Active aortitis in relapsing polychondritis

Relapsing polychondritis (RP) is a rare inflammatory multiorgan disorder affecting cartilaginous structures and other connective tissues. Serious cardiovascular complications have been reported in patients with RP, the most frequent being aortic or mitral regurgitation and aortic aneurysms. Aortitis is a very rare complication. An unusual case of active aortitis in a patient with RP, despite intensive immunosuppressive treatment, is described with a special emphasis on the pathological findings.     

Relapsing polychondritis presenting as cutaneous polyarteritis nodosa

Summary Relapsing polychondritis is an infrequently diagnosed, though not neccessarily uncommon, systemic disorder characterized by recurrent and potentially destructive inflammation of cartilaginous structures, the eye, and the audiovestibular and cardiovascular systems. Although dermal involvement occurs in approximately 25% of patients with relapsing polychondritis, in only few cases has a skin biopsy been obtained revealing lesions such as leukocytoclastic vasculitis, livedo reticularis, erythema nodosum or keratodermia blenorrhagicum. We describe a patient with relapsing polychondritis in whom a cutaneous polyarteritis nodosa preceded cartilage inflammation by 6 months. Cutaneous polyarteritis nodosa is a rare form of vasculitis that appears to be limited primarily to the skin, muscles, and joints. In contrast to the systemic form of the disease it is characterized by the absence of visceral lesions and a relapsing but benign course. The present case and the fact that vasculitis is a concomitant feature in approximately 30% of patients with relapsing polychondritis [21] demonstrates that this condition may not represent a distinct clinical entity.Abbreviations CPN cutaneous polyarteritis nodosa - RP relapsing polychondritis Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Pathological and Immunological Findings in an Autopsy Case

Relapsing polychondritis (RP) is a disorder of unknown etiology characterized by the destruction of cartilage. A case of RP in a 59-year-old male was autopsied, and systemic inflammation of various cartilages was confirmed. We demonstrated the circulating antibodies to Type II (cartilage) collagen. No antibodies to other collagen types were demonstrated. The presence of granular deposits of immunoglobulins, fibrinogen, and the C3 component of complement at the chondrofibrous junction was also demonstrated. From these findings, this case suggested that the pathogenesis of RP is related to an immune mechanism.     

Relapsing polychondritis developing in a patient with Graves' disease: a possible association with propylthiouracil]

A 31-year-old woman presented 1993 with fever, painful swelling of cartilaginous portions of the ears and the bridge of nose, polyarthralgia including costochondroral pains, and episcleritis. She has been taking propylthiouracil since 1991 when she was diagnosed as Graves' disease. Laboratory evaluations revealed an elevated erythrocyte sedimentation rate (ESR) of 133 mm/h, a high CRP level of 13.2 mg/dl and positive antinuclear antibodies and anti-type II collagen antibodies. Histopathological findings of the biopsy specimen from the auricular cartilage included chondrocyte degeneration, matrix destruction and inflammatory cell infiltration. She was diagnosed as RP and treatment with 30 mg/day of prednisolone dramatically improved all symptoms and signs, accompanied by a fall in ESR, CRP and autoantibodies. When prednisolone was tapered to 5 mg/day, a clinical relapse occurred. After discontinuation of propylthiouracil, she has been well without prednisolone. Propylthiouracil-induced SLE-like syndrome or antineutrophil cytoplasmic antibodies (ANCA) related angitis has been reported previously. In addition, recent studies demonstrated that about 20% of sera from patients with relapsing polychondritis are P-ANCA positive. This is the first report suggesting a possible association between the development of relapsing polychondritis and propylthiouracil.     

Relapsing polychondritis. Pathological and immunological findings in an autopsy case

Relapsing polychondritis (RP) is a disorder of unknown etiology characterized by the destruction of cartilage. A case of RP in a 59-year-old male was autopsied, and systemic inflammation of various cartilages was confirmed. We demonstrated the circulating antibodies to Type II (cartilage) collagen. No antibodies to other collagen types were demonstrated. The presence of granular deposits of immunoglobulins, fibrinogen, and the C3 component of complement at the chondrofibrous junction was also demonstrated. From these findings, this case suggested that the pathogenesis of RP is related to an immune mechanism.     

Cryptococcal epididymo-orchitis complicating steroid therapy for relapsing polychondritis.

Disseminated cryptococcosis is a known complication of steroid therapy. Infection within the genito-urinary tract is usually assumed to be part of generalized cryptococcosis complicating a primary pulmonary focus. A case of isolated testicular cryptococcal orchitis complicating steroid therapy for relapsing polychondritis is presented. To the authors' knowledge isolated cryptococcal orchitis has not been previously described.     

IgA nephropathy in relapsing polychondritis

Relapsing polychondritis (RP) is a multisystem autoimmune disease characterized by the presence of antibodies to type II collagen. This collagen is found predominantly in cartilaginous tissues, vitreous humor, aorta and notochord. Involvement of the kidney is rare, only 7 cases having been recorded, and there is no type II collagen in glomeruli. Six of the previous cases had crescentic glomerulonephritis. We report here two cases of biopsy proven RP in which IgA nephropathy was seen, the first examples recorded. Both patients had hematuria and slight proteinuria, with mild impairment of renal function. The histological and immunofluorescence pattern on both biopsies was in keeping with IgA nephropathy. Both patients received steroids with diminution/disappearance of hematuria and proteinuria. In view of the potentially progressive nature of glomerular disease with RP, the renal status should be investigated in all patients with RP.     

Light and electron microscopic study of ear cartilage in a case of relapsing polychondritis evolving under corticoid treatment

Summary Light and electron microscope studies of the ear cartilage in a patient with relapsing polychondritis (RP) under corticoid treatment are reported. Unilateral auricular deformation evolved without inflammatory episodes and the lesions consisted mainly of marginal erosions filled with fine collagen fibrils and containing degenerating perichondrial cells in their basal parts. Degenerative cells were scattered throughout the perichondrium, but cartilage erosions only occured when numerous cells were affected in a same area. Cartilage outside the eroded zones did not seem to be modified. Cartilage lesions thus appear to be a result of a chondrocyte renewal defect leading to loss of proteoglycans and elastic fibers, with only collagen remaining. These data suggest that inflammation is probably not the initial pathogenic process responsible for cartilage injury in RP, but that a metabolic defect in perichondrial cells might be involved.This work was carried out with a grant from the INSERM, CRL No 79. 1 218 4     

The Relapsing Polychondritis Disease Activity Index: Development of a disease activity score for relapsing polychondritis

ObjectiveThe rarity of relapsing polychondritis (RP) has hindered the development of standardized tools for clinical assessment. Here, we describe the development of a preliminary score for disease assessing activity in RP, the Relapsing Polychondritis Disease Activity Index (RPDAI).MethodsTwenty-seven RP experts participated in an international collaboration. Selection and definition of items for disease activity were established by consensus during a 4-round internet-based Delphi survey. Twenty-six experts assessed the Physician's Global Assessment (PGA) of disease activity on 43 test cases on a 0–100 scale, yielding a total of 1118 PGA ratings. The weight of each item was estimated by multivariate regression models with generalized estimating equation, using PGA as the dependent variable.ResultsExperts decided in consensus that the RPDAI should consider the 28-day period before each RPDAI assessment. Inter-rater reliability assessed by the intra-class correlation coefficient for the 1118 PGA ratings was 0.51 (CI95%: 0.41–0.64). The final RPDAI score comprised 27 items with individual weights ranging from 1 to 24 and a maximum theoretical RPDAI score of 265. Correlation between the RPDAI scores calculated based on the weights derived from the final multivariate model, and the 1118 PGA ratings was good (r = 0.56, p < 0.0001).ConclusionWe have developed the first consensus scoring system to measure disease activity in relapsing polychondritis (see www.RPDAI.org for online scoring). This tool will be valuable for improving the care of patients with this rare disease.     

HLA-B8 in Raynaud's phenomenon

A study of the distribution of histocompatibility (HLA) antigens in patients with Raynaud's phenomenon (RP) is presented, based upon the analysis of RP patients with and without connective tissue disease (CTD). In all patients, the phenomenon preceded the other symptoms of CTD by several years. The RP patients with CTD showed a significantly increased frequency (59%) of HLA-B8 compared with the frequency (23%) of that same antigen in the Dutch population. The RP patients without CTD showed no significant difference in frequency of HLA-B8. At least 50% of the patients with RP and HLA-B8 develop a CTD versus 18% of the patients without HLA-B8. It is suggested that HLA testing in patients with isolated RP may help to distinguish the patient in whom RP is the first symptom of CTD from the patient with truly primary RP.     

Appearance of central nervous system lupus during corticosteroid therapy and warfarinization in a patient with pure red cell aplasia and antiphospholipid syndrome]

A 48-year-old woman presented to our hospital with epigastralgia and erythema on the left dorsalis pedis. Her medical history included deep venous thrombosis three months prior to admission to our hospital. Upon admission it was determined that she had severe anemia (hemoglobin level 4.6 g/dl). Bone marrow analysis indicated a markedly decreased number of erythroid progenitor cells. A skin biopsy specimen of the erythema revealed microthrombus. Anticardiolipin-beta2GPI antibody and lupus anticoagulant were positive. The patient was diagnosed with pure red cell aplasia (PRCA) and antiphospholipid syndrome (APS). After steroid pulse therapy and warfarinization, her anemia and purpura improved. Three months later she developed depression with positive anti-ribosomal P protein antibody that was indicative of central nervous system lupus. Although her psychometric condition did not respond to steroid pulse therapy, improvement was seen after she received three courses of cyclophosphamide pulse therapy. We report a rare case of CNS lupus that developed during corticosteroid therapy and warfarinization in a patient with PRCA and APS.     

Immunoregulatory defects of V alpha 24V+ beta 11+ NKT cells in development of Wegener's granulomatosis and relapsing polychondritis

The frequency of either CD4(-)8(-) (double negative; DN) or CD4(+) V alpha 24(+)V beta 11(+) NKT cells, the expression of CD1d and the binding of CD1d-tetramer loaded with alpha-galactosylceramide (alpha-GalCer) to NKT cells were analysed in peripheral blood mononuclear cells (PBMCs) of patients with Wegener's granulomatosis (WG), relapsing polychondritis (RP) and healthy subjects (HS). DN and CD4(+) V alpha 24(+)V beta 11(+) NKT cells as well as CD1d-alpha-GalCer tetramer-positive NKT cells, were significantly decreased in number in both WG and RP patients compared to those from HS. When cytokine profiles were analysed in these PBMCs upon stimulation with phorbol ester and calcium ionophore, CD4(+) T cells from patients with WG and RP exhibited a Th1 bias, whereas CD4(+) NKT cells from WG patients in remission showed a Th2 bias. These findings suggest that NKT cells (especially CD4(+) NKT cells) play a regulatory role in Th1 autoimmunity in patients with WG and RP. The reduction in NKT cell counts appears to be associated with the low responsiveness to alpha-GalCer. The dysfunction of NKT cells to recognize ligands such as alpha-GalCer may also contribute to the defects observed in NKT cells from WG and RP patients.     

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-1β, 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.     

Epidural mass due to aspergillus flavus causing spinal cord compression--a case report and brief update

Aspergillus infection of the central nervous system (CNS) is an uncommon disease. Most of the reported cases are of sinocranial spread and cases with contiguous spread to spinal cord from lung and other organs are uncommon. A case of pulmonary aspergillosis with extension to thoracic vertebrae forming a paraspinal mass resulting in neurological deficit due to Aspergillus flavus, is reported. The 43 year old patient did not have any obvious predisposing condition. He presented with loss of motor function and succumbed to the infection despite operative intervention and antifungal therapy. A brief update on CNS aspergillosis is presented along with detailed clinical, radiological and laboratory work up of the patient.     

Necrotizing sarcoid granulomatosis mimicking an intracranial neoplasm: clinicopathologic features and review of the literature.

We present a unique case of biopsy-proven necrotizing sarcoidosis involving the central nervous system (CNS) in a 52-year-old woman. The patient presented with a 3-month history of left-sided headache and sharp, shooting pains on the left side of her face. She also has a previous history of sarcoidosis, histopathologically confirmed on parotid gland biopsy 24 years before. Imaging studies of the present lesion revealed a 1.8 x 1.4-cm mass in the left temporal lobe with signal intensity suggestive of meningioma or low-grade glial neoplasm. Surgical resection was initiated, and intraoperative consultation with frozen sections revealed granulomata. The lesion was biopsied, and surgical intervention was terminated. Permanent sections failed to reveal bacteria, mycobacteria, fungi, or foreign bodies. A diagnosis of necrotizing neurosarcoidosis was rendered. The patient was administered steroid therapy and clinically responded favorably. At the most recent follow-up almost 2 years later, there was no evidence of recurrence or progression. Necrotizing sarcoidosis has been reported most commonly in the lungs and rarely in other organ systems. We report the first histologically proven case involving the CNS as well as a rare example of sarcoidosis and necrotizing sarcoid granulomatosis in the same patient. Sarcoidosis and its necrotizing variant should be considered in the differential diagnosis of a granulomatous mass lesion involving the CNS, particularly in the context of a history of systemic disease.     

Next-generation genetic testing for retinitis pigmentosa

Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retinal disease genes (n = 111) were captured and simultaneously analyzed using NGS in 100 RP patients without a molecular diagnosis. A systematic data analysis pipeline was developed and validated to prioritize and predict the pathogenicity of all genetic variants identified in each patient, which enabled us to reduce the number of potential pathogenic variants from approximately 1,200 to zero to nine per patient. Subsequent segregation analysis and in silico predictions of pathogenicity resulted in a molecular diagnosis in 36 RP patients, comprising 27 recessive, six dominant, and three X-linked cases. Intriguingly, De novo mutations were present in at least three out of 28 isolated cases with causative mutations. This study demonstrates the enormous potential and clinical utility of NGS in molecular diagnosis of genetically heterogeneous diseases such as RP. De novo dominant mutations appear to play a significant role in patients with isolated RP, having major implications for genetic counselling.     

Diagnosis of congenital and infantile nephrotic syndromes in renal biopsies in Minas Gerais,Brazil: Six case reports

Congenital or infantile nephrotic syndromes (CNS/INS) correspond to a heterogeneous group of rare diseases in which glomerular renal dysfunction and proteinuria are prominent. The aim of this study is to present six cases of possible CNS/INS with diagnoses based on clinical findings and especially histological, ultrastructural, and immunohistochemical characteristics of renal biopsies. Four cases are presented with diffuse mesangial sclerosis, one of them possibly part of Denys–Drash syndrome and two cases with CNS probably of the Finnish type in patients between 3 months old and 13 years old. The study focuses on the late evolution of Denys–Drash syndrome to end-stage renal disease in a 13-year-old patient and the diagnosis of diffuse mesangial sclerosis in an 8-year-old patient. Thus, it contributes to a better epidemiological characterization of these syndromes, demonstrating cases of CNS/INS in infrequent age groups.     

Utility of autopsy brain imprint and squash cytology for detection of lymphoma/leukemia emboli in select patients presenting with rapid decline in mental status

Central nervous system (CNS) hematologic malignancies, whether primary or secondary, are uncommon and their clinical presentations vary. Intravascular lymphoma (IVL) is a very rare, aggressive systemic malignancy that is often difficult to diagnose and susceptible to early CNS involvement. Blast crisis in myeloid leukemias can cause widespread neoplastic emboli. Here, we report two adult patients (72 years and 22 years of age) who presented with altered mental status followed by rapid decline in their conditions leading to death. No prior significant medical history was present for either patient, while acute myeloid leukemia was diagnosed in the younger patient immediately before death. During autopsy, we performed imprint and squash preparations, and frozen sections of representative cerebral cortex, cerebellum, leptomeninges, and the pituitary gland. In the older patient, presence of IVL was readily detected on cytologic preparations. Diffuse involvement of brain vasculature and perivascular parenchyma with acute myeloid leukemia was identified in the other patient. Although examination of the fresh brain is not routinely performed during autopsy, these cases are presented to illustrate that imprint and squash preparations can provide a rapid and reliable provisional autopsy diagnosis in select patients.     

Effectiveness of exposure and ritual prevention for obsessive-compulsive disorder: randomized compared with nonrandomized samples

The efficacy of exposure and ritual prevention (EX/RP) for reducing symptoms of obsessive-compulsive disorder (OCD) has been demonstrated in several randomized controlled trials (RCTs). However, procedures used in these studies to maximize experimental control may have limited their generalizability to typical clinical practice. Treatment outcome data from 110 clinical patients receiving EX/RP on an outpatient fee-for-service basis were compared with findings from 4 RCTs of EX/RP. Adult patients in the clinical sample were not excluded because of treatment history, concomitant pharmacotherapy, psychiatric comorbidity, age, or OCD severity. Clinical patients achieved substantial and clinically meaningful reductions in their OCD and depressive symptoms following EX/RP, which were comparable with those reported in the RCTs. Findings indicate that EX/RP is a potent treatment for OCD, and its benefits are not limited to select patient samples.     

Double valve disease in systemic lupus erythematosus. Case report and literature review

A young, nonhypertensive female with advanced systemic lupus erythematosus (SLE) presented in congestive cardiac failure due to aortic and mitral regurgitation. The valvular lesions resulted from organization of valvular pocket Libman-Sacks vegetations. Her clinical course mimicked infective endocarditis. She is only the third recorded patient with SLE valvular disease warranting double valve replacement. This patient, who had her valvular disease at presentation (prior to initiation of steroid therapy), illustrates that untreated SLE per se may produce severe organic valvular disease.