Increased generation of TRAP expressing multinucleated giant cells in patients with granulomatosis with polyangiitis.

BACKGROUND: Tissue-infiltrating multinucleated giant cells (MNGs) within geographic necrosis are pathologic hallmarks of granulomatosis with polyangiitis (GPA). However, the origin, phenotype, and function of these cells in GPA remain undefined. METHODOLOGY/PRINCIPAL FINDINGS: MNG phenotype in GPA lung tissue was examined by immunohistochemistry using antibody directed against cathepsin K and calcitonin-receptor. Tartrate-resistant-acid-phosphatase (TRAP) expression was assessed using enzymatic color reaction. Peripheral blood mononuclear cells (PBMCs) from 13 GPA patients (5 with localized and 8 with systemic disease) and 11 healthy controls were cultured in the presence of RANKL and M-CSF for 9 days, and TRAP+ MNGs containing 3 or more nuclei were identified. GPA lung granulomata contained numerous MNGs that expressed osteoclastic TRAP and cathepsin K but not calcitonin receptors. In the presence of RANKL and M-CSF, PBMCs of GPA patients formed significantly more MNGs than healthy controls (114 ± 29 MNG/well vs. 22 ± 9 MNG/well, P = 0.02). In a subgroup analysis, patients with systemic disease generated significantly more MNGs than patients with localized disease (161 ± 35 MNG/well vs. 39 ± 27 MNG/well, P<0.01) or healthy controls (P<0.01). MNG production did not differ between localized GPA and control subjects (P = 0.96). CONCLUSIONS/SIGNIFICANCE: MNGs in granulomata in the GPA lung express osteoclastic enzymes TRAP and cathepsin K. GPA patients have a higher propensity to form TRAP+ MNGs from peripheral blood than healthy controls. These data suggest that (i) the tendency to form MNGs is a component of the GPA phenotype itself, and (ii) that lesional MNGs might participate in the destructive process through their proteolytic enzymes.

Persistent or new onset microscopic hematuria in patients with small vessel vasculitis in remission: findings on renal biopsy.

OBJECTIVE: Hematuria is considered a sign of active renal disease in patients with small-vessel vasculitis. In patients who are in apparent clinical remission, presence of persistent or new-onset microscopic hematuria may reflect active vasculitis, damage, or other glomerular pathology. METHODS: We identified 74 patients from the Johns Hopkins Renal Pathology database between 1995 and 2009 with the diagnosis of pauciimmune glomerulonephritis (GN). Among them we identified 9 who were in clinical remission and underwent a renal biopsy for evaluation of persistent or new-onset hematuria. RESULTS: Nine patients with small-vessel vasculitis, 8 antineutrophil cytoplasmic antibody (ANCA)-positive and 1 ANCA-negative, underwent a renal biopsy at variable time periods after remission of vasculitis (6 to 164 months) for persistent microscopic hematuria (n = 6) or new-onset microscopic hematuria (n = 3). All patients were in apparent clinical remission at the time of renal biopsy. Of the 3 patients presenting with new-onset hematuria, 2 had crescentic IgA nephropathy and 1 had healed crescentic pauciimmune GN. Of the 6 patients with persistent hematuria, 2 had arteriosclerosis, 2 had focal segmental glomerulosclerosis, and 2 had global and segmental glomerulosclerosis and healed crescentic GN, and none had active vasculitis. CONCLUSION: Microscopic hematuria in patients with renal vasculitis otherwise in remission could represent chronic glomerular injury from prior episode of vasculitis or may represent new glomerular pathology. Renal biopsy should be considered in these patients to guide therapy.

A medical resident post-discharge phone call study.

BACKGROUND: Several studies have identified the post-discharge period as a time of vulnerability for patients, and an opportunity exists to improve patient care. Adverse drug events are the most common events leading to complications during the post-discharge period. Recent studies have shown that using a scripted medication reconciliation process improves the quality of patient care. OBJECTIVE: Does a phone call from a medical resident within 72 hours after hospital discharge improve patient satisfaction and quality of care? Does this exercise result in improved attitudes and competence for practice-based learning, and improvement and system-based practice of participating residents? MATERIALS AND METHODS: This was a prospective randomized study comparing 1 group of patients that received a medication reconciliation phone call from a medical resident within 72 hours after discharge with a control group that did not receive a call. Adult patients aged ≥ 18 years on a medical resident service for ≥ 2 days and being discharged to home were invited to participate. The primary endpoint of the study was patient satisfaction. Secondary endpoints included readmission rates, emergency department visits, follow-up with the primary care provider, and resident attitudes and competence. RESULTS: The primary and secondary endpoints did not reach statistical significance. However, a medication reconciliation error occurred in 48% of patients, and 93% of residents agreed that the phone call was beneficial to patient care. CONCLUSION: Although patient satisfaction was not improved from this exercise, a follow-up call to patients after hospital discharge can identify otherwise missed medication reconciliation errors. Medical residents found the phone call to be worthwhile and gained valuable insight into their own discharge practices as demonstrated by self-reflection and intended change in discharge practices.

High-dose cyclophosphamide without stem cell rescue for the treatment of refractory Behcet's disease.

OBJECTIVE: Behcet's disease (BD) is a systemic inflammatory disorder characterized by recurrent mucocutaneous ulcerations, ocular inflammation, and numerous severe systemic inflammatory manifestations. While most patients respond to standard immunosuppressive therapies, a subset will develop refractory disease. In this report, the use of a novel therapy for the treatment of BD is described. METHODS: Two patients with severe refractory BD who were treated with nonmyeloablative high-dose cyclophosphamide therapy without stem cell rescue. RESULTS: After treatment, both patients were completely weaned off immunosuppressive therapy and entered disease-free remissions of 18 and 24 months, respectively. CONCLUSIONS: These data suggest high-dose cyclophosphamide therapy without stem cell rescue as an alternative for the treatment of refractory BD.

More than meets the eye.

A 27-year-old woman was hospitalized with fever and visual changes. She had been well until nine months earlier when she developed unilateral blurry vision in the left eye. Ophthalmologic examination revealed bilateral acute anterior uveitis. She was treated with topical steroids and her vision returned to baseline. However, over the next few months, she developed debilitating fatigue and experienced an unintentional fifteen pound weight loss. One month prior to presentation, she noted the onset of daily low grade fevers and chills. On the day of admission, she developed a temperature of 103°F and a severe frontal headache. Here we describe a case where the overlap of clinical features led to an initially broad differential diagnosis of seemingly unrelated diseases. Ultimately, the discovery of a key radiographic finding allowed us to more clearly define the diagnosis.

Transcription of proteinase 3 and related myelopoiesis genes in peripheral blood mononuclear cells of patients with active Wegener's granulomatosis.

OBJECTIVE: Wegener's granulomatosis (WG) is a systemic inflammatory disease that is associated with substantial morbidity. The aim of this study was to understand the biology underlying WG and to discover markers of disease activity that would be useful for prognosis and treatment guidance. METHODS: Gene expression profiling was performed using total RNA from peripheral blood mononuclear cells (PBMCs) and granulocyte fractions from 41 patients with WG and 23 healthy control subjects. Gene set enrichment analysis (GSEA) was performed to search for candidate WG-associated molecular pathways and disease activity biomarkers. Principal components analysis was used to visualize relationships between subgroups of WG patients and controls. Longitudinal changes in proteinase 3 (PR3) gene expression were evaluated using reverse transcription-polymerase chain reaction, and clinical outcomes, including remission status and disease activity, were determined using the Birmingham Vasculitis Activity Score for WG (BVAS-WG). RESULTS: Eighty-six genes in WG PBMCs and 40 in WG polymorphonuclear neutrophils (PMNs) were significantly up-regulated relative to controls. Genes up-regulated in WG PBMCs were involved in myeloid differentiation, and these included the WG autoantigen PR3. The coordinated regulation of myeloid differentiation genes was confirmed by GSEA. The median expression values of the 86 up-regulated genes in WG PBMCs were associated with disease activity (P = 1.3 x 10(-4)), and WG patients with low-level expression of the WG signature genes showed expression profiles that were only modestly different from that in healthy controls (P = 0.07). PR3 transcription was significantly up-regulated in WG PBMCs (P = 1.3 x 10(-5), false discovery rate [FDR] 0.002), but not in WG PMNs (P = 0.03, FDR 0.28), and a preliminary longitudinal analysis showed that the fold change in PR3 RNA levels in WG PBMCs corresponded to changes in the BVAS-WG score over time. CONCLUSION: Transcription of PR3 and related myeloid differentiation genes in PBMCs may represent novel markers of disease activity in WG.

Novel conformation of histidyl-transfer RNA synthetase in the lung: the target tissue in Jo-1 autoantibody-associated myositis.

OBJECTIVE: We previously proposed that novel expression and/or conformation of autoantigens in the target tissue may play a role in generating phenotype-specific immune responses. The strong association of autoantibodies to histidyl-transfer RNA synthetase (HisRS, Jo-1) with interstitial lung disease in patients with myositis led us to study HisRS expression and conformation in the lung. METHODS: Normal human tissue specimens were probed with a novel anti-HisRS antibody recognizing its granzyme B-cleavable conformation by immunoblotting and immunohistochemistry. The HisRS granzyme B site was mapped using site-directed mutagenesis, and its relationship to the antibody recognition domain was evaluated in tandem immunoprecipitation/granzyme B cleavage studies. RESULTS: The HisRS alpha-helical coiled-coil N-terminal domain recognized by autoantibodies is bounded by a granzyme B cleavage site. In immunoprecipitation studies with patient sera, HisRS was found to exist in 2 conformations, defined by sensitivity to cleavage by granzyme B and modification by autoantibody binding. Despite similar global expression of HisRS in different tissue, expression of its granzyme B-cleavable form was enriched in the lung and localized to the alveolar epithelium. CONCLUSION: A proteolytically sensitive conformation of HisRS exists in the lung, the target tissue associated with this autoantibody response. We thus propose that autoimmunity to HisRS is initiated and propagated in the lung.

Cancer and myositis: new insights into an old association.

PURPOSE OF REVIEW: The association between the idiopathic inflammatory myopathies and the development of malignancy has been appreciated for nearly a century, but its meaning and significance have remained unclear. Significant advances in our understanding of the epidemiology and pathophysiology of this association have recently been made. This review will describe the major epidemiological evidence linking inflammatory myopathies with cancer, and will use this evidence to highlight a recently proposed model for the development of cancer-associated myositis. RECENT FINDINGS: The temporal relationship between the development of cancer and myositis is reminiscent of that seen in neurological paraneoplastic disorders, in which antigens targeted for an immune response are expressed at high levels in the inciting tumor and the affected neuronal tissue. It has also recently been observed that regenerating cells in myositis muscle, but not its normal counterpart, express high levels of myositis-specific autoantigens. These same antigens are expressed at high levels in several cancers known to be associated with the development of myositis, but not in corresponding normal tissue. SUMMARY: These observations suggest a model of paraneoplasia focusing on common autoantigen expression and immune targeting between cancer tissues and muscle tissue in myositis.

Anti-aminoacyl tRNA synthetase immune responses: insights into the pathogenesis of the idiopathic inflammatory myopathies.

PURPOSE OF REVIEW: One of the most striking humoral characteristics of the idiopathic inflammatory myopathies is the specific targeting of components of the translational machinery by the immune system. The most commonly targeted of these components are the aminoacyl tRNA synthetase (ARS) molecules. However, the relation between the immune responses to these molecules and the pathogenesis of the inflammatory myopathies remains obscure. This review will examine recent evidence that explores the links between the ARS molecules, inflammation, and apoptosis, with the aim of furthering our current understanding of the underlying pathogenesis of the myositis syndromes. RECENT FINDINGS: Several of the ARS molecules and their proteolytic fragments generated during inflammation and apoptosis have recently been shown to possess chemoattractant properties. The liberation of these fragments in the muscle microenvironment under certain circumstances may provide a proinflammatory context and lead to the influx of lymphocytes, macrophages, and specialized antigen-presenting cells to the site of muscle injury. The subsequent processing and presentation of these autoantigen fragments on major histocompatibility complex class I and II molecules may generate an ARS-specific autoimmune response, which may be responsible for amplification and propagation of muscle injury in these diseases. SUMMARY: The striking association between the inflammatory myopathies and anti-ARS antibodies implies a role for the ARS molecules in the pathogenesis of these syndromes. Recent data suggest that ARS molecules and their proteolytic fragments generated during the cell death process may be responsible for priming and sustaining a specific immune response in situ in myositis. How these molecules become altered and access the immune system in the disease microenvironment is an area of ongoing investigation.

Gastrointestinal involvement in polyarteritis nodosa (1986-2000): presentation and outcomes in 24 patients.

PURPOSE: Gastrointestinal involvement in polyarteritis nodosa carries a poor prognosis. A 1982 review from our institution reported acute abdominal syndromes in 31% of patients with polyarteritis nodosa, and that all 5 patients with acute surgical abdomens died. We reviewed our more recent experience to determine if outcomes have changed since. SUBJECTS AND METHODS: We reviewed the records of all patients with polyarteritis nodosa in our vasculitis database between 1986 and 2000. Inclusion criteria were a diagnosis of polyarteritis nodosa, symptoms or signs of gastrointestinal involvement, and either a mesenteric angiogram consistent with polyarteritis nodosa or histopathologic proof of a medium-vessel vasculitis. We calculated a prognostic (5 factor) score for all patients. RESULTS: We identified 24 patients with polyarteritis nodosa who had gastrointestinal involvement during their illness. Thirteen (54%) of the patients developed acute surgical abdomens, 3 of whom died (P = 0.02 by comparison with the historical cohort). Mean (+/- SD) prognostic scores were higher among patients in the acute abdomen group compared with those who did not have acute abdominal syndromes (1.7 +/- 0.9 vs. 0.6 +/- 0.7, P = 0.002), corresponding with the observed mortality in these groups. CONCLUSION: Gastrointestinal involvement occurs commonly in polyarteritis nodosa and carries a poor prognosis. Compared with a historical cohort at our institution, mortality from this complication may have decreased, perhaps because of earlier diagnosis.

Giant cell arteritis.

Giant cell arteritis (GCA), the most common form of systemic vasculitis in adults, preferentially involves large and medium-sized arteries in patients over the age of 50. The classic manifestations are headache, jaw claudication, polymyalgia rheumatica (PMR), and visual symptoms, but 40% of patients present with a wide range of occult manifestations. Early diagnosis and treatment with prednisone can prevent blindness, the most feared complication of GCA. The pathogenesis of GCA is T-cell dependent and antigen driven. Clinical subsets of GCA appear to result from variable cytokine expression. The risk of developing thoracic aortic aneurysm is increased more than 17-fold in patients with GCA. GCA can also involve large arteries, especially the subclavian and axillary arteries. Color Doppler ultrasound, magnetic resonance imaging, and positron-emission tomography scanning are providing insights into the extent and pathogenesis of the disease but have not replaced temporal artery biopsy as the gold standard for securing the diagnosis. Two recently completed double-blind, placebo-controlled trials concerning whether methotrexate plus prednisone is more effective than prednisone alone reached conflicting conclusions.