Imaging diagnosis in relapsing polychondritis and correlation with clinical and serological data.

OBJECTIVE: We hypothesize that imaging findings from CT and MRI correlate better with clinical markers for assessment of disease activity in patients with the rare relapsing polychondritis (RPC) than with serological inflammatory markers. MATERIALS AND METHODS: Retrospective database search at our institution identified 28 patients (13 females; age 49.0 years±15.0 SD) with RP between September 2004 and March 2014. Institutional review board approval was obtained for this retrospective data analysis. All patients had clinically proven RPC with at least two episodes of active disease. Of those, 18 patients were examined with CT- and MRI and presented all morphologic features of RPC like bronchial/laryngeal/auricular cartilage thickness, contrast enhancement, increased T2-signal intensity. Imaging data was subsequently correlated with corresponding clinical symptoms like fever, dyspnea, stridor, uveitis, pain, hearing impairment as well as with acute-phase-inflammatory parameters like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RESULTS: The clinical parameters were in good agreement with imaging findings and clinical symptoms such as tracheal wall thickening and dyspnea (r =0.65 p=0.05), joint synovitis on MRI and a higher McAdam score (r=0.84 p<0.001). No correlations were found between inflammatory laboratory markers, imaging findings and clinical features. CONCLUSION: Imaging diagnosis in RPC using CT and/or MRI delivers information about the degree of disease activity that correlates better with clinical features than unspecific inflammatory laboratory markers. Additionally, clinically unapparent cartilage involvement can be assessed adding value to the clinical diagnosis and therapy planning in this rare disease.

Serum level of soluble triggering receptor expressed on myeloid cells-1 as a biomarker of disease activity in relapsing polychondritis.

OBJECTIVES: We aimed to identify a serum biomarker for evaluating the disease activity of relapsing polychondritis (RP). METHODS: We measured and compared serum levels of 28 biomarkers potentially associated with this disease, including soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), high-sensitivity C-reactive protein (hs-CRP), and cartilage oligomeric matrix protein (COMP), in 15 RP patients and 16 healthy donors (HDs). We divided the 15 RP patients into active RP (n = 8) and inactive RP (n = 7) groups, depending on the extent of the disease, and compared candidate markers between groups. The localization of membrane-bound TREM-1 in the affected tissue was examined by immunohistochemistry. RESULTS: Serum levels of sTREM-1, interferon-γ, chemokine (C-C motif) ligand 4, vascular endothelial growth factor, and matrix metalloproteinases-3 were significantly higher in RP patients than HDs. Among these markers, sTREM-1 had the highest sensitivity and specificity (86.7 and 86.7 %, respectively). Furthermore, the serum level of sTREM-1 was significantly higher in active RP patients than inactive RP patients (p = 0.0403), but this was not true for hs-CRP or COMP. TREM-1 was expressed on endothelial cells in RP lesions. CONCLUSIONS: The serum level of sTREM-1 may be a useful marker of disease activity in RP.

Mechanical model of steady-state and inflammatory conditions in patients with relapsing polychondritis: A review.

ABSTRACT: Relapsing polychondritis (RP) is a multisystem inflammatory disorder, considered to associate with immune aberration.Increased T helper type-1 cell-related cytokines were reported in RP patients. mRNA expressions of a regulatory T cell cytokine interleukin (IL)-10 increased, whereas pro-inflammatory cytokines IL1ß and IL6 mRNA expressions decreased in freshly isolated peripheral blood mononuclear cells of RP patients compared with those in healthy individuals. Upon in vitro stimulation with mitogen, IL10 mRNA expressions decreased, and IL1ß and IL6 mRNA expressions increased in RP patients.This short-time dynamic change of gene expressions from anti-inflammatory to pro-inflammatory features of immune cells may be associated with the "relapsing" disease course of patients with RP. IL1ß mRNA expressions of peripheral blood mononuclear cells exhibited positive correlations with serum matrix metalloproteinase (MMP)-3 concentrations in patients with respiratory involvement. Such positive correlation was not found in those without respiratory involvement.In a metagenomic analysis, an altered composition of gut microbes was found, suggesting that microbe metabolites such as short-chain fatty acids may affect T cell responses of the patients.In this review, the relationships among RP-related inflammatory molecules were summarized. The data support a hypothesis that the immune conditions are different between steady-state and inflammation in RP patients.

Efficacy of adalimumab for a refractory case of relapsing polychondritis with reduction of pro-inflammatory cytokines.

A 68-year-old man with a fever of unknown origin was admitted to our hospital. Bilateral auricularis and nasal root inflammation, with auricular perichondritis positive for anti-type II collagen (CII) antibody, led to a diagnosis of relapsing polychondritis (RP). Because the patient was refractory for high-dose glucocorticoid therapy, adalimumab was used. After the initiation of 40 mg of adalimumab, a rapid improvement of clinical manifestations, with a reduction in tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), together with a titer of anti-CII antibody was observed.

Serum cartilage oligomeric matrix protein (COMP) level is a marker of disease activity in relapsing polychondritis.

OBJECTIVES: Relapsing polychondritis (RP) is a rare and severe disease which may lead to destruction of elastic cartilages. Until now, no reliable biomarker of disease activity in RP has been available. This study was designed to measure serum levels of cartilage biomarkers during both active and inactive phases of the disease. METHODS: Serum levels of cartilage oligomeric matrix protein (COMP), chondroitin sulfate 846 epitope (CS846) of proteoglycan aggrecan and collagen type II collagenase cleavage neoepitope (C2C) were measured retrospectively in 21 subjects with RP. The Wilcoxon matched-pairs signed-rank test was used for statistical comparisons of biomarker levels in active and inactive phases of RP. RESULTS: Only the serum level of COMP was significantly increased during disease flares. Steroids did not alter the serum cartilage-related biomarker levels. However, during the active phase, C2C levels were significantly higher in steroid treated patients compared with non-steroid treated patients. CONCLUSIONS: This study suggests that serum COMP level may be useful for monitoring disease activity of RP. Further prospective studies are required to confirm this result.

ANCA positive relapsing polychondritis, Graves disease, and suspected moyamoya disease: A case report.

RATIOINALE: Relapsing polychondritis (RP) is a rare and heterogeneous disease complex of unknown origin which basically affects cartilaginous structures, 40% of which accompanied by rheumatic, hematologic, and endocrine disease. Among them, vasculitis is the most common accompanying type and usually presented with positive antineutrophilic cytoplasmic antibody (ANCA). The presence of ANCA could be primary or drug-induced like propylthiouracil (PTU). Central involvement of RP is very rare, and there is almost no report of cerebral vasculopathy manifested as moyamoya. PATIENT CONCERNS: A 26-year-old woman complained about recurrent fever, auricular chondritis, ocular inflammation, and arthritis. She had an 8-year drug intake of PTU for Graves disease. Myeloperoxidase antineutrophilc cytoplasmic antibodies (MPO-ANCA) were found positive. Magnetic resonance angiography (MRA) detected multiple intracranial vasculopathy which we highly suspected it as moyamoya disease. DIAGNOSES: Relapsing polychondritis, Graves disease and suspected moyamoya disease were clinically diagnosed. INTERVENTIONS AND OUTCOMES: In case of possible PTU-induced vasculitis and the aggravation of vasculopathy, PTU was replaced by Iodine-131 (I) therapy. Induction treatment included oral prednisone 30 mg daily and oral cyclophosphamide 100 mg daily. Symptoms rapidly relieved before discharge. Inflammation markers were normal and MPO-ANCA decreased in 3 weeks after admission. Prednisone was gradually tapered to 7.5 mg daily and at month 10 azathioprine was continued for maintenance. LESSONS: RP can overlap with Graves disease and moyamoya disease; comprehensive tests should be performed when admission. When relapsing polychondritis is accompanied with Graves disease, especially when ANCA is positive, PTU should be avoided.

Monoclonal autoantibodies from patients with autoimmune diseases: specificity, affinity and crossreactivity of MAbs binding to cytoskeletal and nucleolar epitopes, cartilage antigens and mycobacterial heat-shock protein 60.

Serum autoantibodies produce typical immunofluorescence staining patterns on HEp-2 cells, which are frequently used for diagnostic purposes. These include antibodies recognizing cytoskeletal and nuclear epitopes. The detailed analysis of human monoclonal antibodies (MAbs) should help to understand which antigens or autoantigens were involved in the generation of these immune responses. Here, three MAbs are described staining HEp-2 cells in a characteristic pattern. They were derived from peripheral blood B cells of two patients with rheumatic diseases (rheumatoid arthritis and relapsing polychondritis). Their binding reactivities were characterized in detail in several assay systems and their affinities measured. Although the antibodies differed in their fine specificity and crossreactivity, all three MAbs (2 IgM, 1 IgA) bound to purified cytoskeletal antigens (desmin) and, in addition, to cartilage antigens (human collagen type II, proteoglycans). The binding to HEp-2 cells could be inhibited specifically with soluble antigens as shown by intracellular flow cytometry. The affinities for both groups of antigens were relatively high (examples: K(D) (desmin) = 0.1 x 10(-7) M; K(D) (collagen) = 3.5 x 10(-7) M). Two of the MAbs also bound to heat-shock protein 60 (HSP60) derived from Mycobacterium tuberculosis. The results prove that antibodies and B cells with reactivity to both intracellular cytoskeletal and nuclear antigens and exogenous antigens (e. g. HSP60) exist in patients with rheumatic diseases. Similar to an animal model such human B cells may be induced by the exogenous antigen (HSP60) and crossreact with local auto-antigens related to the disease (cartilage). In this way they might contribute to pathogenic processes. Due to their additional crossreactivity with intracellular cytoskeletal and nuclear antigens, these antibodies simultaneously can be detected in the HEp-2 immunofluorescence assay.

Relapsing polychondritis: a report of eight cases.

OBJECTIVE: To investigate clinical manifestations of relapsing polychondritis and to clarify the significance of type II collagen antibody in the disease. METHODS: Clinical manifestations and antibody titers were examined in eight cases of relapsing polychondritis which had been treated at Otolaryngology Department, Hokkaido University during the eight years from 1991 to 1998. Anti-type II collagen antibody titer was measured by ELISA method. RESULTS: The most frequent symptom was auricular chondritis; it was seen in 88% (7/8) of the cases. Ocular symptom, nasal chondritis, arthritis, respiratory tract chondritis, and audio-vestibular symptom were also common in the cases. Compared with previous reports, no difference was recognized in the manifestation frequency. Considering none of the samples from the controls was positive for anti-type II collagen antibody, two samples from the disease group were positive. The antibody positive rate was 25% (2/8). CONCLUSION: Though the measurement of type II collagen antibody titer is not a decisive factor for detection of relapsing polychondritis, it is useful as one of the complementary factors for the diagnosis, since there is no specific test for this disease.

Pathogenesis of relapsing polychondritis: a 2013 update.

Relapsing polychondritis (RP) is a systemic inflammatory disease primarily affecting not only the cartilaginous structures of the ears, nose and tracheobronchial tree but also the joints, the inner ear, the eyes, and the cardiovascular system. RP is an immune-mediated disease during which target antigens are still unknown, but data from human studies and murine models strongly support a role of both Collagen Type II (CII) and matrilin-1 as potential candidates. RP is likely a Th1-mediated disease as serum levels of interferon (IFN)-γ, interleukin [IL]-12, and IL-2 parallel changes in disease activity, while the levels of Th2 cytokines do not. Serum levels of sTREM-1, interferon-γ, CCL4, vascular endothelial growth factor, and matrix metalloproteinases-3 are significantly higher in RP patients than in healthy donors, with sTREM-1 correlating with disease activity. Patients with active RP also have significantly higher levels of MCP-1, MIP-1ß, MIF, and IL-8 than controls. These pro-inflammatory chemokines are involved in the modulation and recruitment of monocytes and neutrophils. Altogether, these data suggest that a complex cytokine network orchestrates the recruitment of infiltrating cells in RP lesions. Cytokine modulation using TNFα blockers, rituximab, anakinra, tocilizumab, and abatacept has recently been shown effective in some RP cases but further data are needed. Better understanding of the repertoire of infiltrating cells may provide interesting clues to further define the putative RP auto-antigens. Study of circulating mononuclear cells during RP flares may also provide crucial information about the ongoing cellular trafficking and recruitment processes involved in this rare disease.

Mice expressing HLA-DQ6alpha8beta transgenes develop polychondritis spontaneously.

Relapsing polychondritis (RP) is a human autoimmune disease of unknown etiology in which cartilaginous sites are destroyed by cyclic inflammatory episodes beginning, most commonly, during the fourth or fifth decade of life. We have previously described collagen-induced polychondritis that closely mirrors RP occurring in young (6-8 weeks old) HLA-DQ6alphabeta 8alphabeta transgenic Abeta0 mice, following immunization with heterologous type II collagen (CII). We present evidence here that transgenic strains expressing the DQ6alpha8beta transgene develop spontaneous polychondritis (SP) at the mouse equivalent of human middle age (4.5-6 months and 40-50 years old, respectively) and display polyarthritis, auricular chondritis and nasal chondritis--three of the most common sites affected in RP. Auricular chondritis in SP, like RP but unlike CII-induced polychondritis, exhibited a relapsing/remitting phenotype, requiring several inflammatory cycles before the cartilage is destroyed. Elevated serum levels of total IgG corresponded with the onset of disease in SP, as in RP and CII-induced polychondritis. No CII-specific immune response was detected in SP, however--more closely mirroring RP, in which as few as 30% of RP patients have been reported to have CII-specific IgG. CII-induced polychondritis displays a strong CII-specific immune response. SP also demonstrated a strong female preponderance, as some workers have reported in RP but has not observed in CII-induced polychondritis. These characteristics of SP allow for the examination of the immunopathogenesis of polychondritis in the absence of an overwhelming CII-specific immune response and the strong adjuvant-induced immunostimulatory influence in CII-induced polychondritis. This spontaneous model of polychondritis provides a new and unique tool to investigate both the initiatory events as well as the immunopathogenic mechanisms occurring at cartilaginous sites during the cyclic inflammatory assaults of polychondritis.

Susceptibility to relapsing polychondritis is associated with HLA-DR4.

OBJECTIVE: To determine the frequency of HLA class II antigens in Caucasian central European patients with relapsing polychondritis (RP). METHODS: HLA class I, DR, and DQ specificities were identified in 41 patients with RP, and the frequencies were compared with those in 204 healthy, unrelated control subjects. HLA typing was performed using the standard complement-dependent microcytotoxicity assay. HLA-DR genotyping of 12 DR4-positive RP patients and 57 controls was performed by allele-specific oligonucleotide probing after amplification of genomic DNA by polymerase chain reaction. RESULTS: A significant increase in DR4 antigen frequency was found in the patients (56.1%) as compared with that in healthy controls (25.5%) (Pcorr < 0.001). Genotyping of DR4-positive patients and controls revealed no predominance of any DR4 subtype. CONCLUSION: There are important clinical similarities and overlaps between RP and rheumatoid arthritis (RA). In RA, the association with DR4 has been well established. Our findings show that although there is a DR4 association with RP, the situation is sufficiently distinct from that of RA to imply considerable differences in pathogenesis of the two conditions.

Serum cytokine profiles in relapsing polychondritis suggest monocyte/macrophage activation.

OBJECTIVE: There is evidence that autoimmunity plays a significant role in the pathogenesis of relapsing polychondritis (RP). This study was designed to investigate circulating levels of various cytokines in relation to the etiology of this rare disorder, and to compare the pattern of cytokine elevations in RP with that in another autoimmune disease, rheumatoid arthritis (RA). METHODS: Serum from 22 patients with active RP and an equal number of age- and sex-matched healthy controls and RA patients were available for analysis. The following cytokines were measured: interleukin-1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-gamma (IFNgamma), tumor necrosis factor alpha, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1beta (MIP-1beta). Results were analyzed by nonparametric Mann-Whitney test with Holm stepdown adjustment for multiple testing. RESULTS: The levels of 3 of these cytokines showed significant differences between RP patients and controls. Compared with controls, mean serum levels of MCP-1, MIP-1beta, and IL-8 were all much higher in patients with active RP. In contrast, RA patients showed a more general increase in all cytokines measured, with much higher levels of IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-13, IFNgamma, G-CSF, GM-CSF, MCP-1, and MIP-1beta compared with controls. CONCLUSION: Levels of 3 serum cytokines were significantly higher in RP patients than in age- and sex-matched controls. One of these 3 cytokines, IL-8, was not significantly elevated in RA samples. Overall, in RP, a more discrete group of cytokines exhibited significantly increased levels than was found in RA. Each of the 3 cytokines that were elevated in RP is a proinflammatory chemokine, characteristic of activation of the monocyte and macrophage lineage, and in the case of IL-8, also of neutrophils. These data suggest a major role for a cell-mediated immune response in the pathophysiology of RP.

Articular involvement in patients with relapsing polychondritis.

Our objective was to study joint symptoms in patients with relapsing polychondritis (RP) and their relationship to other clinical manifestations and laboratory findings. Fourteen patients who met the diagnostic criteria proposed by Michet et al. for RP were studied. Clinical symptoms were recorded and a detailed laboratory analysis with HLA-DR typing was carried out. In 2 patients arthritis was the first manifestation. During the follow-up, 10 patients developed arthritis. It was polyarticular in 6, and oligoarticular in 4 cases. The development of arthritis was unrelated to the appearance of chondritis at other sites. HLA class II typing was determined in 7 patients. Six of them were positive for HLA-DR4. Arthritis in RP is a frequent manifestation occurring in approximately 70% of patients with an asymmetric articular involvement. There is no correlation between articular involvement and any particular clinical or laboratory feature. Susceptibility to RP is significantly related to the presence of HLA-DR4.

The occurrence of autoantibodies to matrilin 1 reflects a tissue-specific response to cartilage of the respiratory tract in patients with relapsing polychondritis.

OBJECTIVE: Relapsing polychondritis (RP) is an inflammatory disease that mainly affects cartilage tissue in the auricle, nose, and lower respiratory tract. When tracheolaryngeal cartilage is involved, the disease is occasionally fatal. Matrilin 1 is a cartilage-specific protein most prominently expressed in tracheal cartilage, but not in joint cartilage. Immunization with the protein in rats and mice induces respiratory distress and nasal destruction, as seen in RP. We investigated the response to matrilin 1 and other cartilage proteins in sera from patients with RP, 4 additional groups of patients with other major connective tissue diseases, and healthy control subjects. METHODS: Sera were analyzed by enzyme-linked immunosorbent assay (ELISA) for antibody responses to matrilin 1, types II, IX, and XI collagen, and cartilage oligomeric matrix protein (COMP). Titers above the mean + 3SD of controls were considered positive. Specificity of matrilin 1 recognition was further investigated by the capacity of high-titer sera to block the binding of a matrilin 1-specific monoclonal antibody in inhibition ELISAs. In vivo reactivity and specificity were tested by injecting sera into neonatal mice, and antibody binding was detected by immunohistochemical staining. RESULTS: Serum antibodies from RP patients bound tracheolaryngeal and nasal cartilage in vivo and inhibited the binding of anti-matrilin 1-specific monoclonal antibodies. Thirteen of the 97 RP patients had increased titers of matrilin 1 antibody. Positive titers correlated with respiratory symptoms in 69% of the cases. Significant responses to type II collagen and COMP were also detected. CONCLUSION: Antibodies to matrilin 1 bind tracheolaryngeal cartilage in vivo and are correlated with an inflammatory attack on tracheolaryngeal cartilage that is often seen in RP.

Relapsing polychondritis presenting with recurrent venous thrombosis in association with anticardiolipin antibody.

We describe a case of relapsing polychondritis with recurrent venous thrombosis associated with detectable anticardiolipin antibody. This association has not been previously reported, although venous and arterial thrombosis has been recognized in association with relapsing polychondritis.

Classical rheumatoid arthritis associated with nondeforming relapsing polychondritis.

Two patients with classical rheumatoid arthritis and a mild nondeforming relapsing polychondritis are presented. DR4 antigen and depressed C4 levels were found and possible autoimmune mechanisms are discussed. The need for specific questioning to detect this rare association is proposed.