Polychondritis Research Articles

Treatment of relapsing polychondritis: a systematic review.

Due to the rarity of relapsing polychondritis (RP), no randomised clinical trial has been conducted to date and treatment remains empirical. We performed a systematic literature review to assess the efficacy of the main conventional immunosuppressants and biotherapies used in RP. We searched MEDLINE for original articles without language restriction. Abstracts from American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) were also considered for inclusion. Observational studies and clinical trials reporting on the efficacy of conventional immunosuppressants and biotherapies in adult patients with RP were selected and pooled response rates for each treatment were computed. Of 304 articles and abstracts identified, 31 underwent full-text review, and 11 were included. The studies involved a total of 177 patients, exposed to a total of 247 lines of treatments. The main treatments studied (by number of lines) were: TNF inhibitors (TNFi), n=92; methotrexate (MTX), n=38; tocilizumab (TCZ), n=26; anakinra (ANA), n=21; rituximab (RTX), n=16; abatacept (ABT), n=14; cyclophosphamide (CYC), n=14; azathioprine (AZA), n=13. The pooled response rates across studies were: 72% [95% CI: 42-95] for ABT, 66% [95% CI: 49-82] for TCZ, 64% [95% CI: 53-74] for TNFi, 56% [95% CI: 37-73] for MTX, 47% [95% CI: 26-68] for ANA, 43% [95% CI: 20-68] for RTX. Based on more limited data, response rates for AZA and CYC ranged from 38 to 100% and from 25 to 100%, respectively. In this systematic review of available evidence regarding the treatment of relapsing polychondritis, ABT, TCZ and TNFi were the drugs associated with the best outcomes. ABT efficacy must be interpreted in light of the small number of patients treated. While MTX had slightly less efficacy, it is one of the drugs for which data are the most robust.

Ocular Involvement in Relapsing Polychondritis.

Relapsing polychondritis (RPC) is a rare systemic immune-mediated disease characterized by recurrent inflammation of cartilaginous and proteoglycan-rich tissues throughout the body. Auricular, nasal, tracheal, and articular chondritis and arthritis are common systemic symptoms in patients with RPC. Ocular tissues are also targets of inflammation in RPC, and a variety of ocular symptoms are observed in approximately half of the patients with RPC. Scleritis/episcleritis, uveitis, and conjunctivitis are common symptoms associated with RPC. Less frequently, keratitis, retinopathy, optic neuropathy, muscle palsy, and orbital inflammation are also observed. Ocular inflammation could also be the first manifestation of RPC. Although RPC is a potentially fatal and sight-threatening disease, the rarity of the disease and its protean clinical presentation may lead to delayed diagnosis or misdiagnosis. Given the high prevalence of ocular involvement in RPC, to avoid misdiagnosis, physicians should be suspicious of RPC when they see patients with recurrent ocular inflammatory conditions and various systemic symptoms. In this article, we provide a comprehensive review of ocular manifestations associated with RPC.

Association of common variable immunodeficiency and rare and complex connective tissue and musculoskeletal diseases. A systematic literature review

To perform a systematic literature review (SLR) on the association of common variable immunodeficiency (CVID) and rare and complex connective tissue and musculoskeletal diseases, namely systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), idiopathic inflammatory myopathies (IIM), systemic sclerosis (SSc), relapsing polychondritis, antiphospholipid syndrome, immunoglobulin (Ig) G4-related disease, as well as undifferentiated and mixed connective tissue disease. An SLR on studies and cases about the association of CVID and rare and complex connective tissue and musculoskeletal diseases was performed. Animal studies were excluded. 170 publications fulfilled the inclusion criteria. Sjögren's syndrome was the most frequent connective tissue disease in CVID-patients. Most case reports exist on SLE and CVID with SLE mostly preceding the manifestation of CVID. Multiple cases were published reporting the concurrence of CVID and inclusion body myositis and single cases were found on CVID and antisynthetase syndrome, polymyositis, limited SSc and relapsing polychondritis, respectively. There are no cases of CVID and antiphospholipid syndrome, IgG4-related disease, as well as undifferentiated and mixed connective tissue disease. The concurrence of CVID and complex connective tissue and musculoskeletal diseases, especially SS, IIM, SSc and relapsing polychondritis is rare but relevant. The measurements of Ig-levels should be performed before the initiation of immunosuppressive therapy to allow for the differentiation of primary and secondary Ig-deficiency and substitute IG if necessary.

Membranous nephropathy complicating relapsing polychondritis: A case report

Background: Relapsing polychondritis is a rare systemic disease characterized by recurrent inflammation, and often destruction, of cartilaginous tissues. Renal manifestations are rare. Membranous nephropathy complicating relapsing polychondritis has been reported only once previously, and there is no standardized treatment for membranous nephropathy associated with relapsing polychondritis. Case presentation: A 67-year-old Caucasian man with a history of chronic renal disease presented with 9 months of progressive dyspnea on exertion and 5 months of erythema, pain, and collapse of auricular cartilage. Imaging studies confirmed active inflammation of laryngeal, auricular, and costal cartilage and he was diagnosed with relapsing polychondritis. Patient had longstanding proteinuria and renal biopsy demonstrated membranous nephropathy. Patient initially showed renal and respiratory improvement with etanercept, a tumor necrosis factor alpha inhibitor, treatment. However, subsequent disease and treatment-related complications led to a progressive overall clinical decline and patient died approximately 1 year following relapsing polychondritis diagnosis. Conclusion: Membranous nephropathy may rarely complicate relapsing polychondritis. In our case, both the cartilaginous inflammation and the renal disease improved after treatment with tumor necrosis factor alpha blockade, however complications of existing airway disease led to recurrent hospitalizations and eventually death.

Discordance in patient and physician global assessment in relapsing polychondritis.

Relapsing polychondritis (RP) is a rare, heterogeneous, systemic inflammatory disease that targets cartilage. Patient-reported outcome measures may differ from physician assessment. This study compared patient global assessment (PtGA) and physician global assessment (PhGA) scores in a prospective cohort of patients with RP. Adult patients with RP underwent a standardized comprehensive evaluation at ∼6 month intervals. At each visit, three physicians scored PhGA by consensus. The patient independently completed four patient-reported outcomes: PtGA, 36-item Short Form Health Survey (SF-36), Brief Illness Perception Questionnaire (BIPQ) and Multidimensional Fatigue Inventory (MFI). Patient-physician discordance was defined as a difference between PtGA and PhGA of ≥3 on a 0-10 scale. A total of 76 patients were evaluated over 154 visits. The median PhGA was 3 [interquartile range (IQR) 2-3] and the median PtGA was 5 (IQR 4-7). PtGA and PhGA were concordant in 66 visits (42.9%) and patients scored disease severity ≥3 points higher than physicians scored disease activity (positive discordance) in 84 visits (54.5%). Compared with visits with concordance, visits with positive discordance were associated with significantly worse scores on the MFI, BIPQ, SF-36 physical component score and SF-36 mental component score. Patients with RP typically self-report high PtGA that does not align with PhGA. Discordance is likely driven by the high physical and psychological burden of illness experienced by patients. Multifaceted treatment approaches that address the burden of disease in RP from the patient perspective are needed.

The New Device for Studying the Psychomotor Components of Writing

Relapsing polychondritis (RP) is characterized by recurrent systemic inflammation of the cartilages and is accompanied by central airway collapse. We report a case wherein three-dimensional imaging of respiratory system resistance (Rrs) and respiratory system reactance (Xrs) by using MostGraph (CHEST M.I., Tokyo, Japan), a forced oscillation system, revealed that Rrs and Xrs in the inspiratory and expiratory phases correlated with proximal airway collapse. The degree of difference in Rrs and Xrs between the supine and sitting positions reflected airway collapse more closely than did the pulmonary function test. MostGraph could be a useful tool for assessing airway collapse in RP.

Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS.

Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count <200 ×103 /μl differentiated VEXAS-RP from RP with 100% sensitivity and 96% specificity. Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.

MDS-029: Prevalence of VEXAS Syndrome in MDS/CMML Patients with Systemic Inflammatory and Auto-Immune Disease

Context: Systemic inflammatory and auto-immune diseases (SIAD) are observed in 25% of patients with MDS or CMML, who harbor a high frequency of mutations in TET2, IDH1/2 and SRSF2 as we previously reported (Zhao et al, Leukemia 2021). Recently, the identification of mutations in UBA1 in patients with autoinflammatory disorders, some of whom have dysplastic bone marrow, defined novel disease called VEXAS syndrome (Beck et al, NEJM 2020). Objective: To explore the prevalence of UBA1 mutations in our initial cohort of MDS/CMML patients with SIAD (n=85) (Zhao et al, Leukemia 2021). Design and Patients: All male patients for whom material was available (n=33) were analyzed for the presence of UBA1 mutations. Primary Outcome: UBA1 mutations screening with Sanger sequencing. Results: Four out of 33 (12%) patients had UBA1 mutations. All of them had MDS without excess of blasts. Cytomorphologic review of bone marrow smears showed numerous vacuoles in precursors in all 4 cases. Karyotype was normal in 3/4 patients, and one patient had deletion 9q. One patient also had somatic mutations in DNMT3A (VAF 11%) and TP53 (VAF 2%), and another patient had a mutation of TET2 (VAF 18%). Three patients in our MDS/CMML SIAD cohort had relapsing polychondritis, and 2 of them had UBA1 mutations, while 6 patients from our initial SIAD cohort had a diagnosis of Sweet syndrome, including 2 with UBA1 mutations. Three out of 4mut patients had steroid refractory SIAD and were heavily treated with other immunosuppressive therapies including methotrexate, azathioprine or cytokine targeting agents. At last follow-up, none of the 4 patients with UBA1 mutations had MDS progression, and one of them had died from a stroke, 2.4 years after MDS diagnosis. Conclusions: Our retrospective study represents the first assessment of VEXAS syndrome among patients with myeloid malignancies associated with SIAD. The low prevalence of UBA1 mutations in our cohort suggests that other pathological mechanisms may drive inflammation in the large majority of MDS/CMML patients with associated SIAD, likely in relation with mutations in epigenetic regulators TET2/IDH and SRSF2 as we previously proposed.

Subglottic Stenosis as an Isolated Clinical Manifestation in Relapsing Polychondritis – A Case Report

Relapsing Polychondritis is a rare, multisystem autoimmune disease still of unknown origin, characterized by recurrent inflammation of the hyaline cartilages. The involvement of Laryngotracheal cartilages in polychondritis is one of the most serious known complications, observed in 50% of patientswith worse prognosis. Among the causesof death, laryngotracheal stenosis associated with pneumonia or severe respiratory failure stands out, and may be found in 10% to 50% of patients with the disorder. We describe a case of relapsing polychondritis in a female patient, with dyspnea as an initial manifestation, in which Grade III Cotton-Myer Laryngotracheal Stenosis was later confirmed. During the 10 years of investigation, clinical treatment stabilized the disease, but the respiratory distress persisted, which prompted the patient to be submittedto surgical correction of laryngotracheal stenosis.

27641 Achieving remission of relapsing polychondritis: A case series observing diagnostic and therapeutic approaches

Introduction: Relapsing polychondritis (RP) is a rare autoimmune condition characterized by recurrent cartilaginous inflammation. Though auricular and nasal structures are most commonly affected, laryngotracheal and cardiovascular involvement may lead to fatal complications. Due to multisystem disease, diagnosis is challenging and a standard therapeutic regimen is not established. We aim to discuss current evaluation criteria and propose a therapeutic ladder.

Characteristics and Clinical Outcomes of 295 Patients With Relapsing Polychondritis.

This study analyzes the clinical features of Chinese patients with relapsing polychondritis (RP). The clinical data of 295 patients with RP at Beijing Tongren Hospital were retrospectively analyzed. The mean age of onset was 41.0 ± 15.0 years. The sex ratio was 1:1. Up to 70.5% of the patients had airway involvement during the disease course; among them, the larynx was most commonly affected (82.2%). One-quarter (25.7%) of the patients with laryngeal involvement underwent tracheotomy as a result of progressive dyspnea or acute laryngeal obstruction. Younger age at onset and respiratory symptoms at initial presentation were independent risk factors for tracheotomy in patients with RP with laryngeal involvement. The risk of tracheotomy in patients who presented with respiratory symptoms was 2.35 times higher than that of patients who presented with other symptoms (HR 2.35, 95% CI 1.23-4.50, P = 0.01). The risk of tracheotomy increased by 4.8% for every 1-year decrease in the age at onset (HR 0.95, 95% CI 0.93-0.97, P < 0.001). The incidence of lower respiratory tract infection was much higher in patients with airway involvement than in those without airway involvement. The main cause of death was respiratory failure as a result of airway obstruction. There is a high prevalence of airway involvement in Chinese patients with RP. Laryngeal involvement is associated with a high risk of death. More attention should be paid to patients with RP with laryngeal involvement who are young at disease onset and present with respiratory symptoms.

C-ANCA positivity in a patient with relapsing polychondritis: Co-incidence or not? A case and review of the literature

c-ANCA positivity in a patient with relapsing polychondritis: Co-incidence or not? A case and review of the literature

Propylthiouracil-Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitis after COVID-19 Vaccination.

We report the case of a patient who developed antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) after receiving the coronavirus disease 2019 (COVID-19) vaccine BNT162b (Pfizer–BioNTech). A 37-year-old Japanese woman had been taking propylthiouracil for Graves’ disease. She had erythema on her forearm on the 12th day after receiving the first dose of the vaccine, fever on the 13th day, and redness and swelling of her left auricle on the 25th day. Her serum myeloperoxidase-ANCA and proteinase 3-ANCA levels, which were negative before the Graves’ disease treatment, were elevated. She had unilateral auricular symptoms but no other typical relapsing polychondritis findings. She was diagnosed with propylthiouracil-induced AAV. She was treated with oral glucocorticoids, and her symptoms improved. Propylthiouracil is considered to be the main cause of the onset of AAV in this case, but it cannot be ruled out that BNT162b may have had some effect on the onset of the disease. Although the development of propylthiouracil-induced AAV in this case may have been incidental and unrelated to the vaccination, this report provides important data for evaluating the safety of the vaccine.

Presentation, Diagnosis, and Management of Subglottic and Tracheal Stenosis During Systemic Inflammatory Diseases

Subglottic stenosis (SGS) and tracheal stenosis (TS) are characterized by a narrowing of the airways. The goal of this study was to describe the characteristics and prognosis of nontraumatic and nontumoral SGS or TS. What are the inflammatory etiologies of SGS and TS, and what are their characteristics and prognosis? This multicenter, observational retrospective study was performed in patients with SGS or TS that was neither traumatic nor tumoral. Eighty-one patients were included, 33 (41%) with granulomatosis with polyangiitis (GPA) and 21 (26%) with relapsing polychondritis (RP). GPA-related stenoses exhibited circumferential subglottic narrowing in 85%of cases, without calcifications. In contrast, RP-related stenoses displayed anterior involvement in 76%, in a longer distance from vocal cords (4cm), with calcifications in 62%, and extension to bronchi in 86%. Other diagnoses included bullous dermatoses (n= 3), amyloidosis (n= 3), sarcoidosis (n= 2), and Crohn's disease (n= 2); the remaining stenoses (n= 15) were idiopathic. SGS/TS was the initial manifestation of the disease in 66%of cases, with a median interval from stenosis to disease diagnosis of 12months (interquartile range, 0-48months). Despite the use of glucocorticoids in 80%, combined with methotrexate in 49%, endoscopic procedures were required in 68%of patients. Relapses of stenoses occurred in 76%without any difference between causes (82%in GPA, 67%in RP, and 75%in idiopathic SGS/TS). Three patients died due to the stenosis, two of RP and one of GPA. These data show that GPA and RP are the two main inflammatory diseases presenting with SGS/TS. GPA-related stenoses are mostly subglottic and circumferential, whereas RP-related stenoses are mostly tracheal, anterior, and calcified with a frequent extension to bronchi. Relapses of stenoses are common, and relapse rates do not differ between causes. Diagnosis and management of SGS/TS require a multidisciplinary approach.

Serum MMP3 Correlated With IL1β Messenger RNA Expressions of Peripheral Blood Mononuclear Cells in Patients With Relapsing Polychondritis With Respiratory Involvement.

ObjectiveRespiratory involvement was intimately associated with poorer prognosis in patients with relapsing polychondritis (RP). We previously reported that high serum matrix metalloproteinase‐3 (MMP3) was frequently observed in patients with RP with respiratory involvement. Elevated MMP3 secreted through local inflammation may be associated with the development of airway lesions.MethodsWe collected peripheral blood mononuclear cells (PBMCs) and sera from 30 patients with RP and 14 healthy individuals. Interleukin (IL) 1β, IL6, and tumor necrosis factor (TNF) α messenger RNA (mRNA) expressions were analyzed in freshly isolated and cultured PBMCs with phytohemagglutinin and phorbol myristate acetate stimulation by real‐time reverse transcription polymerase chain reaction and serum MMP3 by enzyme‐linked immunosorbent assay (ELISA).ResultsWe confirmed our previous finding that patients with respiratory involvements showed higher serum MMP3 compared with patients lacking respiratory involvement. IL1β mRNA expression was significantly higher in patients with RP than in healthy individuals after mitogenic stimulation. TNFα mRNA expression after stimulation was significantly lower in patients with RP compared with in healthy individuals. We performed correlation analyses between MMP3 and cytokine mRNA expressions in patients with RP. In patients with respiratory involvement, MMP3 correlated with IL1β and IL6 after stimulation. In patients without respiratory involvement, no positive correlations between MMP3 and cytokine mRNA expressions were observed regardless of culture condition. We did not find any positive correlations between MMP3 and TNFα mRNA expression in patients with RP.ConclusionIt is possible that IL1β mRNA expression associates by some means with airway inflammation via the secretion of MMP3 in patients with RP. Involvement of proinflammatory cytokines, including IL1β, was suggested for the pathophysiology of airway lesions in patients with RP.

Hiding in plain sight - relapsing polychondritis disguised as uncontrolled asthma.

A 55-year-old man was evaluated at the emergency department because of increasing shortness of breath and cough [...]

Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis

ObjectivesTo determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 (UBA1).MethodsFourteen patients with RP who met...

Three new inflammatory markers C reactive protein to albumin ratio, neutrophil to lymphocyte ratio, and platelet to lymphocyte ratio correlated with relapsing polychondritis disease activity index.

The novel inflammatory markers C-reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) were associated with the disease activity of many autoimmune diseases. The aim of this study was to evaluate the association of these new inflammatory indexes with relapsing polychondritis disease activity index (RPDAI). The data of relapsing polychondritis (RP) patients hospitalized between 2004 and 2020 at Peking Union Medical College Hospital were collected. One of the exclusive criteria was that RP patients overlapped with other diseases. Another was the RP patients with incomplete data. A total of 170 RP patients and 170 healthy controls (HCs) were included. The association of new inflammatory makers with RPDAI was assessed by Spearman's correlation analysis. Compared to HCs, the CAR, NLR, and PLR were significantly higher in RP patients (both p < 0.001). The CAR, NLR, PLR, erythrocyte sedimentation rate and neutrophil counts in peripheral blood positively correlated with RPDAI. Blood albumin, lymphocyte count, hemoglobin (Hb) negatively correlated with RPDAI. The association of CAR, NLR, and PLR with RPDAI was demonstrated by Spearman's correlation analysis. The novel inflammatory markers CAR, NLR and PLR were associated with RPDAI. Key Points • This is the first research to explore the association of CAR, NLR, and PLR with disease activity in patients with RP • CAR, NLR, and PLR are positively correlated with RPDAI • CAR, NLR, and PLR might be the potential predictors of disease activity in RP.

Pathogenic UBA1 variants define a subset of relapsing polychondritis.

Two new studies have identified mutations in UBA1 associated with the newly identified condition VEXAS syndrome in cohorts of patients with relapsing polychondritis, supporting the concept that relapsing polychondritis is more than one disease.

Natural closing of a tracheal tear caused by intubation in a patient with relapsing polychondritis.

Key messageRelapsing polychondritis (RP) often develops into severe tracheobronchial stenosis with malacia. Although tracheal tears rarely occur by intubation, treatment decisions for tears can be difficult due to airway inflammation in RP patients. In this case, due to advanced age and immunosuppressive treatment, we decided against invasive surgery.