Perceived health of patients with common variable immunodeficiency - a cluster analysis.

Common variable immunodeficiency (CVID) is a complex disease with various influences on perceived health, which correlate with different outcomes, including new morbidity and mortality. Our hypothesis was that CVID patients fall into distinct clusters of perceived health which can inform care. Ward hierarchical cluster analysis and K-means cluster analysis were performed on data of 209 CVID patients to identify subgroups regarding their self-reported physical and mental health status, assessed by the physical (PCS) and mental component scores (MCS) of the Short Form-12 (SF-12). Four clusters of CVID-patients were identified. Cluster 1 was the largest cluster, characterized by a relatively high physical and mental health status (44·0%). In contrast, cluster 2 (21·1%) included patients with low physical and mental health status. Clusters 3 and 4 were mixed groups with high mental and low physical health (15·8%) and vice versa (19·1%). Significant differences between the clusters were found for patient-reported outcomes such as work ability and health literacy, but not for CVID-associated complications such as enteropathy, interstitial lung disease, granulomatosis, lymphadenopathy and autoimmune cytopenia or laboratory parameters such as immunoglobulin levels or B cell-based classification. The results suggest different subgroups of CVID patients with contrasting individual needs which, surprisingly, did not differ in clinical or laboratory characteristics. The main finding of this study is that patients with CVID fall into four distinct clusters according to perceived health, which are largely independent of CVID complications.

Screening protocols to monitor respiratory status in primary immunodeficiency disease: findings from a European survey and subclinical infection working group.

Many patients with primary immunodeficiency (PID) who have antibody deficiency develop progressive lung disease due to underlying subclinical infection and inflammation. To understand how these patients are monitored we conducted a retrospective survey based on patient records of 13 PID centres across Europe, regarding the care of 1061 adult and 178 paediatric patients with PID on immunoglobulin (Ig) G replacement. The most common diagnosis was common variable immunodeficiency in adults (75%) and hypogammaglobulinaemia in children (39%). The frequency of clinic visits varied both within and between centres: every 1-12 months for adult patients and every 3-6 months for paediatric patients. Patients diagnosed with lung diseases were more likely to receive pharmaceutical therapies and received a wider range of therapies than patients without lung disease. Variation existed between centres in the frequency with which some clinical and laboratory monitoring tests are performed, including exercise tests, laboratory testing for IgG subclass levels and specific antibodies, and lung function tests such as spirometry. Some tests were carried out more frequently in adults than in children, probably due to difficulties conducting these tests in younger children. The percentage of patients seen regularly by a chest physician, or who had microbiology tests performed following chest and sinus exacerbations, also varied widely between centres. Our survey revealed a great deal of variation across Europe in how frequently patients with PID visit the clinic and how frequently some monitoring tests are carried out. These results highlight the urgent need for consensus guidelines on how to monitor lung complications in PID patients.

7(th) International Immunoglobulin Conference: Poster presentations.

Immunoglobulin (Ig) therapy is the mainstay of treatment for primary antibody deficiency disorders and has proved to be efficacious in specific autoimmune and inflammatory diseases. Additionally, due to the role of Ig in complement activation, it is being used increasingly in solid organ transplantation. Furthermore, Ig is the primary or secondary treatment in some immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) or multifocal motor neuropathy (MMN). This session discusses trends of Ig use in Europe, proposed mechanisms of action, adverse effects and the potential role of Ig therapy in transplantation. Dr Sedivá reported that Ig therapy is available in all European countries, although dosing is not always optimal, due partly to reimbursement plans. Subcutaneous immunoglobulin (SCIg) has become increasingly accessible in recent years; however, the chosen route of administration still varies widely between countries. Dr Berger's presentation on optimization of Ig therapy in neuropathies, and Dr Rojavin's report on a pharmacometric model to determine the serum IgG levels achieved by different dosing regimens in primary antibody deficiency (PAD) patients, led to the challenging concept of using individualized dosing strategies. Dr Klehmet reported on the potential benefit of using antigen-specific T cell responses as a biomarker of IVIg responsiveness in CIDP patients, while Dr von Gunten provided an insight into the mechanisms of action of Ig preparations, suggesting that the immunoregulatory effects of IgG may be mediated by IgG antibodies against glycans. Dr Basta reported on the potential thrombogenic adverse effects associated with Ig therapy. Although these adverse events are rare, further studies are needed to clarify the relationship between Ig replacement and immunomodulatory therapy and these adverse reactions. In transplantation, Dr Carbone described that prophylactic IVIg treatment was found to decrease the incidence of severe infection in IgG hypogammaglobulinaemia patients undergoing heart transplantations. Furthermore, Dr Clatworthy reported that inactivating polymorphisms in the inhibitory receptor FcγRIIB do not impact upon kidney allograft survival.

7th International Immunoglobulin Conference: Poster presentations.

The pan-European survey provides useful information on the accessibility and trends of intravenous and subcutaneous immunoglobulin (IVIg/SCIg) therapy, which is used to treat primary immunodeficiency disorders (PIDs). Although immunoglobulin (Ig) therapy is the first-line treatment for PIDs, the mechanisms of action of Ig therapy may differ according to the condition it is used to treat. Moreover, intriguing presentations suggest that further investigation is required to understand more clearly both the haematological and immunoregulatory effects of therapeutic immunoglobulin. This can ultimately provide more information on optimizing Ig therapy efficacy, and establish whether individualized dosing regimens for patients will be conducive to better clinical outcomes. In addition to treating autoimmune and inflammatory conditions, there is evidence to suggest that immunoglobulins can potentially play a role in transplantation, which warrants further investigation for future use.

A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency.

X-linked inhibitor of apoptosis (XIAP) deficiency, caused by mutations in BIRC4, is an immunodeficiency associated with immune dysregulation and a highly variable clinical presentation. Current diagnostic screening tests such as flow cytometry for XIAP expression or lymphocyte apoptosis assays have significant limitations. Based on recent evidence that XIAP is essential for nucleotide-binding and oligomerization domains (NOD)1/2 signalling, we evaluated the use of a simple flow cytometric assay assessing tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. We investigated 12 patients with XIAP deficiency, six female carriers and relevant disease controls. Irrespective of the diverse clinical phenotype, the extent of residual protein expression or the nature of the mutation, the TNF response was severely reduced in all patients. On average, L18-MDP induced TNF production in 25% of monocytes from healthy donors or female carriers, while fewer than 6% of monocytes responded in affected patients. Notably, the assay clearly discriminated affected patients from disease controls with other immunodeficiencies accompanied by lymphoproliferation, hypogammaglobulinaemia or inflammatory bowel disease. Functional testing of the NOD2 signalling pathway is an easy, fast and reliable assay in the diagnostic evaluation of patients with suspected XIAP deficiency.

Quantification of IgM and IgA anti-pneumococcal capsular polysaccharides by a new ELISA assay: a valuable diagnostic and prognostic tool for common variable immunodeficiency.

PURPOSE: Existing ways of assessing CVID patients at risk of pulmonary infections are not universally accepted. The need to identify additional prognostic factors allowed us to evaluate the anti-polysaccharide IgA and IgM responses in 125 CVID patients immunized with the 23-valent pneumococcal polysaccharide (PS) vaccine (Pneumovax(®)). METHODS: We used a new anti-PS23 IgM and IgA ELISA assay, which evaluates a global response to all 23 polysaccharides contained in Pneumovax(®). RESULTS: Anti-PS23 IgM and/or IgA antibodies were detectable in a minority of CVID patients. Antibody responses were correlated to B cell subpopulations and serum immunoglobulin concentrations. The non responders had a higher incidence of pneumonia and bronchiectasis and responders had the lowest incidence of respiratory complications. CONCLUSIONS: This new ELISA assay allows for studying vaccine response in patients on Ig replacement therapy. This test also is an additional method of evaluation of specific antibody responses representing a valuable contribution to identify prognostic marker in CVID patients.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

[Common variable immunodeficiency: a clinical challenge]. / Variabler Immundefekt : Eine klinische Herausforderung.

Common variable immunodeficiency (CVID) represents the most common clinically relevant form of primary immunodeficiency. This heterogeneous antibody deficiency syndrome is characterized not only by susceptibility to bacterial respiratory tract infections but displays additional signs of immune dysregulation, such as autoimmunity, chronic inflammation and lymphoproliferation in more than 30 % of the patients. Due to poor awareness the diagnosis is often delayed by 4-6 years. A close collaboration in patient care with a center specialized in primary immunodeficiency is recommended. Regular follow-up visits include assessment of adequate immunoglobulin replacement therapy and screening for manifestation of secondary complications. Regular substitution with intravenous or subcutaneous immunoglobulins has more or less normalized life expectancy of patients with isolated susceptibility to bacterial infections. Therefore, the current core task in the management of CVID patients is the elaboration of more effective and safer forms of prophylaxis and treatment of sequelae of immune dysregulation in the lungs, intestines and liver of affected patients.

[Vaccination in adult patients with chronic inflammatory rheumatic diseases]. / Impfung bei erwachsenen Patienten mit chronisch entzündlichen rheumatischen Erkrankungen.

Patients with chronic inflammatory rheumatic diseases often have an intrinsic and therapy associated increased susceptibility to infections which substantially contributes to morbidity and mortality of the patients. A large proportion of these infections are preventable by vaccination. For this reason in 2005 the standing vaccination committee (STIKO) recommended for patients with immunosuppression vaccination against pneumococcus, influenza, Haemophilus influenza b and meningococcus in addition to standard vaccinations, independent of age. Every patient should therefore be informed about a possible increase in susceptibility to infections and the recommended prevention by vaccination before implementation of immunosuppressive therapy.

Importance of B cell co-stimulation in CD4(+) T cell differentiation: X-linked agammaglobulinaemia, a human model.

We were interested in the question of whether the congenital lack of B cells actually had any influence on the development of the T cell compartment in patients with agammaglobulinaemia. Sixteen patients with X-linked agammaglobulinaemia (XLA) due to mutations in Btk, nine patients affected by common variable immune deficiency (CVID) with <2% of peripheral B cells and 20 healthy volunteers were enrolled. The T cell phenotype was determined with FACSCalibur and CellQuest Pro software. Mann-Whitney two-tailed analysis was used for statistical analysis. The CD4 T cell memory compartment was reduced in patients with XLA of all ages. This T cell subset encompasses both CD4(+)CD45RO(+) and CD4(+)CD45RO(+)CXCR5(+) cells and both subsets were decreased significantly when compared to healthy controls: P = 0·001 and P < 0·0001, respectively. This observation was confirmed in patients with CVID who had <2% B cells, suggesting that not the lack of Bruton's tyrosine kinase but the lack of B cells is most probably the cause of the impaired CD4 T cell maturation. We postulate that this defect is a correlate of the observed paucity of germinal centres in XLA. Our results support the importance of the interplay between B and T cells in the germinal centre for the activation of CD4 T cells in humans.

[Interdisciplinary AWMF guideline for the diagnostics of primary immunodeficiency]. / Interdisziplinäre AWMF-Leitlinie zur Diagnostik von primären Immundefekten (S2k).

BACKGROUND: Primary immunodeficiencies are potentially life-threatening diseases. Over the last years, the clinical phenotype and the molecular basis of an increasing number of immunological defects have been characterized. However, in daily practice primary immunodeficiencies are still often diagnosed too late. Considering that an early diagnosis may reduce morbidity and mortality of affected patients, an interdisciplinary guideline for the diagnosis of primary immunodeficiencies was developed on behalf of the Arbeitsgemeinschaft Pädiatrische Immunologie (API) and the Deutsche Gesellschaft für Immunologie (DGfI). METHODS: The guideline is based on expert opinion and on knowledge from other guidelines and recommendations from Germany and other countries, supplemented by data from studies that support the postulated key messages (level of evidence III). With the contribution of 20 representatives, belonging to 14 different medical societies and associations, a consensus-based guideline with a representative group of developers and a structured consensus process was created (S2k). Under the moderation of a representative of the Association of the Scientific Medical Societies in Germany (AWMF) the nominal group process took place in April 2011. RESULTS: The postulated key messages were discussed and voted on following a structured consensus procedure. In particular, modified warning signs for primary immunodeficiencies were formulated and immunological emergency situations were defined.

The transcription factor early growth response 1 (Egr-1) advances differentiation of pre-B and immature B cells.

In mature B lymphocytes, the zinc finger transcription factor early growth response 1 (Egr-1) is one of the many immediate-early genes induced upon B cell antigen receptor engagement. However, its role during earlier stages of lymphopoiesis has remained unclear. By examining bone marrow B cell subsets, we found Egr-1 transcripts in pro/pre-B and immature B lymphocytes, and Egr-1 protein in pro/pre-B-I cells cultivated on stroma cells in the presence of interleukin (IL)-7. In recombinase-activating gene (RAG)-2-deficient mice overexpressing an Egr-1 transgene in the B lymphocyte lineage, pro/pre-B-I cells could differentiate past a developmental block at the B220(low) BP-1(-) stage to the stage of B220(low) BP-1(+) pre-B-I cells, but not further to the B220(low) BP-1(+) CD25(+) stage of pre-B-II cells. Therefore, during early B lymphopoiesis progression from the B220(low) BP-1(-) IL-2R- pro/pre-B-I stage to the B220(low) BP-1(+) IL-2R+ pre-B-II stage seems to occur in at least two distinct steps, and the first step to the stage of B220(low) BP-1(+) pre-B-I cells can be promoted by the overexpression of Egr-1 alone. Wild-type mice expressing an Egr-1 transgene had increased proportions of mature immunoglobulin (Ig)M+ B220(high) and decreased proportions of immature IgM+ B220(low) bone marrow B cells. Since transgenic and control precursor B cells show comparable proliferation patterns, overexpression of Egr-1 seems also to promote entry into the mature B cell stage. Analysis of changes in the expression pattern of potential Egr-1 target genes revealed that Egr-1 enhances the expression of the aminopeptidase BP-1/6C3 in pre-B and immature B cells and upregulates expression of the orphan nuclear receptor nur77 in IgM+ B cells.

Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency.

Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαß+CD4-CD8- double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID.

[Clinical and serological findings of giant-cell arteritis]. / Internistische und serologische Befunde der Riesenzellarteriitis.

Giant cell arteritis (GCA) frequently appears as cranial arteritis (eg. temporal arteritis) with headache, pain on chewing and visual disturbances. In addition, extracranial manifestations are often observed leading to aneurysmatic dilatations and dissections of the aorta as well as stenoses of large thoracic, abdominal or limb arteries. The vascular signs are accompanied by general disease symptoms, e.g. malaise, elevated temperatures, weight loss and depression. Polymyalgia rheumatica (PMR) is the most frequent rheumatic manifestation of GCA but also occurs independently from GCA. The structural correlate for the PMR symptoms is first and foremost extra-articular inflammation (tenosynovitis, bursitis) of large joints and the vertebral column (interspinal bursitis). In addition, vasculitis of large arteries in PMR must be considered particularly in the presence of high inflammatory activity. While specific laboratory markers for GCA and PMR are lacking elevated values for the erythrocyte sedimentation rate and C-reactive protein are present in almost all patients at disease onset. Besides the clinical evaluation, the serological acute phase reaction represents the main parameter for the course during therapy of this relatively frequent disease in elderly people.

[Cyclophosphamide versus bolus in Wegener's granulomatosis and other ANCA-related vasculitides: advantages and disadvantages]. / Cyclophosphamid oral vs. Bolus bei Wegener-Granulomatose und anderen ANCA-assoziierten Vaskulitiden: Pro und Contra.

Cyclophosphamide remains the therapy of choice in severe ANCA positive vasculitis. In order to avoid the considerable side effects of high cumulative doses sometimes manifesting themselves years later, induction therapy with a low cyclophosphamide dose and an early switch to cyclophosphamide-free maintenance regimens should be aimed for. This can be achieved by an induction therapy of 3--6 months of intravenous pulse therapy (pCYC) or oral therapy (oCYC). The metaanalysis of therapeutic trials in ANCA vasculitis demonstrates a slightly higher induction rate of remission, but an increased relapse rate of pCYC compared to oCYC. The incidence of adverse events seems to be higher in oCYC compared to pCYC. The results of the first controlled prospective multicenter trial (CYCLOPS) directly comparing pCYC and oCYC treatment of ANCA-positive vasculitis are eagerly awaited. It will be important to extend the follow-up over several years in order to reach a valid estimate of the incidence of secondary malignancies due to CYC therapy.

Mural inflammatory hyperenhancement in MRI of giant cell (temporal) arteritis resolves under corticosteroid treatment.

OBJECTIVE: To determine the effect of corticosteroid treatment on mural inflammatory hyperenhancement in MRI in GCA. METHODS: MRI of the superficial temporal artery with sub-millimetre in-plane spatial resolution (195 x 260 microm) was performed in 17 patients with proven GCA at the initiation of corticosteroid treatment and after 16 months of therapy. Visual MRI scores for mural inflammation were correlated with clinical and laboratory findings. RESULTS: Intensity of inflammatory hyperenhancement decreased significantly under corticosteroid therapy (2.3 +/- 0.6 vs 0.5 +/- 0.6, P < 0.001, with MRI score >2 indicating vasculitis). This finding correlated with the clinical and serological remission in 15/17 patients. Of the two patients with active disease, one had persisting mural inflammation in MRI indicative of relapsing disease. The other patient presenting with signs of polymyalgia rheumatica had no inflammatory changes of the superficial temporal arteries on MRI scan at follow-up. CONCLUSIONS: Mural contrast enhancement in high-resolution MRI is pronounced in active disease and decreases under corticosteroid treatment, correlating well with laboratory remission.

Ultrasonography in the assessment of peripheral joint involvement in psoriatic arthritis : a comparison with radiography, MRI and scintigraphy.

The objective of our study was to investigate the role of musculoskeletal ultrasound (US) in the assessment of hand and foot small joints in psoriatic arthritis (PsA). Thirteen consecutive patients with PsA of hands or feet underwent B-mode US using a 9- to 13-MHz transducer and simultaneous magnetic resonance imaging (MRI), bone scintigraphy and radiography. US findings were compared with radiography, MRI and scintigraphy in 190, 182 and 109 joints, respectively. To assess the sensitivity and specificity of US, radiography was considered as gold standard for the detection of erosions and osteoproliferations and MRI as gold standard for the detection of joint effusion and synovitis. US, MRI and scintigraphy had a higher sensitivity in the detection of overall joint pathology than radiography in painful and/or swollen joints (71%, 72%, 82% vs 32%) and clinically unaffected joints (17%, 21%, 9% vs 2%). US and radiography detected more erosions and osteoproliferations than MRI, with low agreement between the methods in the detection of erosions. Radiography was superior to US in the visualisation of osteoproliferations. Joint effusions and/or synovitis were more frequently detected by MRI than US. Agreement between both imaging methods was better in carpal joints, carpometacarpal joint I, metacarpophalangeal (MCP)/metatarsophalangeal (MTP) joint I, II and V than in MCP/MTP III, IV, PIP and DIP joints. Compared with MRI, radiography and scintigraphy, the specificity of US ranges between 0.84 and 0.94, depending on the joint pathology. In conclusion, the diagnostic sensitivity of US in the detection of PsA-related synovitis of hands and feet is lower than MRI and depends on the joint region. However, the low cost and the acceptable specificity suggest that US is a useful imaging method in addition to radiography in PsA of hands and feet.

Influence of corticosteroid treatment on MRI findings in giant cell arteritis.

Giant cell arteritis (GCA) remains a diagnostic challenge. With the use of a high-resolution MRI protocol, visualization of the superficial cranial arteries is feasible and mural inflammation can be assessed noninvasively. Until today, it is not known how soon inflammatory signals in diagnostic MR imaging vanish after initiation of treatment. Here, we report sequential MR imaging findings during the initial weeks of corticosteroid treatment in a 79-year-old female patient with histologically proven GCA. Mural inflammatory changes decreased within the first 2 weeks and have almost entirely vanished after 2 1/2 months of continued treatment. Moreover, MR angiography revealed sequential stenoses of the subclavian artery, which improved in variable extent with some residuals despite high dose steroid medication. This report underlines the value of high-resolution MRI in diagnosis and follow-up of GCA and illustrates the potential of MRI to detect and monitor intra- and extra-cranial involvement patterns of GCA in high detail.