Diagnostic Strategy Using Color Doppler Ultrasound of Temporal Arteries in Patients With High Clinical Suspicion of Giant Cell Arteritis : A Prospective Cohort Study.

BACKGROUND: Giant cell arteritis (GCA) is the most prevalent systemic vasculitis in people older than 50 years. Any delay in diagnosis impairs patients' quality of life and can lead to permanent damage, particularly vision loss. OBJECTIVE: To evaluate a diagnostic strategy for GCA using color Doppler ultrasound of the temporal artery as a first-line diagnostic test, temporal artery biopsy (TAB) as a secondary test, and physician expertise as the reference method. DESIGN: Prospective multicenter study with a 2-year follow-up. (ClinicalTrials.gov: NCT02703922). SETTING: Patients were referred by their general practitioner or ophthalmologist to a physician with extensive experience in GCA diagnosis and management in one of the participating centers: 4 general and 2 university hospitals. PATIENTS: 165 patients with high clinical suspicion of GCA, aged 79 years (IQR, 73 to 85 years). INTERVENTION: The diagnostic procedure was ultrasound, performed less than 7 days after initiation of corticosteroid therapy. Only ultrasound-negative patients underwent TAB. MEASUREMENTS: Bilateral temporal halo signs seen on ultrasound were considered positive. Ultrasound and TAB results were compared with physician-diagnosed GCA based on clinical findings and other imaging. RESULTS: Diagnosis of GCA was confirmed in 44%, 17%, and 21% of patients by ultrasound, TAB, and clinical expertise and/or other imaging tests, respectively. Their diagnosis remained unchanged at 1 month, and 2 years for those with available follow-up data. An alternative diagnosis was made in 18% of patients. The proportion of ultrasound-positive patients among patients with a clinical GCA diagnosis was 54% (95% CI, 45% to 62%). LIMITATION: Small sample size, no blinding of ultrasound and TAB results, lack of an objective gold-standard comparator, and single diagnostic strategy. CONCLUSION: By using ultrasound of the temporal arteries as a first-line diagnostic tool in patients with high clinical suspicion of GCA, further diagnostic tests for patients with positive ultrasound were avoided. PRIMARY FUNDING SOURCE: Tender "Recherche CH-CHU Poitou-Charentes 2014."

Polyclonal hypergammaglobulinaemia: towards definition of a threshold.

BACKGROUND: Polyclonal hypergammaglobulinaemia (PH) represents a classic diagnosis problem in internal medicine. However, there is no consensus threshold for PH. The aim of this study was to define a threshold for PH. METHODS: We conducted a retrospective multicentric study using laboratory biological databases between 1 January 2016 and 31 December 2016 in two university hospitals and one non-university hospital. All patients 18 years old or over and with at least one serum protein electrophoresis (SPE) available in 2016 were included. Exclusion criteria were monoclonal, biclonal, or oligoclonal spikes or, in case of hypogammaglobulinaemia, proven free light chain gammopathy. The main endpoint was to define the threshold values for PH in this population. Another objective was to define the 95th percentile of the distribution. RESULTS: 20 766 SPEs were included in this cohort. The PH threshold on 95th percentile was 18.9 g/L. The threshold varied according to geographical areas. CONCLUSIONS: This is the first study to scientifically define a PH threshold. The main limitation is that our threshold is only biological. The study was not designed to associate this threshold with a clinically active disease. In conclusion, while the 19 g/L cut-off seems the most relevant threshold, but it will need to be validated by prospective studies.

Rituximab plus methotrexate combination as a salvage therapy in persistently active granulomatosis with polyangiitis.

OBJECTIVE: The aim of this study was to describe the efficacy and safety of rituximab and MTX (RTX/MTX) combination therapy in ANCA-associated vasculitides (AAV). METHODS: A retrospective French nationwide study was conducted in patients with AAV who received RTX/MTX combination therapy for persistently active disease. RESULTS: Seventeen patients were included. All patients had granulomatosis with polyangiitis (GPA), with positive ANCA in 76% of them, mainly with PR3-ANCA specificity. Sixteen patients (94%) had priorly failed to achieve remission with RTX and 11 (65%) with CYC. Patients had experienced a median of 3 (2-4) flares. Manifestations requiring RTX/MTX combination therapy were subglottic or bronchial stenosis in 6 patients (35%), orbital mass in 6 (35%), disabling ENT involvement in 2 (12%), and epiduritis and pachymeningitis in 1 case (6%) each. The median follow-up duration for the RTX/MTX combination therapy was 11 months (11-26 months). At 6 months, global response had been achieved in 15 patients (88%), including partial response in 11 (65%) and complete response in 4 (24%). At last evaluation, global response had been achieved in 16 patients (94%). Seven patients (41%) experienced severe adverse events (grade 3 or 4), including infections in 4 (24%) and hepatitis in 2 (12%). Combination therapy was withdrawn in 4 patients (24%), but never for safety concerns. In contrast, the MTX dose was decreased in 2 patients (12%) because of adverse events. One patient died of an unknown cause. CONCLUSION: RTX/MTX combination therapy could be an effective salvage therapy to treat persistently active GPA with granulomatous manifestations, with an acceptable safety profile.

Polyclonal hypergammaglobulinaemia: towards definition of a threshold.

BACKGROUND: Polyclonal hypergammaglobulinaemia (PH) represents a classic diagnosis problem in internal medicine. However, there is no consensus threshold for PH. The aim of this study was to define a threshold for PH. METHODS: We conducted a retrospective multicentric study using laboratory biological databases between 1 January 2016 and 31 December 2016 in two university hospitals and one non-university hospital. All patients 18 years old or over and with at least one serum protein electrophoresis (SPE) available in 2016 were included. Exclusion criteria were monoclonal, biclonal, or oligoclonal spikes or, in case of hypogammaglobulinaemia, proven free light chain gammopathy. The main endpoint was to define the threshold values for PH in this population. Another objective was to define the 95th percentile of the distribution. RESULTS: 20 766 SPEs were included in this cohort. The PH threshold on 95th percentile was 18.9 g/L. The threshold varied according to geographical areas. CONCLUSIONS: This is the first study to scientifically define a PH threshold. The main limitation is that our threshold is only biological. The study was not designed to associate this threshold with a clinically active disease. In conclusion, while the 19 g/L cut-off seems the most relevant threshold, but it will need to be validated by prospective studies.

Clinical value of a [18F]-FDG PET-CT muscle-to-muscle SUV ratio for the diagnosis of active dermatomyositis.

OBJECTIVE: To study a muscle-to-muscle standardised uptake value (SUV) ratio with FDG-PET/CT (FDG-PET) as a marker for the detection of disease activity in dermatomyositis (DM). METHODS: Patients with DM (n = 24) who met the European Neuro-Muscular Centre diagnostic criteria were retrospectively identified over a 3-year period through a national survey. Muscle biopsy was performed in all patients. Maximum SUV was measured in proximal muscles (SUVPROX) that had the highest radiotracer uptake on visual grading as well as in the musculus longissimus thoracis (SUVMLT), whereas mean SUV was measured for the liver (SUVLIV). Muscle-to-liver SUV ratios for either muscle group were compared and a SUVPROX/SUVMLT ratio was calculated. SUVPROX/SUVMLT of DM patients were compared with age- and sex-matched control subjects (n = 24) with melanoma who had received FDG-PET scans. RESULTS: DM patients presented with proximal and symmetrical muscle uptake. Differences in SUVPROX/SUVLIV and SUVMLT/SUVLIV ratios in DM subjects were significant (p < 0.001). SUVPROX/SUVMLT ratios in DM and their controls also differed significantly (p = 0.0012). The SUVPROX/SUVMLT ratio threshold between DM subjects and controls was 1.73 with a sensitivity of 50% (CI95%, 29.1 to 70.9%) and specificity at 83.3% (CI95%, 62.6 to 95.3%). When amyopathic DM patients were removed from the analysis, specificity was increased to 95% (CI95%, 75.1 to 99.9%) with a likelihood ratio of 10 and an AUC of 83.4% (CI95%, 71.4 to 95.4%). CONCLUSION: A muscle-to-muscle SUVPROX/SUVMLT ratio with a cut-off value of 1.73 in FDG-PET imaging might serve as a non-invasive marker to determine disease activity in dermatomyositis. KEY POINTS: • [18F]-FDG PET-scanner standardised uptake value (SUV) could reflect disease activity in dermatomyositis (DM). • A ratio of SUV in proximal muscles (SUVPROX) to SUV in musculus longissimus thoracis (SUVMLT) could be used to determine active DM. • Active disease is suspected for SUV PROX /SUV MLT ratios greater than 1.73.

High risk of cancer in autoimmune necrotizing myopathies: usefulness of myositis specific antibody.

Cancer can occur in patients with inflammatory myopathies. This association is mainly observed in dermatomyositis, and myositis-specific antibodies have allowed us to delineate patients at an increased risk. Malignancy is also reported in patients with necrotizing autoimmune myopathies, but the risk remains elusive. Anti-signal recognition particle or anti-HMGCR antibodies have been specifically associated with necrotizing autoimmune myopathies. We aimed at screening the incidence of cancer in necrotizing autoimmune myopathies. A group of patients (n = 115) with necrotizing autoimmune myopathies with or without myositis-specific antibodies was analysed. Malignancy occurred more frequently in seronegative necrotizing autoimmune myopathies patients and in HMGCR-positive patients compared to anti-signal recognition particle positive patients. Synchronous malignancy was diagnosed in 21.4% and 11.5% of cases, respectively, and incidence of cancer was higher compared to the general population in both groups. No specific type of cancer was predominant. Patients suffering from a synchronous cancer had a decreased median survival time. Cancer screening is necessary in seronegative necrotizing autoimmune myopathies and in HMGCR-positive patients but not in anti-signal recognition particle-positive patients.

A new family with hereditary lysozyme amyloidosis with gastritis and inflammatory bowel disease as prevailing symptoms.

BACKGROUND: Systemic amyloidoses is a heterogeneous group of diseases either acquired or hereditary. Amyloidoses can involve the gastrointestinal tract and the nature of the precursor protein that forms the fibrils deposits should be identified to adjust the treatment and evaluate the prognosis. Lysozyme amyloidosis (ALys) is a rare, systemic non neuropathic hereditary amyloidosis with a heterogenous phenotype including gastrointestinal, renal and hepatic symptoms. CASE PRESENTATION: We report and describe symptoms and gastrointestinal tract involvement in a new family with hereditary lysozyme amyloidosis. Clinical manifestations and organ involvement of nine affected members of a new family with the p.Trp82Arg ALys variant were recorded. All affected individuals suffered with prevailing gastrointestinal symptoms leading to the diagnosis of ALys. 8/9 had non specific upper gastrointestinal symptoms and 3/9 had rectocolic inflammation evoking inflammatory bowel disease. No other organ involvement by amyloidosis was found. Histological examination revealed amyloid deposits in all cases and all carried the p.Trp82Arg ALys variant at a heterozygous state. CONCLUSION: Hereditary amyloidosis associated with the p.Trp82Arg lysozyme variant in this new family is predominantly associated with mild upper gastrointestinal tract involvement and in some cases with inflammatory bowel disease. Amyloidosis should be considered in atypical or treatment resistant, upper or lower chronic gastrointestinal symptoms. When associated with a familial history a lysozyme gene mutation must be searched.

[IgG4-related disease]. / Maladie associée aux immunoglobulines G de type 4.

IgG4-related disease is an emerging pathological condition characterized by one or several fibrosing and inflammatory organ involvements. Histological findings are typical and associate storiform fibrosis with polyclonal lymphocytic and plasma-cell infiltrate, with predominant IgG4-expressing plasma cells. Sclerosing lymphoplasmocytic pancreatitis, or type 1 auto-immune pancreatitis, and other organ involvements have been reported: sclerosing cholangitis, sialadenitis, dacryoadenitis, retroperitoneal fibrosis, aortitis, interstitial nephritis, polyadenopathy and inflammatory pseudo-tumors. Serum IgG4 level is elevated in most of patients, but the histological documentation remain necessary for the diagnosis. Dramatic response to steroids is usual but relapses are frequent.

Pathophysiology of IgG4-related disease: A T follicular helper cells disease?

IgG4-related disease is a chronic inflammatory disease characterized by clinical, biological and pathological unifying findings. Because these criteria are not always all together available in patients and because biological and pathological markers are not totally specific, the diagnosis should be retained after exclusion of mimickers. Since the individualization of IgG4-RD, several studies have allowed to better characterize immunological abnormalities associated with this particular condition. B and T cell oligoclonal activation is associated with T helper 2 cytokine production leading to IgG4 production and profibrotic cytokine release. A central role for T follicular helper 2 cells is suggested from recent findings. We summarize here recent advances in understanding of immune abnormalities in IgG4-related disease.

Clinical presentation, treatment and outcome of IgG4-related pachymeningitis: From a national case registry and literature review.

Pachymeningitis is rare, either idiopathic or secondary to inflammatory disorders, after tumoral, surgical or infectious causes have been excluded. The fibroinflammatory IgG4-related disease is one of the etiologies of pachymeningitis with only few cases reported yet. From a single referral regional center, we evaluated the frequency of IgG4-related disease as the cause of inflammatory pachymeningitis in 10% of cases. From a National case registry of IgG4-related disease the pachymeningitis frequency was 4.1%. We report eight new cases with cranial, spinal or both involvements and a literature review of 46 pathological proven cases. We observed that IgG4-related pachymeningitis is in most cases not associated to extra-neurological manifestations of the disease. Only 27% of spinal and 40% of cranial IgG4-related pachymeningitis are associated with other disease localizations. First line treatment strategies included surgery and steroids. The use of immunosuppressants or rituximab was necessary in 18% of spinal and 54% of cranial localizations. Some patients remained with sequellae and clinical and/or radiological improvement can be difficult to obtain.

Ophthalmic manifestations in IgG4-related disease: Clinical presentation and response to treatment in a French case-series.

IgG4-related disease (IgG4-RD) is characterized by variable tissue or organ involvements sharing common pathological findings. Orbital or orbital adnexa involvement of the disease has been reported in a few case series. The aim of our study was to characterize and analyze ophthalmic manifestations from a nationwide French case-series.Patients with IgG4-RD and orbital or orbital adnexa involvement included in the French multicentric IgG4-RD case-registry were identified. Only patients fulfilling "modified" comprehensive diagnostic criteria with pathological documentation were retained for the study. Clinical, biological, pathological, radiological findings and data regarding the response to treatment were retrospectively analyzed.According to our data registry, the frequency of IgG4-related ophthalmic disease (IgG4-ROD) was 17%. Mean age at diagnosis was 55.1 ±â€Š7.1 years with a male/female ratio of 2.2. The 19 cases of IgG4-ROD consisted of lacrimal gland (68.4%), soft tissue (57.9%), extra-ocular muscles (36.8%), palpebral (21.1%), optical nerve (10.5%), orbital bone (10.5%), and mononeuritis (V1 and/or V2, 10.5%) involvements. IgG4-ROD was bilateral in 57.9% of cases. Extra-ophthalmic manifestations were reported in 78.9% of cases. All patients responded to prednisone but two-thirds of patients relapsed within a mean (SD) of 9.8 (3.5) months and 72.2% required long-term glucocorticoids and/or immunosuppressive agents. Eight patients were treated by rituximab with a favorable response in 87.5% of cases.Lacrimal involvement is the most frequent ophthalmic manifestation of IgG4-RD and is frequently associated with extra-orbital manifestations. Despite initial favorable response to steroids, the long-term management of relapsing patients needs to be improved.

T Cell Polarization toward TH2/TFH2 and TH17/TFH17 in Patients with IgG4-Related Disease.

IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder involving virtually every organ with a risk of organ dysfunction. Despite recent studies regarding B cell and T cell compartments, the disease's pathophysiology remains poorly understood. We examined and characterized subsets of circulating lymphocytes in untreated patients with active IgG4-RD. Twenty-eight consecutive patients with biopsy-proven IgG4-RD were included in a prospective, multicentric study. Lymphocytes' subsets were analyzed by flow cytometry, with analysis of TH1/TH2/TH17, TFH cells, and cytokine release by peripheral blood mononuclear cells. Results were compared to healthy controls and to patients with primary Sjögren's syndrome. Patients with IgG4-RD showed an increase of circulating T regulatory, TH2, TH17, and CD4+CXCR5+PD1+ TFH cell subsets. Accordingly, increased levels of IL-10 and IL-4 were measured in IgG-RD patients. TFH increase was characterized by the specific expansion of TFH2 (CCR6-CXCR3-), and to a lesser extent of TFH17 (CCR6+CXCR3-) cells. Interestingly, CD4+CXCR5+PD1+ TFH cells normalized under treatment. IgG4-RD is characterized by a shift of circulating T cells toward a TH2/TFH2 and TH17/TFH17 polarization. This immunological imbalance might be implicated in the disease's pathophysiology. Treatment regimens targeting such T cells warrant further evaluation.

Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients.

OBJECTIVES: To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4-related disease (IgG4-RD) patients. METHODS: Nationwide retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model. RESULTS: Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 ±21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 ±11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow-up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia ≤5 g/l in 3 patients. CONCLUSION: RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy.