Calcium pyrophosphate deposition disease: a frequent finding in patients with long-standing erosive gout.

OBJECTIVE: To characterize patients with both monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in their synovial fluid (SF). METHOD: Forty-nine gout patients with acute arthritis were included. Those patients with MSU crystals only in their SF were compared to those patients with both MSU and CPP crystals in their SF. RESULTS: A total of 36 out of 49 patients (73.5%) had only MSU crystals, whereas 13 out of 49 (26.5%) had both MSU and CPP crystals in their SF. Co-deposition of CPP crystals was associated with long-standing gout disease (p = 0.022), kidney dysfunction (p = 0.024), and erosive arthritis (p = 0.049), but not with age. CONCLUSION: Long-standing gout may be a risk factor for CPP deposition disease, and the frequency of CPP co-deposition may be higher than expected.

Low immunoglobulin E flags two distinct types of immune dysregulation.

During the last two decades, hyper-immunoglobulin (Ig)E syndromes have been characterized clinically and molecularly in patients with genetically determined primary immunodeficiencies. However, the detection of low IgE levels, defined here as below detection limit in the routine clinical immunology laboratory, has received little attention. We analysed the association of serum IgA, IgM and IgG levels (including IgG subclasses) with low, normal or high serum IgE levels in patients evaluated in a single-centre out-patient immunodeficiency and allergy clinic. The correlation of serum IgE levels with IgG subclasses depended on the clinical phenotype. In patients with immunodeficiencies, IgE correlated with IgG2 and IgG4 but not with IgG3. In contrast, in patients referred for signs of allergy, IgE correlated with IgG3 but not with IgG2. A low IgE result was associated with low IgG3 and IgG4 in allergy referrals, while immunodeficiency referrals with a low IgE result had significantly lower IgG1, IgG2 and IgG4 levels. Hierarchical clustering of non-IgE immunoglobulin profiles (IgM, IgA, IgG, IgG1-4) validated that non-IgE immunoglobulin levels predict the clinic referral, i.e. phenotype, of low-IgE patients. These results suggesto guide the clinical management of patients with low serum IgE levels.

[Mesenchymal stem/stroma cells : Therapeutic potential in the treatment of autoimmune diseases]. / Mesenchymale Stamm-/Stromazellen : Therapeutisches Potenzial in der Behandlung von Autoimmunerkrankungen.

Mesenchymal stem and stromal cells (MSC) are propagated for the treatment of autoimmune and autoinflammatory processes. These cells can be relatively easily obtained from various tissues. The MSC feature anti-inflammatory and immunosuppressive properties in vitro as well as in animal models. Initial reports on the clinical application of MSC for various diseases are available, some with promising results and so far no reported toxicity; however, data from phase III studies are still lacking and crucial questions are still unanswered. The MSC preparations used are heterogeneous and also differ depending on the source and it is unclear whether autologous (own) or allogeneic (foreign) MSC are more suitable for therapeutic use. Long-term consequences, such as possible malignant transformation and possible endogenous tumor growth stimulation cannot be completely excluded. Ultimately, these questions can only be answered through randomized controlled trials for defined clinical indications with defined MSC.

The potential use of microcalorimetry in rapid differentiation between septic arthritis and other causes of arthritis.

Current diagnostic methods in differentiating septic from non-septic arthritis are time-consuming (culture) or have limited sensitivity (Gram stain). Microcalorimetry is a novel method that can rapidly detect microorganisms by their heat production. We investigated the accuracy and time to detection of septic arthritis by using microcalorimetry. Patients older than 18 years of age with acute arthritis of native joints were prospectively included. Synovial fluid was aspirated and investigated by Gram stain, culture and microcalorimetry. The diagnosis of septic arthritis and non-septic arthritis were made by experienced rheumatologists or orthopaedic surgeons. Septic arthritis was diagnosed by considering the finding of acute arthritis together with findings such as positive Gram stain or positive culture of synovial fluid or positive blood culture. The sensitivity and specificity for diagnosing septic arthritis and the time to positivity of microcalorimetry were determined. Of 90 patients (mean age 64 years), nine had septic arthritis, of whom four (44 %) had positive Gram stain, six (67 %) positive synovial fluid culture and four (44 %) had positive blood culture. The sensitivity of microcalorimetry was 89 %, the specificity was 99 % and the mean detection time was 5.0 h (range, 2.2-8.0 h). Microcalorimetry is an accurate and rapid method for the diagnosis of septic arthritis. It has potential to be used in clinical practice in diagnosing septic arthritis.

The ultrasound compression sign to diagnose temporal giant cell arteritis shows an excellent interobserver agreement.

OBJECTIVES: To compare the diagnostic performance between a vascular specialist and a rheumatologist not familiar with vascular ultrasound when applying the compression sign for the diagnosis of temporal arteritis. METHODS: Sixty consecutive patients with suspicion of giant cell arteritis were examined by both examiners. Compression of the temporal artery on both sides (stem and both branches) was performed to define whether signs of vasculitis, no vasculitis or an indefinite result were present. Each examiner was blinded to the result of the other. RESULTS: In 59/60 patients, the examiners found an identical result. The interobserver agreement (Krippendorf alpha) was 0.92. CONCLUSIONS: The new compression sign for the diagnosis of temporal arteritis is a simple and robust sonographic marker with an excellent interobserver agreement.

Risk factors for pneumocystis pneumonia in giant cell arteritis: a single-centre cohort study.

OBJECTIVES: Pneumocystis jiroveci pneumonia (PCP) is a life-threatening opportunistic infection. Few PCP cases in giant cell arteritis (GCA) have been described, but it remains unknown, which patients need PCP prophylaxis. METHODS: Sixty-two patients with GCA from a prospective cohort were studied to identify treatment-related predictors of PCP infection. RESULTS: Four PCP infections occurred, all in patients treated with methotrexate in addition to prednisone. Moreover, PCP is associated with higher cumulative PDN doses and severe lymphocytopenia (<400/µl). CONCLUSIONS: Our findings support PCP-prophylaxis in GCA patients who are treated with methotrexate and PDN, and need high prednisone doses to achieve remission, or develop severe lymphocytopenia.

Autologous hematopoietic stem cell transplantation reverses skin fibrosis but does not change skin vessel density in patients with systemic sclerosis.

Hematopoetic stem cell transplantation (HSCT) improves survival in patients with severe systemic sclerosis (SSc) by resetting the immune system. We studied how HSCT acts on the key SSc skin pathology findings (fibrosis and vascularization). In mean, 3 skin punch biopsies per patient (range 2-6) were analyzed from 13 patients (5 females) with severe diffuse SSc before and up to 96 months after HSCT. Fibrosis of the four skin layers was graded semi-quantitatively and an overall fibrosis score was then calculated. Vessel numbers and calibers were assessed in the superficial and deeper dermis after immune-staining for endothelial antigens (CD31, VE-cadherin and vWF). The median age of patients at HSCT was 47 (24-64) years. The overall median modified Rodnan skin score decreased from 24 to 10 (P=0.003) at first follow-up within a median of 9 (6-36) months after HSCT as did the histological skin score (P=0.03). The modified Rodnan skin score and the fibrosis score correlated positively (r=0.589, P<0.001). The vessels density did not significantly change after HSCT nor did the expression of the tested endothelial markers. Although improving skin fibrosis in patients with SSc, HSCT does not alter vessel density within skin biopsies.

Retinal vessel oxygen saturation in giant cell arteritis patients without ocular symptoms.

BACKGROUND: The aim of this study was to determine subclinical ocular ischemia related to giant cell arteritis (GCA) by means of retinal oximetry (RO) measurements. PATIENTS AND METHODS: Four test-retest RO images per eye were taken with the retinal vessel analyser (IMEDOS Systems UG, Jena). RO measurements in arterial (A-SO2) and venous (V-SO2) retinal vessels and their difference (A-V SO2) were calculated in GCA patients and compared to those of age-matched controls. RESULTS: GCA biopsy and duplex sonography positive patients (n=8, 13 eyes) from the Basler Riesenzellarteriitis Kohorte study (BARK) were recruited. In controls (n=6, 10 eyes), the mean (± SD) A-SO2 and V-SO2 were measured at 93.89% (± 3.0) and at 55.60% (± 3.4), respectively. In the GCAs, a reduction in the A-SO2 to 93.37% (± 3.3) and an increase in V-SO2 to 61.13% (± 3.6) were found. The A-V SO2 difference was reduced in the GCAs to 32.24% (± 3.8) whereas in the controls the difference was 38.31% (± 2.8). CONCLUSIONS: Oxygen metabolism is affected in cases with GCA. Thus, RO may provide additional data in the diagnosis of GCA, even when no ophthalmic symptoms have been reported.

Temporal artery compression sign--a novel ultrasound finding for the diagnosis of giant cell arteritis.

PURPOSE: In patients with suspected giant cell arteritis (GCA), a search for the perivascular halo sign, a sophisticated color duplex ultrasound (CDU) finding, at experienced centers reliably identifies inflamed temporal arteries (TA). We tested whether TA compression in patients with GCA, a simple, largely operator-independent maneuver, elicits contrasting echogenicity between the diseased artery wall and the surrounding tissue (compression sign). MATERIALS AND METHODS: 80 individuals with suspected GCA were prospectively enrolled in this single-center study. In all study participants, bilateral ultrasound examination of the TA established the presence/absence of the halo and compression sign. A positive compression sign was defined as visibility of the TA upon transducer-imposed compression of the artery. Based on ACR criteria, a team of specialized physicians independently grouped patients as GCA versus non-GCA. RESULTS: 43/80 study participants were grouped as GCA. Both the halo sign and the compression sign were positive in 34/43 patients in the GCA group, and negative in all 37/37 of the non-GCA group, resulting in a sensitivity of 79 % and a specificity of 100 % for both the halo and the compression sign. CONCLUSION: In this cohort of individuals with suspected GCA, the halo sign and the compression sign were equal in their diagnostic performance. The simplicity of the compression sign suggests a level of reliability warranting further evaluation.

[A patient with fever of unknown origin - a common cause with an atypical presentation]. / Der Fall eines Patienten mit Fieber unklarer Genese - eine bekannte Ursache mit atypischer Präsentation.

Fever of unknown origin (FUO) is a common medical diagnosis by exclusion. In these cases, fever is the predominant symptom of an underlying disease. We describe the case of a 60-year old patient with FUO. Intensive search for the causative disease was carried out. Unfortunately all the investigations remained fruitless. Eventually, the patient was discharged with the diagnosis of common variable immunodeficiency, based on hypogammaglobulinemia and Cytomegalovirus replication. Two weeks after discharge, the patient presented in the outpatient clinic with the typical symptoms of giant cell arteriitis (GCA). The diagnosis was confirmed by a repeated ultrasound imaging and biopsy findings. The clinical condition of the patient improved rapidly after beginning of treatment with steroids. This case illustrates the importance of a longitudinal observation of patients presenting with FUO if the diagnosis remains unclear after intensive investigations.

Sclerosing skin disorders in association with multiple sclerosis. Coincidence, underlying autoimmune pathology or interferon induced?

OBJECTIVES: To describe and analyse the manifestation of sclerosing skin disorders in patients with multiple sclerosis (MS). CASE REPORTS: We describe three patients with relapsing-remitting MS who developed skin sclerosis while receiving interferon (IFN)-beta treatment and review nine further cases of systemic sclerosis (SSc) in MS from the literature. Of all 12 patients reported, eight had limited cutaneous SSc, three had diffuse cutaneous SSc and one patient had an antisynthetase syndrome. Localised scleroderma such as morphoea was not described. The mean age at diagnosis was 25.2 years for MS (range 12 to 51) and 38.3 years for SSc (range 16 to 66). Eleven patients developed SSc after the onset of MS and manifested with skin sclerosis after a mean of 14.9 years (range 1 to 45). In five patients IFN-beta was commenced before the development of skin sclerosis (mean 4.6 years, range 1 to 8 years). There was no relationship between the onset of skin sclerosis and MS activity. With the exception of one individual, all patients had antinuclear antibodies. CONCLUSIONS: Sclerosing skin disorders may develop in the course of MS. The relatively early age of SSc onset in patients with MS suggests a genetic predisposition and/or an IFN-associated trigger.

High incidence of severe ischaemic complications in patients with giant cell arteritis irrespective of platelet count and size, and platelet inhibition.

OBJECTIVE: Vision loss and ischaemic stroke are feared complications in GCA. We investigated how platelet count and size and platelet inhibition with ASA relate to ischaemic complications in patients with GCA. METHODS: Charts of patients with GCA were retrospectively analysed. Jaw claudication, amaurosis fugax, blurred vision, ischaemic stroke and permanent visual loss were classified as 'ischaemic events'; ischaemic stroke and permanent visual loss were sub-grouped as 'severe ischaemic events'. The incidence of ischaemia and the association to the pre-defined covariates age, fever, ESR, platelet count and size and ASA treatment were assessed. RESULTS: Eighty-five patients (mean age 73 yrs, 60% women, 78% biopsy-proven) were included in the analysis. Of the 85 patients, 62 (73%) presented with ischaemic events, 29/85 patients (34%) with severe ischaemic events. At the time of diagnosis 22/85 patients (26%) were treated with ASA. Of these 22 patients, 15 (68%) presented with ischaemic events, 7/22 patients (32%) with severe ischaemic events. In multivariate analysis, neither platelet count nor size or ASA treatment were significantly associated with ischaemic or severe ischaemic events. CONCLUSIONS: The incidence of severe ischaemic events in patients with GCA was high, irrespective of platelet count and size and established ASA treatment.

Phenotypical and functional characteristics of in vitro expanded bone marrow mesenchymal stem cells from patients with systemic sclerosis.

BACKGROUND: Mesenchymal stem cells (MSCs) have a potential immunomodulatory role in autoimmune disease; however, the qualitative properties and haematopoietic support capacity of MSCs derived from patients with autoimmune disease is unclear. OBJECTIVES: To further characterise phenotypically and functionally bone marrow (BM)-derived MSCs from patients with systemic sclerosis (SSc). METHODS: Key parameters of BM-derived MSC function and phenotype were assessed in 12 patients with SSc and compared with 13 healthy normal controls. The parameters included the ability to: form colony-forming unit fibroblasts (CFU-F), differentiate along the adipogenic and osteogenic lineages, express cell surface antigens defining the MSCs population, support normal haematopoiesis and suppress in vitro lymphocyte proliferation induced by either anti-CD3epsilon plus anti-CD28 monoclonal antibodies or the mixed lymphocyte reaction. RESULTS: SSc MSCs were shown to have a similar characteristic phenotype, capacities to form CFU-F and to differentiate along adipogenic and osteogenic lineages as those of healthy donor MSCs. The ability of SSc MSCs to support long-term haematopoiesis was also identical to that of controls. Both healthy donor and SSc BM MSCs reduced the proliferation of autologous and allogeneic peripheral blood mononuclear cells in a cell number dependent fashion. CONCLUSIONS: These results show that BM-derived MSCs from patients with SSc under the described culture conditions exhibit the same phenotypic, proliferative, differentiation potential and immunosuppressive properties as their healthy counterparts and could therefore be considered in an autologous setting. Further studies are needed to ensure the quality and safety of large-scale expansion of patient MSCs prior to their potential use in clinical trials.

Rheumatic conditions in human immunodeficiency virus infection.

Many rheumatic diseases have been observed in HIV-infected persons. We, therefore, conducted a comprehensive literature search in order to review the prevalence, presentation and pathogenesis of rheumatic manifestations in HIV-infected subjects. Articular conditions (arthralgia, arthritis and SpAs) are either caused by the HIV infection itself, triggered by adaptive changes in the immune system, or secondary to microbial infections. Muscular symptoms may result from rhabdomyolysis, myositis or from side-effects of highly active anti-retroviral therapy (HAART). Osseous complications include osteonecrosis, osteoporosis and osteomyelitis. Some conditions such as the diffuse infiltrative lymphocytosis syndrome and sarcoidosis affect multiple organ systems. SLE may be observed but may be difficult to differentiate from HIV infection. Some anti-retroviral agents can precipitate hyperuricaemia and are associated with arthralgia. When indicated, immunosuppressants and even anti-TNF-alpha agents can be used in the carefully monitored HIV patient. Thus, rheumatic diseases and asymptomatic immune phenomena remain prevalent in HIV-infected persons even after the widespread implementation of highly active anti-retroviral therapy.

Serum procalcitonin for discrimination between septic and non-septic arthritis.

BACKGROUND: Early differentiation between septic and non-septic arthritis is difficult. A previous study showed promising diagnostic accuracy of serum Procalcitonin (PCT) in septic arthritis, limited by a low sensitive PCT test kit. OBJECTIVE: To investigate the diagnostic value of PCT in patients with septic and non-septic arthritis using a novel test with low detection limit. METHODS: Forty-two patients, 28 with non-septic and 14 with septic arthritis were prospectively included. For each patient, gram stain, culture and polarization microscopy of synovial fluid was done and PCT, C-reactive protein (CRP), white blood cell count, uric acid and blood cultures were taken. Patients with septic arthritis, patients with non-septic arthritis with and without concomitant infection were compared. RESULTS: Patients with septic arthritis had a significant higher PCT concentration than patients with non-septic arthritis (p<0.0001). At a cut-off of 0.1 (0.25) ng/ml, sensitivity for septic arthritis was 100(93)% and specificity 46(75)%. Specificity rose to 93% after exclusion of patients with non-septic arthritis and concomitant infection. Both sensitivity and specificity for the diagnosis of septic arthritis were higher for PCT than CRP. CONCLUSIONS: Our data suggest that PCT seems to be a highly sensitive and specific marker for septic arthritis, depending on the clinical setting. Further studies are warranted.

Increased cardiovascular comorbidities in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia presenting with systemic inflammatory and autoimmune manifestations.

Myelodysplastic syndromes (MDS) and associated diseases, like chronic myelomonocytic leukemias (CMML), are heterogeneous, clonal disorders affecting the hematopoietic stem cells. They are characterized by dysplasia and a propensity to evolve toward acute myeloid leukemia. Systemic inflammatory and autoimmune manifestations (SIAMs) occur with a prevalence of 10% to 20% in myeloid malignancies, but the underlying pathogenetic mechanisms remain obscure. In this study, we aimed to characterize patient- and disease-based differences in MDS and CMML patients with and without SIAMs and explore the impact of SIAMs on progression and survival. We performed a retrospective, single-centre, and case-control study in a cohort of 93 patients diagnosed with MDS and CMML between 01/2008 and 12/2015. Thirty patients (32%) were identified with SIAMs: musculoskeletal and connective tissue (26.8%), vascular (19.5%), systemic autoinflammation (17%), skin (12.2%), gastrointestinal (9.8%), and others (14.6%). SIAMs were treated with glucocorticoids (60%), methotrexate (16.7%), biologicals (13.3%), and cyclosporine (3.3%). No significant differences between the SIAM and non-SIAM patients were observed in age, gender, or previous exposure to cancer treatment. Cardiovascular comorbidities were significantly more frequent in patients with SIAMs (63.1% vs 90%; OR 5.5; P < .01), but no differences were observed for other comorbidities or IPSS and IPSS-R risk scores. CMML and refractory anemia with excess blasts 1/2 subtypes were by tendency more frequent in patients with and refractory cytopenia with multilineage dysplasia (RCMD) in those without SIAMs. Finally, time to progression, leukemia free survival and overall survival were similar for both groups. Despite patient heterogeneity and small cohort size, we were able to identify a significant association of SIAMs with cardiovascular comorbidities but without influence on progression or survival.

Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients?

This EBMT Autoimmune Disease Working Party study aimed to evaluate the influence of CD34+ positive graft selection (CD34+) on the outcome of systemic sclerosis (SSc) patients after autologous hematopoietic stem cell transplantation (AHSCT). Clinical and laboratory data from 138 SSc patients at diagnosis, before and after AHSCT were retrospectively analyzed. CD34+ selection was performed in 47.1% (n=65) patients. By multivariate analysis adjusting for all factors differing between the two groups (without or with CD34+), there was no statistically significant difference in terms of overall survival (hazard ratio (HR): 0.98, 95% confidence interval (CI) 0.40-2.39, P=0.96), PFS (HR: 1.55, 95% CI 0.83-2.88, P=0.17) and incidence of relapse or progression (HR: 1.70, 95% CI 0.85-3.38, P=0.13). We demonstrate that CD34+ does not add benefit to the outcome of SSc patient treated with AHSCT. These findings should be further confirmed by prospective randomized trials.

Autologous stem cell transplantation of treatment-resistant systemic vasculitis--a single center experience and review of the literature.

AIMS: Autologous peripheral blood stem cell transplantation (autoPBSCT) is increasingly and successfully applied to patients with treatment-resistant autoimmune diseases, mainly multiple sclerosis and systemic sclerosis, but also juvenile idiopathic arthritis and systemic lupus erythematosus. We intended to analyze the effects of autoPBSCT in patients with treatment-resistant systemic vasculitis by analyzing the outcome of 4 patients from our own hospital, and comparing them to cases reported in the literature. METHODS: 4 patients with treatment-resistant vasculitis (Wegener granulomatosis, Churg Strauss syndrome, Takayasu arteritis and relapsing polychondritis) received an autologous PBSCT. Stem cell mobilization was performed with cyclophosphamide (CY) and G-CSF, stem cells were purged by positively selecting CD34+ stem cells over a CliniMacs device, and the conditioning was performed with high dose CY and anti-thymocyte globulin (ATG). RESULTS: AutoPBSCT was well tolerated in all 4 patients. The patient with WG achieved complete remission although cANCA persisted, the other patients are in good partial remissions and respond to maintenance treatments which had been ineffective before PBSCT (CSA, azathioprin). Glucocorticosteroids (GC) could be reduced to a maximum of 10 mg in all patients. Shortly after the procedure, reactivation of viruses from the herpes family occurred in 3 of the patients and had to be treated. In the data base, 25 patients transplanted for severe systemic vasculitis are registered, in the literature, 6 additional vasculitis patients remitting after autoPBSCT are reported. CONCLUSIONS: Autologous PBSCT is feasible and effective in severe, treatment-resistant forms of systemic vasculitis. Data are sparse, further prospective studies are needed. These should also aim at evaluating more optimal regimens for conditioning and purging during PBSCT, as in most of the vasculitis patients reported until now, mostly good partial remissions, but less complete remissions were achieved.

Familial inflammatory Sneddon's syndrome-case report and review of the literature.

Sneddon's syndrome (SNS) which originally was a clinical diagnosis, is now regarded as a common clinical manifestation of different disease entities. It has been divided into idiopathic, autoimmune and thromboembolic subsets or in systemic lupus erythematosus (SLE)-associated, antiphospholipid syndrome (APS)-associated and primary forms. Familial occurrence of Sneddon's syndrome is rare. We present a familial case of Sneddon's syndrome with inflammatory disease pattern, early disease onset and association with autoimmune thyroid disease and anticardiolipin antibodies. Although most authors reporting on adult cases of SNS consider it a non-inflammatory, thromboembolic process, the study of cases with early onset brings attention to the possible inflammatory origin of the syndrome.