg/dl 89
5 mm/h 10 mg/dl 47
ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; APS, antiphospholipid syndrome; VDRL, venereal disease research laboratory; FTA-ABS, fluorescent treponemal antibody-absorption; -, unremarkable. Note the improvement of activity markers and RPDAI after the treatment with infliximab.
(a)
(b)
(c)
Figure 3 CT with intravenous contrast medium in trachea level. Note the circumferential tracheal wall thickening before the tracheostomy (a). Three-dimensional reconstruction of trachea using computed tomography imaging after the tracheostomy. The tracheostomy cannula is well positioned (black arrows). Distal to the cannula, there are several irregular narrowings of the trachea, main bronchi, and carina (white arrows). The diameter of the airway is recovered at the level of the segmental bronchi (b, c)
unavailable at that time, and IFX was the only solution to
not require ventilatory support and was withdrawn (Fig. 4), and
resolve the imminent death from respiratory collapse. The
the echocardiographic follow-up in the eighth week ruled out
doses of IFX were 5 mg/kg given at weeks 0, 2, 6, and 8. After
any abnormality. The same dose was then administered
the second dose, a rapid improvement in respiratory, chondral, and polyarticular compromise was found; inflammation and
monthly, and six months later, the patient remains in remission. Unfortunately, chondral nasal and ear damage, secondary hear-
peripheral joint pain decreased. The tracheal stenosis improved
ing loss, and joint damage are irreversible despite final RPDAI
with a more extended endoluminal diameter, which allowed a
score of 47 points with ESR 5 mm/h and CRP 10 mg/dl. To
better ventilatory pattern. At week 4 of follow-up, the patient did
date, the patient has had no adverse effects (see Table 1).
ª 2017 The International Society of Dermatology
International Journal of Dermatology 2017
3
4
Report
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
monocyte/macrophage system. Once activated, the macrophage produces IL-8, which attracts neutrophils to damage the cartilage with greater exposure of epitopes; cell signaling involves the activation of T and B cells with subsequent production of antibodies (IgG, IgA, IgM) and formation of immune complexes which could explain the vasculitis and glomerulonephritis in these patients.23–27
Figure 4 CT with intravenous contrast medium in trachea level after the treatment with infliximab. Note the decrease in thickness and the circumference of the tracheal wall
Discussion Etiology and pathophysiology The etiology of RPC remains unknown, and though there are several theories, the most current correspond to the genetic predisposition inculcated to the region Ir of human leukocyte antigen (HLA) class II, responsible for the expression of the disease in rodents and primates immunized with native type II or XI cartilage collagen.17 Another association is with HLA DR4/ DQ8 in antigen presenting cells and CD4T helper positive lymphocytes at lesion sites.18 Some evidence suggests that each type of cartilage and its respective antigens have shared epitopes of collagen type II, IX, and XI, and specific fractions of proteoglycan and matriline-1, all of which are components of the intracellular matrix of several tissues, including extrachondral involvement of the disease.17,19–22 In fact, the immunization of rats with matrilin-1 produces RPC-like syndrome. This could be correlated with a case series where the anti-matrilin 1 antibodies were presented in 69% of the cases of respiratory tract chondritis in patients with RPC; this increase in matrilin-1 antibodies resulted from the cartilage destruction.13,19–22 In addition, some cases suggest that events such as mechanical, chemical, infectious aggressions, and cancer directed toward cartilaginous structures may precipitate the onset of RPC in genetically susceptible patients.12,13,17,19–23 The cellular response appears to be mediated by cytokines expressed and stored by chondrocytes and CD4T helper such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF), all of which inhibit the activity of insulin-like growth factor, which is an essential factor for the anabolic function of the chondrocytes. It is possible that this explains the clinical improvement with some type of biological therapy. Other molecules involved are monocyte chemoattractant protein-1 and macrophage inflammatory proteins-1 beta, which activate the International Journal of Dermatology 2017
Clinical features and diagnosis The most frequent clinical manifestations are the chondral involvement of the nose and ears, being the deformities in “saddle nose” and “cauliflower the most characteristic sequels; the airway has a middle participation but is potentially fatal. In the cohort study by Dion et al.14 (N = 32/200), laryngotracheal symptoms occurred in 55% of the cases and were correlated with visible structural changes in up to 23%, and usually it requires invasive maneuvers with ventilatory support and extensive medication as in our case and other studies described.1–3,25,26,28,29 Chest radiography may reveal tracheal narrowing, consolidations, or atelectasis that are induced by airway obstruction, pulmonary edema, and calcification of tracheal or laryngeal cartilage.29–31 The CT scanning plays an important role for active inflammatory airway, and it helps to define the location and extent of the airway narrowing and wall thickening.30,31 However, tracheobronchial luminal narrowing is not specific to RPC, and other causes such as infection or amyloidosis should be considered.14,30,31 Fluorine-18 fluorodeoxyglucose plus PET/CT (positron emission tomography with multislice helical computed tomography) has been proven to be a useful radiological tool for assessing early organ involvement and determining the extent of inflammation before and after treatment.32 The main joint manifestations are arthralgias related to monooligoarticular arthritis of large and small joints. The studies of synovial fluid are negative, and the disease is adequately controlled with NSAIDs, in cases with low activity.1,2,9,14,15,28,29 Our case presented asymmetric polyarthralgias, so it was necessary to rule out other differential diagnoses such as connective tissue disease (CTD) or a myelodysplastic syndrome (MDS).14,28,29 The eye involvement is not a strange manifestation, being the scleritis and episcleritis are the earliest manifestations of RPC; however, posterior uveitis is the most severe ocular manifestation, as occurred in our patient, and these data are consistent with Dion J et al. cohort and Mayo Clinic study.2,30 The spectrum of cutaneous manifestations is very broad; three groups have been revealed, the first one related to RPC with MDS with a worse prognosis, the second related to vasculitis and CTD with RPC, and the third related only to RPC. In all groups, the most frequent manifestations were purpura and nodules (41%), followed by urticarial papules (32%), phlebitis (27%), and livedo reticularis (23%). In global terms, cutaneous manifestations were more related to MDS and vasculitis.5,12,14,24,26,28,29,36 In our patient, skin manifestations were not found (See Table 2).1–3,14,33–40 ª 2017 The International Society of Dermatology
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
Report
Table 2 Clinical features of relapsing polychondritis
Principal features
Present at disease onset (%)
Cumulative presence over disease course (%)
Dion J et al. Present at disease onset
Dion J et al. Present over disease course (%)
Other features
Ear involvement Auricular chondritis Reduced hearing Joint involvement Arthritis
43 7
89 40
41 –
89 27
Tinnitus, hypoacusia, and Meniere’s disease.
32
72
32
69
Chronic pain sternoclavicular, costochondral, and manubriosternal joints
Nose involvement Nasal chondritis Vestibular dysfunction Saddle nose Ocular inflammation Episcleritis Scleritis
21 4 11 18 – –
61 28 25 59 – –
22 – – 18 – –
63 – 15–10 56 – 8
Hypogeusia and secondary respiratory distress
Airway involvement Tracheal and bronchial stenosis
23 15
55 23
– –
– 22
Renal involvement Microhematuria Elevated creatinine
7 15 7
10 26 13
– – –
– – –
Skin involvement Vasculitis Isolated oral aphthosis Nodules on the limbs Purpura Sterile pustules Livedo reticularis Ulcerations Erythema elevatum diutinum
4–12 2 – – – – – – –
25–36 14 11 15 10 7 6 5 1
15 – – – – – – – –
29 50 – – – – – – –
Heart involvement Aortic regurgitation Mitral regurgitation Aortic valve Mitral valve Aortic aneurysm
– – – – –
10–12 7.7 1.8 1.6 4
– – – – –
27 17 12 – 10
Aortitis, pericarditis, coronary vasculitis, heart failure, heart block, IM, heart failure, and death
–
–
–
11 3.3
Hemiplegia, seizures, organic brain syndrome, dementia, myelitis, peripheral neuropathy, aseptic meningitis, lymphocytic meningoencephalitis, rhombencephalitis, limbic encephalitis
Nervous system involvement Cranial neuropathies of the second, sixth, seventh, and eighth nerves
Proptosis, uveitis, salmon patch conjunctival lesion and ulcerative keratitis Breathing distress and failure, malignancy, secondary infection, obstructive bronchiectasis and dynamic tracheal/bronchial collapse and death Mesangial expansion, IgA nephropathy, tubule interstitial nephritis and segmental necrotizing crescentic glomerulonephritis and death Complex aphthosis, bluish-red papules, purpura, pustules, nodules, superficial thrombophlebitis
Update and modified with permission from: McAdam L 1976; Michet CJ 1986; Marshall DA et al. 1992; Kent PD et al. 2004; Frances C 2001; Dion J 2016. The first and second columns represent the data derived from a large series of 337 patients. McAdam L 1976; Michet CJ. The third and fourth columns summarize the data obtained from 200 patients from Dion J. The fifth column synthesize the other clinical features of a large case series and reviews.
ª 2017 The International Society of Dermatology
International Journal of Dermatology 2017
5
6
Report
Cuestas et al.
Relapsing polychondritis, an dermatological urgency
The histological findings help to guide the diagnosis in nonclassic cases. In the early stages, cartilage biopsy reveals a
the Fc (constant) domain is of human origin. It has been reported previously in other reviews by Kemta et al.40, which demon-
loss of basophil staining, mixed polymorphonuclear infiltrate in
strated rapid improvement in the signs of nasal, auricular, and
the dermis, and perivascular lymphohistiocytic infiltration. In
laryngotracheal chondritis and complications such as tracheal
later stages, there is loss of architecture, calcification areas,
thickening, dyspnea, dysphonia, obstructive ventilatory impair-
granulation tissue, and rearrangement of elastic fibers with
ment, and sensorineural deafness.40,41 Moreover, it was partially
fibrous tracts.23–25
effective to treat aortic involvement, aortitis, episcleritis, airway
Finally, in clinical practice, antibodies against type II collagen
scleritis, ulcerative keratitis, urticaria, cutaneous vasculitis, arthri-
and matriline-1 are not standardized because they have low sensitivity and specificity. Also, they may be produced in
tis, meningitis, encephalitis, and MAGIC syndrome (mouth and genital ulcers with RPC).41–47 The efficacy of IFX seems to last
rheumatoid arthritis, osteoarthritis of the hip and knee, seroneg-
over 9 months up to three and allows steroid-sparing.29 Further-
ative spondyloarthropathies, and CTD such as systemic lupus €gren’s syndrome. In erythematosus, systemic sclerosis, and Sjo
more, the IFX has been used in some cases of RPC with CTD
fact, it is not uncommon to find evidence of other autoimmuni-
case, the patient presented imminent risk of death, and this treat-
ties or MDS accompanying the RPC; for this reason, it is impor-
ment resulted in a remarkable improvement of laryngotracheal,
tant
exclude
bronchial, costochondral, and articular compromise. As a curious
them.1,2,15,26,28,29 CRP and ESR are the most common laboratory used to evaluate the activity disease. However, approxi-
fact, visual acuity improved over the second week of biological treatment, which did not respond so effectively to the topical cor-
mately more than 10% of patients have a normal CRP level
ticosteroid. ETA (50 mg/week), a fusion protein between a
even during flares of the disease.14,16,29
human IgG1 Fc tail and TNF receptor and ADA (40 mg/
Treatment and prognosis RPC does not have an established management algorithm; the treatments are guided on empirical experience and RPDAI.1–3,16,26 The first line of management are oral steroids, which are used as maintenance therapy, NSAIDs are used for pain control and inflammation in nonsevere forms of auricular or nasal chondritis and arthritis. Parenteral corticosteroids (methylprednisone 1 g/day) and dapsone (50 to 100 mg/day-25 mg increments every one to two weeks) may be helpful for extra chondral involvement. However, they should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency or history of allergy. Azathioprine (2 mg/kg/day for 2 weeks), cyclophosphamide (1 mg/kg/day for 2 weeks with 25 mg increments every 2 weeks), and cyclosporine (5 mg/kg/ day) are considered as second line therapy. These are used to obtain better control of corticosteroid-resistant, corticosteroidsparing effect or if the first line therapy has failed.4,14,15,26,29 The available information on the use of methotrexate is very limited, and the risk of hepatotoxicity associated with the use of azathioprine should be considered. Physicians using these agents should be familiar with the adverse effects of each one. The third line of management is the biological therapy, used in severe forms of disease when second line therapies have failed. The TNF-alpha antagonists are the most effective in RPC; a broad review by Mathian et al.29, reported that the main TNFalpha antagonist agents used are IFX, ETA, and adalimumab (ADA), of which the IFX has management evidence in different multisystem compromises. In our case, this was an additional reason to choose IFX between the different TNF-alpha antagonist and another type of biological therapy; IFX (3–10 mg/kg every 6–8 weeks) is a chimeric monoclonal antibody to TNFalpha, in which the fab (variable) domain is of murine origin and
chondral, eye, and skin involvement with livedo reticularis and
to
consider
complementary
test
to
and vasculitis overlap such as Takayasu arteritis.41–47 In our
m3 weeks) fully human IG1 antibody, showed similar efficacy for
International Journal of Dermatology 2017
Raynaud syndrome with skin necrosis; however, the clinical response with ADA was longer than the IFX.29,40,48 As for the other biological therapies, the IL-1 receptor antagonist, anakinra (100 mg/day), has been used after a lack of efficacy of anti-TNF agents, and the clinical spectrum is similar to them.49,50 Abatacept (750 mg/mo) has limited reports and is used when 3 anti-TNF agents plus anakinra have failed.51 TCZ (8 mg/kg/mo), an anti-IL-6 receptor blocker, is perhaps the most effective biological therapy for all, but its efficacy in airway involvement is the same as anti-TNF agents.29,40,52 In our case, TCZ is used in our hospital for patients with rheumatoid arthritis and other spondyloarthropathies associated with inflammatory bowel disease; however, it was not possible to use in our patients because it was not accessible. Finally, rituximab, a chimeric Mab against the protein CD20, which depletes B cells, has few reports with inconclusive results.53 In our hospital, it is quite difficult to obtain the other agents mentioned because of lack of health policies in our country.
Conclusion RPC is a progressive and potentially lethal autoimmune disease; the experience treatment is extremely limited with heterogeneous results because of the rarity of this disease and the varied clinical manifestations that do not allow to perform clinical trials for establishing evidence-based therapeutic recommendations. For this reason, the physician must be trained in the recognition of all clinical possibilities to not delay its treatment. We present a case of RPC in which an imminent death was avoided. This case represents the teamwork of the dermatology and rheumatology departments. ª 2017 The International Society of Dermatology
Cuestas et al.
Ethical standards and consent This case report was approved by the Institutional Ethical Com, mittee from Samaritana, University Hospital - ESE, Bogota Colombia. All techniques were performed according to the Helsinki declaration of 1975 and all modifications about it. In addition, informed consent was obtained from the patient for publication of this report and any accompanying images.
Acknowledgments Drs. Daniel Mauricio Cuestas and Ingrid Galvis want to extend ~ aranda, and a special thanks to Drs. Sergio Mora, Elkin Pen Carolina Cortes for their love of science. This study did not receive any type of funding.
Reference 1 McAdam LP, O’Hanlan MA, Bluestone R, et al. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore) 1976; 55: 193–215. 2 Kent PD, Michet CJ, Luthra HS. Relapsing polychondritis. Curr Opin Rheumatol 2004; 16: 56–61. 3 Rafeq S, Trentham D, Ernst A. Pulmonary manifestations of relapsing polychondritis. Clin Chest Med 2010; 31: 513–518. ~as C, et al. Relapsing 4 Quintana Duque M.A, Toro CE, Can polychondritis. A study of 19 cases in Colombia. Salud Uninorte. Barranquilla (Col.) 2007; 23: 1–8. 5 Tronquoy AF, Quatrebarbes J, Picard D, et al. Papular and annular fixed urticarial eruption: a characteristic skin manifestation in patients with relapsing polychondritis. J Am Acad Dermatol 2011; 65: 1161–1166. 6 Jaksch-Wartenhorst R. Polychondropathia. Wien Arch J Intern 1923; 6:93. 7 Pearson CM, Kline HM, Newcomer VD. Relapsing polychondritis. N Engl J Med 1960; 263: 51–58. 8 Damiani JM, Levine HM. Relapsing polychondritis: report of ten cases. Laryngoscope. 1979; 89: 929–946. th A, Pa ll N, Molna r K, et al. A nationwide study of the 9 Horva epidemiology of relapsing polychondritis. Clin Epidemiol 2016; 8: 211. 10 Hazra N, Dregan A, Charlton J, et al. Incidence and mortality of relapsing polychondritis in the UK: a population-based cohort study. Rheumatology (Oxford) 2015; 54: 2181. 11 Sacco O, Fregonese B, Oddone M, et al. Severe endobronchial obstruction in a girl with relapsing polychondritis: treatment with Nd YAG laser and endobronchial silicon stent. Eur Respir J 1997; 10: 494–496. 12 Smylie A, Malhotra N, Brassard A. Relapsing polychondritis: a review and guide for the dermatologist. Am J Clin Dermatol 2016; 18: 77–89. 13 Arnaud L, Mathian A, Haroche J, et al. Pathogenesis of relapsing polychondritis: a 2013 update. Autoimmun Rev 2014; 13: 90–95. ne D, et al. Relapsing 14 Dion J, Costedoat-Chalumeau N, Se polychondritis can be characterized by three different clinical phenotypes: analysis of a recent series of 142 patients. Arthritis Rheumatol 2016; 68: 2992. 15 Sharma A, Gnanapandithan K, Sharma K, et al. Relapsing polychondritis: a review. Clin Rheumatol 2013; 32: 1575–1583.
ª 2017 The International Society of Dermatology
Relapsing polychondritis, an dermatological urgency
Report
16 Arnaud L, Devilliers H, Peng SL, et al. The Relapsing Polychondritis Disease Activity Index: development of a disease activity score for relapsing polychondritis. Autoimmun Rev 2012; 12: 204–209. 17 Zeuner M, Straub RH, Rauh G, et al. Relapsing polychondritis: clinical and immunogenetic analysis of 62 patients. J Rheumatol 1997; 24: 96. 18 Lamoureux JL, Buckner JH, David CS, et al. Mice expressing HLA-DQ6alpha8beta transgenes develop polychondritis spontaneously. Arthritis Res Ther 2006; 8: R134. 19 Buckner JH, Van Landeghen M, Kwok WW, et al. Identification of type II collagen peptide 261-273-specific T cell clones in a patient with relapsing polychondritis. Arthritis Rheum 2002; 46: 238. 20 Hansson AS, Johannesson M, Svensson L, et al. Relapsing polychondritis, induced in mice with matrilin 1, is an antibodyand complement-dependent disease. Am J Pathol 2004; 164: 959. re G, Hartmann DJ, Vignon E, et al. Antibodies to types 21 Charrie I, II, IX, and XI collagen in the serum of patients with rheumatic diseases. Arthritis Rheum 1988; 31: 325. 22 Hansson AS, Heinegard D, Piette JC, et al. The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis. Arthritis Rheum 2001; 44: 2402. 23 Lahmer T, Treiber M, Von WA, et al. Relapsing polychondritis: an autoimmune disease with many faces. Autoimmun Rev 2010; 9: 540–546. 24 Rapini R, Warner N. Relapsing polychondritis. Clin Dermatol 2006; 24: 482–48. 25 Chopra R, Chaudhary N, Kay J. Relapsing polychondritis. Rheum Dis Clin N Am 2013; 39: 263–276. 26 Vitale A, Sota J, Lopalco G, et al. Relapsing Polychondritis: an update on pathogenesis, clinical features, diagnostic tools, and therapeutic perspectives. Curr Rheumatol Rep 2015; 18: 1–12. 27 Stabler T, Piette JC, Chevalier X, et al. Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation. Arthritis Rheum 2004; 50: 3663. 28 Letko E, Zafirakis P, Baltatzis S, et al. Relapsing polychondritis: a clinical review. Semin Arthritis Rheum 2002; 31: 384–395. 29 Mathian A, Miyara M, Cohen F, et al. Relapsing polychondritis: a 2016 update on clinical features, diagnostic tools, treatment and biological drug use. Best Pract Res Clin Rheumatol 2016; 30: 316–333. 30 Zhou H, Su M, Li L. 18F-FDG PET/CT imaging of relapsing polychondritis. Medicine 2016; 95: 33. 31 Thaiss WM, Nikolaou K, Spengler W, et al. Imaging diagnosis in relapsing polychondritis and correlation with clinical and serological data. Skeletal Radiol 2016; 3: 339–346. 32 Yamashita H, Takahashi H, Kubota K, et al. Utility of fluorodeoxyglucose positron emission tomography/computed tomography for early diagnosis and evaluation of disease activity of relapsing polychondritis: a case series and literature review. Rheumatology 2014; 53: 1482–1490. 33 Chang-Miller A, Okamura M, Torres VE, et al. Renal involvement in relapsing polychondritis. Medicine (Baltimore) 1987; 66: 202. 34 Marshall DA, Jackson R, Rae AP, et al. Early aortic valve cusp rupture in relapsing polychondritis. Ann Rheum Dis 1992; 51: 413. 35 Buckley LM, Ades PA. Progressive aortic valve inflammation occurring despite apparent remission of relapsing polychondritis. Arthritis Rheum 1992; 35: 812.
International Journal of Dermatology 2017
7
8
Report
Relapsing polychondritis, an dermatological urgency
s C, el Rassi R, Laporte JL, et al. Dermatologic 36 France manifestations of relapsing polychondritis. A study of 200 cases at a single center. Medicine (Baltimore) 2001; 80: 173–179. 37 Longo L, Greco A, Rea A, et al. Relapsing polychondritis: a clinical update. Autoimmun Rev 2016; 15: 539–543. 38 Jun S, Hiroshi O, Yoshihisa Y, et al. Cutaneous manifestations of patients with relapsing polychondritis: an association with extracutaneous complications. Clin Rheumatol 2016; 35: 781. 39 Ormerod AD, Clark LJ. Relapsing polychondritis–treatment with cyclosporin A. Br J Dermatol 1992; 127: 300. 40 Kemta LF, Kraus VB, Chevalier X. Biologics in relapsing polychondritis: a literature review. Semin Arthritis Rheum 2012; 41: 712–719. 41 Mpofu S, Estrach C, Curtis J, et al. Treatment of respiratory complications in recalcitrant relapsing polychondritis with infliximab. Rheumatology 2003; 42: 1117–1118. 42 Cazabon S, Over K, Butcher J. The successful use of infliximab in resistant relapsing polychondritis and associated scleritis. Eye (Lond) 2005; 19: 222. 43 Ratzinger G, Kuen-Spiegl M, Sepp N. Successful treatment of recalcitrant relapsing polychondritis with monoclonal antibodies. J Eur Acad Dermatol Venereol 2009; 23: 474–475. 44 Carter JD. Treatment of relapsing polychondritis with a TNF antagonist. J Rheumatol 2005; 32: 1413. 45 Marie I, Lahaxe L, Josse S, et al. Sustained response to infliximab in a patient with relapsing polychondritis with aortic involvement. Rheumatology (Oxford) 2009; 48: 1328–1329.
International Journal of Dermatology 2017
Cuestas et al.
46 Saadoun D, Deslandre CJ, Allanore Y, et al. Sustained response to infliximab in 2 patients with refractory relapsing polychondritis. J Rheumatol 2003; 30: 1394–1395. 47 Soares de Barros AP, Nakamura NA, Santana Tde F, et al. Infliximab in relapsing polychondritis. Rev Bras Rheumatol 2010; 50: 211–221. 48 Moulis G, Sailler L, Pugnet G, et al. Biologics in relapsing polychondritis: a case series. Clin Exp Rheumatol 2013; 31: 937e9. 49 Vounotrypidis P, Sakellariou GT, Zisopoulos D, et al. Refractory relapsing polychondritis: rapid and sustained response in the treatment with an IL-1 receptor antagonist (anakinra). Rheumatol Oxf 2006; 45: 491e2. 50 Wendling D, Govindaraju S, Prati C, et al. Efficacy of anakinra in a patient with refractory relapsing polychondritis. Jt Bone Spine 2008; 75: 622e4. 51 Moulis G, Sailler L, Astudillo L, et al. Abatacept for relapsing polychondritis. Rheumatology (Oxford) 2010; 49: 1019. 52 Kawai M, Hagihara K, Hirano T, et al. Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis. Rheumatology (Oxford) 2009; 48: 318–319. 53 Leroux G, Costedoat-Chalumeau N, Brihaye B, et al. Treatment of relapsing polychondritis with rituximab: a retrospective study of nine patients. Arthritis Rheum 2009; 61: 577e82.
ª 2017 The International Society of Dermatology
