Autoimmunity and Autoinflammation: Relapsing Polychondritis and VEXAS Syndrome Challenge.

Relapsing polychondritis is a chronic autoimmune inflammatory condition characterized by recurrent episodes of inflammation at the level of cartilaginous structures and tissues rich in proteoglycans. The pathogenesis of the disease is complex and still incompletely elucidated. The data support the important role of a particular genetic predisposition, with HLA-DR4 being considered an allele that confers a major risk of disease occurrence. Environmental factors, mechanical, chemical or infectious, act as triggers in the development of clinical manifestations, causing the degradation of proteins and the release of cryptic cartilage antigens. Both humoral and cellular immunity play essential roles in the occurrence and perpetuation of autoimmunity and inflammation. Autoantibodies anti-type II, IX and XI collagens, anti-matrilin-1 and anti-COMPs (cartilage oligomeric matrix proteins) have been highlighted in increased titers, being correlated with disease activity and considered prognostic factors. Innate immunity cells, neutrophils, monocytes, macrophages, natural killer lymphocytes and eosinophils have been found in the perichondrium and cartilage, together with activated antigen-presenting cells, C3 deposits and immunoglobulins. Also, T cells play a decisive role in the pathogenesis of the disease, with relapsing polychondritis being considered a TH1-mediated condition. Thus, increased secretions of interferon γ, interleukin (IL)-12 and IL-2 have been highlighted. The "inflammatory storm" formed by a complex network of pro-inflammatory cytokines and chemokines actively modulates the recruitment and infiltration of various cells, with cartilage being a source of antigens. Along with RP, VEXAS syndrome, another systemic autoimmune disease with genetic determinism, has an etiopathogenesis that is still incompletely known, and it involves the activation of the innate immune system through different pathways and the appearance of the cytokine storm. The clinical manifestations of VEXAS syndrome include an inflammatory phenotype often similar to that of RP, which raises diagnostic problems. The management of RP and VEXAS syndrome includes common immunosuppressive therapies whose main goal is to control systemic inflammatory manifestations. The objective of this paper is to detail the main etiopathogenetic mechanisms of a rare disease, summarizing the latest data and presenting the distinct features of these mechanisms.

Progress and challenges in the use of blood biomarkers in relapsing polychondritis.

Relapsing polychondritis (RP) is a rare inflammatory disease with significant individual heterogeneity that involves systemic organs. The diagnosis of RP mainly depends on the clinical manifestations; currently, there are no molecular biomarkers routinely evaluated in clinical practice. Biomarkers have diagnostic or monitoring values and can predict response to treatment or the disease course. Over the years, many biomarkers have been proposed to facilitate diagnosis and prognosis. Unfortunately, ideal biomarkers to diagnose RP have not yet been discovered. Most of the molecular biomarkers in RP are immunological biomarkers, with autoantibodies and proteins related to cartilage damage in the blood being the most common. Alterations in some genes (HLA typing and UBA1 somatic mutation) were detected in patients with RP, which could serve as a potential biomarker for the diagnosis of RP. Moreover, proinflammatory cytokines and lymphocyte levels, and certain laboratory tests, have certain values of RP diagnosis and disease activity assessment but lack specificity and sensitivity. This review describes the different types of biomarkers and their clinical correlation with respect to the diagnosis of RP and disease activity. Research on biomarkers and disease pathology is ongoing to identify the ideal biomarkers that are sensitive and specific for RP.

Coexistence of relapsing polychondritis and eosinophilic granulomatous with polyangiitis: A rare entity.

Abstract: Relapsing polychondritis (RP) is a a rare multisystemic disease and it affects cartilaginous tissue and proteoglycan rich organs. The spectrum of clinical features are intermittent inflammation involving especially the auricular and nasal regions. In some patients with RP, systemic vasculitis, autoimmune diseases or malignancy may accompany. Although rare, any of the ANCA-associated vasculitis have been reported in patients with RP. Eosinophilic granulomatous with polyangiitis (EGPA) is a multisystem small vessel vasculitis associated with asthma and eosinophilia. Here we present a case of coexistence of RP and EGPA.

Relapsing Polychondritis in a Patient with Ankylosing Spondylitis under Two Different Tumor Necrosis Factor Alpha Inhibitors Treatment.

Abstract: Relapsing polychondritis (RP) is a rare autoimmune disease char-acterized by multi-systemic involvement characterized by recurrent and progressive inflammation of the cartilaginous tissue. Auricular inflammation is a characteristic finding of RP. Anti-tumor necrosis fac-tor alpha (anti-TNF) is a highly effective drug used in the treatment of inflammatory arthritis. There are several case reports showing potential relationship between the RP development and anti-TNF treatment. Here, we present a case of RP in a patient with ankylosing spondylitis under the two different tumor necrosis factor alpha inhibitors therapy.

Ultrasonography of auricular cartilage is a potential tool for diagnosing relapsing polychondritis and monitoring disease activity.

AIM: To assess the clinical utility of ultrasonography in the diagnosis and monitoring of disease activity in relapsing polychondritis (RP). METHODS: Auricular and nasal chondritis of 6 patients with RP were assessed by ultrasonography before treatment initiation. Changes in the ultrasonographic and clinical findings and serum inflammatory markers were longitudinally assessed. Ultrasonography was also performed in 6 patients with repeat ear trauma, 6 patients with auricular cellulitis and 6 healthy controls for comparison among groups. RESULTS: In all cases of RP, ultrasonographic findings before treatment revealed low-echoic swollen auricular and nasal cartilage and perichondral soft-tissue with increased power Doppler signals (PDS) corresponding to biopsy findings. After 2-month treatment with prednisolone (PSL) combined with methotrexate, clinical and serum inflammatory markers were completely resolved. Although swollen perichondral soft-tissue, cartilage and PDS on auricular ultrasonography were also significantly improved, PDS remained in 2 of 6 cases, which showed flare early after tapering PSL. Finally, ultrasonographic findings of RP were substantially differentiated between patients with repeat trauma and cellulitis and healthy controls based on the thickness of soft tissue around the cartilage, PDS and subperichondral serous effusion. CONCLUSION: Assessment of RP lesions by ultrasonography is useful for the evaluation of cartilaginous lesions and monitoring of disease activity, especially when considering the treatment response and the timing of drug tapering.

Relapsing polychondritis after treatment with PD-1 blockade.

Nivolumab, a programmed death 1 blockade drug, is used in various types of cancers and can cause a unique immune-related adverse event (irAE). Relapsing polychondritis (RP) is a rare autoimmune disease that mainly involves inflammation of the auricle, nose and airway cartilage. A 72-year-old man with mandibular cancer received nivolumab after surgery for the primary lesion and radiation therapy for lung metastases. He then developed radiation pneumonitis, and prednisolone (PSL) was started. During the tapering of PSL, he developed exertional dyspnea and cough. The condition of mandibular cancer and radiation pneumonitis had not deteriorated. Fluorodeoxyglucose (FDG)-PET/CT showed a thickening of and abnormal FDG uptake in the tracheobronchial and nasal septum cartilage. These characteristic findings were not observed before nivolumab was initiated; thus, we clinically diagnosed the patient as having RP induced by nivolumab. Since the symptoms were mild, the patient's condition was carefully managed with inhaled corticosteroids, and the RP has not progressed thus far. Physicians should be aware that RP can occur as an irAE because RP may progress to serious respiratory symptoms.

Relapsing polychondritis associated with heart block.

OBJECTIVE: The present article aims at describing a rare case of an RP patient who evolved with heart block and was successfully treated with corticoid pulse therapy, without the need for pacemaker insertion. PATIENTS AND METHODS: A systematic research on relapsing polychondritis (RP) and heart block (HB) published in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo from 1966 to August 2020 was performed. RESULTS: It was found 10 studies on RP associated with HB, and we added a case. Most were male (7/10) with ages 30 to 66 years old. RP disease duration was 1 week-6 years. In most cases (7/10), the RP was active when the HB occurred. A complete HB was observed in 4/7, followed by type II degree block in 3/7, and one patient had a sinus node dysfunction. Most patients received glucocorticoids. A pacemaker was inserted in 4/9 cases. Good outcome was observed in 3/9 patients and mortality in 2/10. CONCLUSIONS: We report the first case of an RP patient who had a heart block and was successfully treated with methylprednisolone pulse therapy. The authors suggest that in these RP cases, an attempt with a glucocorticoid pulse therapy may be offered to treat the heart block and prevent the insertion of a pacemaker.

Overlapping Clinical Syndromes in Patients with Glial Fibrillary Acidic Protein IgG.

OBJECTIVE: The aim of this paper is to report 2 cases with overlapping syndromes in autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. METHODS: Antibodies were detected by indirect immunofluorescence assay. Patient data were analyzed retrospectively. RESULTS: One patient presented with overlapping neuromyelitis optica spectrum disorder (NMOSD) and positive GFAP-IgG and aquaporin-4-IgG. His main symptoms included vision loss, hiccups, fever, headache, and ataxia. High leukocyte count and protein levels were found in cerebrospinal fluid. Brain magnetic resonance imaging (MRI) revealed abnormalities in the hippocampus, midbrain, pons, medulla, and meninges. Characteristic radial enhancing patterns were seen. The other patient was a male with relapsing polychondritis (RP) and positive GFAP-IgG. His main manifestations were meningoencephalitis and dementia. MRI showed extensive abnormalities in the white matter around the ventricles, temporal lobe, and thalamus, with enhancement. Both patients responded well to the treatment with steroids and immunosuppressants. CONCLUSIONS: Although overlapping syndromes are rare, we report positive GFAP-IgG in 2 cases with NMOSD or RP. Both patients had clinical features of GFAP astrocytopathy, but diagnosis of the condition was very challenging because of the overlapping presentation.

Relapsing Polychondritis with a Cobble-stone Appearance of the Tracheal Mucosa, Preceded by Posterior Reversible Encephalopathy Syndrome.

A 25-year-old woman had convulsions and disturbance of consciousness. Head magnetic resonance imaging (MRI) showed punctate areas in the occipital lobes with increased signals on T2-weighted imaging. The MRI abnormalities responded well to steroid pulse therapy, so we made a diagnosis of posterior reversible encephalopathy syndrome (PRES). Three months later, she developed a fever and dyspnea. Chest computed tomography revealed marked thickness of the tracheal and bronchial wall, and bronchoscopy showed a cobble-stone appearance of the tracheal mucosa, indicative of relapsing polychondritis (RPC). We consider that PRES had developed due to autoimmune vasculitis in the brain with RPC.

Treatment of auricular relapsing polychondritis in a Saudi child using only non-steroidal anti-inflammatory drugs: a case report.

Relapsing polychondritis (RP) is an autoimmune disease that can involve multiple sites within the human body. It is characterized by recurrent bouts of painful cartilage inflammation, and it can cause severe complications if it affects the vital organs. This report describes the case of a five-year-old child with limited auricular RP. The patient's history was obtained from his family, and a physical examination was performed at a pediatric rheumatology clinic. The patient was successfully treated using only a non-steroidal anti-inflammatory drug, and he completely recovered. This treatment and recovery have not been reported in the literature. Therefore, these results are worthy of mention in order to avoid the use of immunosuppressant medications with localized involvement.

Is 18F-FDG PET/CT useful for diagnosing relapsing polychondritis with airway involvement and monitoring response to steroid-based therapy?

BACKGROUND: 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is a promising tool for diagnosing relapsing polychondritis (RP). However, its usefulness in assessing RP with airway involvement is unknown. OBJECTIVE: This study aimed to further evaluate and confirm the potency of 18F-FDG PET/CT in diagnosing RP with airway involvement and monitoring response to steroid-based therapy. METHODS: A total of 30 patients from a dedicated respiratory centre, diagnosed with RP in accordance with McAdam, Damiani or Levine criteria, were included in this study. All patients underwent baseline 18F-FDG PET/CT, and 10 patients underwent second scans after 2.5-15 months of steroid-based therapy. Visual scores (VS) and maximal standard uptake values (SUVmax) were analysed. RESULTS: In the initial scan, 83.3% (25/30) of patients were found to have FDG uptake in more than one cartilage. The median VS and SUVmax in the cartilages were 3 (range, 1-3) and 3.8 (range, 1.9-17.9), respectively. Positive rates for PET/CT-guided biopsy in nasal, auricular, and tracheal/bronchial cartilages were 100% (5/5), 88.9% (8/9), and 10.5% (2/19), respectively, but the positive biopsy rate in the auricular cartilage was 92.3% (12/13) even without PET/CT assessment. Based on biopsy-proven sites, the sensitivity of PET/CT was 55.6%, and the specificity was 5.3%. Compared with the baseline scan, the second scan showed much lower median VS (2 vs 3, respectively; p < 0.0001) and SUVmax (2.9 vs 3.8, respectively; p < 0.001). Of 10 patients who underwent second PET/CT, 8 had complete therapeutic response, while 2 had partial response. CONCLUSION: 18F-FDG PET/CT assists in identifying multiple cartilage involvement in RP, but it seems neither a sensitive nor specific modality in diagnosing RP with airway involvement. Moreover, PET/CT has limited utility in locating biopsy sites and monitoring therapeutic response to corticosteroids.

Thoracic Manifestations of Ankylosing Spondylitis, Inflammatory Bowel Disease, and Relapsing Polychondritis.

Ankylosing spondylitis, inflammatory bowel disease (IBD), and relapsing polychondritis are immune-mediated inflammatory diseases with variable involvement of lungs, heart and the chest wall. Ankylosing spondylitis is associated with anterior chest wall pain, restrictive lung disease, obstructive sleep apnea, apical fibrosis, spontaneous pneumothorax, abnormalities of cardiac valves and conduction system, and aortitis. Patients with IBD can develop necrobiotic lung nodules that can be misdiagnosed as malignancy or infection. Relapsing polychondritis involves large airways in at least half of the patients. Relapsing polychondritis can mimic asthma in some patients. Medications used to treat these inflammatory conditions can cause pulmonary complications such as infections, pneumonitis, and rarely serositis.

Limited auricular relapsing polychondritis in a child treated successfully with infliximab.

Relapsing polychondritis (RP) is a rare progressive and destructive multisystem disorder characterised by recurrent inflammation of cartilaginous structures. It is a rare disease in paediatrics compared with adults. In children, the diagnosis is either delayed or overlooked due to low incidence. Auricular chondritis has been described in more than half of paediatric cases with RP. However, isolated auricular chondritis has not been reported as the only presentation of pediatric-onset RP. We described a lad who presented with isolated auricular chondritis, which is refractory to conventional treatment, including glucocorticoids and methotrexate as steroid-sparing agent. Remission of his disease's relapses was sustained with infliximab. Limited auricular involvement as a presenting feature of RP in the absence of systemic association is very rare in children. We describe a case of successful use of infliximab on limited auricular chondritis disease.

The relapsing polychondritis damage index (RPDAM): Development of a disease-specific damage score for relapsing polychondritis.

OBJECTIVES: Relapsing polychondritis is a rare, multi-systemic and inflammatory condition of unknown origin. We currently lack a core set of measures to assess and follow damage in patients suffering from this condition. Our primary aim was to derive a disease-specific damage measuring tool for relapsing polychondritis, the Relapsing Polychondritis Damage Index (RPDAM). METHODS: We performed an international 4-round multicenter Delphi study during which experts were asked to rate the relevance of potential damage items for relapsing polychondritis (141 items were obtained from a literature review and 12 from expert suggestion), using a Likert Scale. The selection of items for each subsequent round was based on the median rating of each item. RESULTS: Twenty-four experts from 11 nationalities participated in round 1 and 22 in rounds 2, 3 and 4. From the initial 153 potential damage items, 44 items were selected during round 1, 30 items during round 2 and 16 during round 3. During round 4, we refined the index to a total of 17 items referring to ear nose and throat, eye, respiratory, cardiovascular and hematological systems as well as to treatment-related specific damage items. CONCLUSION: We have developed by international consensus a scoring system to assess damage in patients with relapsing polychondritis. Following its validation, the RPDAM may contribute to improve the care of patients suffering from this rare condition as well as to standardize data collection for future clinical trials.

Limbic encephalitis with relapsing polychondritis: persistent white matter lesions and brain atrophy.

Relapsing polychondritis (RP) is a rare autoimmune disorder affecting cartilage. Limbic encephalitis is a rare central nervous system manifestation of RP. This current case report describes a 66-year-old Chinese male patient who complained of developing myoclonus in the left leg, ataxia and speech difficulties 3 weeks prior to hospital admission. The patient presented with cognitive impairment, sleep disorder and extrapyramidal symptoms. The patient was diagnosed with RP that affected auricular cartilage, which also manifested as limbic encephalitis. Magnetic resonance imaging showed bilateral temporal lobe lesions involving the hippocampi and basal ganglia. Signal abnormalities in the white matter persisted during the 15-month follow-up period after treatment with corticosteroids and intravenous immunoglobulin. Over the same period, the bilateral hippocampi showed significant atrophy.