Only one study had clearly defined the endpoints during evaluation of the effects of rituximab in nine patients. been evidenced.39C41 Table 1 Systemic vasculitis and connective tissue disorders associated with relapsing polychondritis (not exhaustive) Systemic vasculitisBeh?ets disease (MAGIC syndrome), granulomatosis with polyangiitis, polyarthritis nodosa, Churg and Strausss syndromeConnective tissue diseasesSj?grens syndrome, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue diseases, systemic sclerosisSpondyloarthritisAnkylosing spondylitis, psoriatic arthritis, reactive arthritis, inflammatory bowels diseasesOther autoimmune diseasesAutoimmune thyroiditis, type 1 diabetes, familial Mediterranean fever, myasthenia gravis, primary biliary cirrhosisMalignanciesMyelodysplastic syndromes, lymphomas, myeloproliferative neoplasms, thymomaDermatosisSweets syndrome, neutrophilic dermatosis, pyoderma gangrenosum, leukocytoclastic vasculitis, psoriasis Open in a separate window Abbreviation: MAGIC, mouth and genital ulcers with inflamed cartilage Nevertheless, all those relevant pathogenic hypotheses need to be confirmed. The problem we are facing with is usually that we have no reliable animal model of relapsing polychondritis. And because the disease is usually rare, it is important to recruit larger number patients in any study, which underlines the necessity of international collaborative works. Clinical manifestations: a real bazaar! Relapsing polychondritis is usually a disorder evolving by flare remission. It is characterized by clinical polymorphism, requiring a team approach with different medical and surgical specialties. The onset of the disease is generally brutal and acute. The most common initial clinical picture is usually chondritis of ears associated with pain, erythema, and edema, followed by chondritis of nose (Physique 1). Chondritis of chondro-costal joints and upper airways, scleritis and episcleritis, arthralgia, and various mucocutaneous lesions can subsequently occur. Repeated inflammation can lead to the destruction of the cartilage and deformity of the nose, ears and respiratory tract. Tracheobronchomalacia and ascending aorta involvement are the most feared complications. Fever, asthenia, weight loss, or rash may be inaugural symptoms. Rheumatologic involvement varies from simple arthralgia to asymmetric, migratory, and non-erosive arthritis of small and large joints, with a predilection for chondro-costal joints. All of these manifestations generally occur gradually with time and CID-2858522 their frequency varies with disease duration, activity, and severity (Table 2). This clinical heterogeneity is usually a source of diagnostic errors, particularly since the initial manifestations in a given patient are extra-chondritic and clinical ignorance of this rare disease.1C5 Open in a separate window Determine 1 Relapsing polychondritis: auricular chondritis during acute phase (A); chronic phase with collapse of the cartilage of the upper pole of the ear (B); saddle nose deformity (C); episcleritis (D). Note: Reproduced with permission from Club Rhumatismes et Inflammations. [website around the Internet]. Available from http://www.cri-net.com/autres-projets/base_images/display_rub.asp?rub=poly_atro.79 Table 2 Comparison of demographics and clinical features of 10 cohorts around the world thead th valign=”top” align=”left” rowspan=”1″ colspan=”1″ /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ McAdam et al8 br / (USA) /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Michet et al10 br / (USA) /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Zeuner et al25 br / (Germany) /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Trentham and Le5* br / (USA) /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Mathew et al17 br / (USA) /th Bglap th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Sharma et al3 br / (India) /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Shimizu et al42 br / (Japan) /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Lin et al12 br / (China) /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Dion et al13 br / (France) /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Pallo et al54 br / (Brazil) /th /thead Number of patients (n)1591126266432623915814230Mean age at diagnosis (years)44514646444553454349Female/male CID-2858522 (n)76/8355/5726/6349/1723/2016/10112/12763/9586/5621/9Mean follow-up (months)NR72129684NR64NR15672Auricular chondritis (%)898593958896786889100Hearing impairment (%)46301942374227252730Laryngotracheal involvement (%)56483067371150694357Nasal chondritis (%)NR295620358139546310Arthritis (%)81525385605439186960Ocular involvement (%)65515057574246445637Cardiovascular involvement (%)962282711710223Skin involvement (%)17282438NR26144629NR Open in a separate window Note: *Based on 36 patients with relapsing polychondritis and 30 patients from literature review. Abbreviation: NR, not recorded. The difficulty is usually often not CID-2858522 to evoke the diagnosis of relapsing polychondritis in presence of nasal or ear chondritis. The differential diagnosis concerns more each organ involvement that may appear immediately in a given patient but most of the time appears gradually with an average of 2 symptoms at the onset of the disease.13 When rheumatologic involvement precedes auricular and nasal chondritis (and/or when episodes of chondritis have been neglected), the diagnosis of relapsing polychondritis becomes very difficult, not to say impossible because few clinicians would include relapsing polychondritis in diagnoses to be evoked in front of a patient with arthritis. Once the differential diagnoses have been eliminated, CID-2858522 the next step is to make a distinction between symptoms and signs associated with relapsing polychondritis and those related to possible associated diseases, as presented in Table 1.1C5 Indeed, one-third of patients with relapsing polychondritis have an intercurrent disease including systemic vasculitis and inflammatory or hematological diseases. Theses concomitant disease may precede, occur after, or present simultaneously with relapsing polychondritis.1C5,13 Establishing the diagnosis early is a challenge when relapsing polychondritis or systemic vasculitis is suspected. Indeed, differential diagnosis can be difficult.