Immunoadsorption for collagen and rheumatic diseases.

The field of therapeutics has seen remarkable progress in the recent years, which has made mainstream drug treatment possible for collagen and rheumatic diseases. However, treatment of intractable cases where drug effectiveness is poor is a challenge. Furthermore, organ damage, concurrent illnesses or allergic reactions make adequate drug therapy impossible. For such cases, therapeutic apheresis is very significant, and it is important how this should be valued related to drug therapies. Therapeutic apheresis for collagen and rheumatic diseases involves the removal of factors that cause and exacerbate the disease; the aim of immunoadsorption, in particular, is to improve the clinical condition of patients with autoimmune disease by selectively removing pathogenic immune complexes and autoantibodies from their plasma. Immunoadsorption, in particular, unlike plasma exchange and DFPP, utilizes a high-affinity column that selectively removes autoantibodies and immune complexes, leaving other plasma components intact. There is no need to replenish fresh frozen plasma or blood products such as albumin and gamma globulin preparations. Immunoadsorption is thus superior in terms of safety, as the risk of infection or allergic reaction relating to these preparations can be avoided. We anticipate future investigations of application of synchronized therapy using drugs and therapeutic apheresis, most notably immunoadsorption, in combination to treat intractable clinical conditions such as collagen and rheumatic diseases. In this paper, our discussion includes the indications for immunoadsorption such as collagen and rheumatic diseases, the relevant conditions and types, as well as the latest understanding related to methods and clinical efficacy.

Risk of cytomegalovirus reactivation in patients with immune-mediated inflammatory diseases undergoing biologic treatment: a real matter?

The use of biological agents has grown exponentially in immune-mediated inflammatory diseases (IMID), often achieving a good control of disease progression and improving patients' quality of life. However, their use resulted in an increased risk of adverse events, including reactivation of chronic/latent infectious diseases. As for the risk of Cytomegalovirus (CMV) reactivation, very few data are available. We reviewed the literature reporting cases of CMV infection in IMID patients during biological therapy. Although the risk of CMV reactivation cannot be excluded, we concluded that there is no evidence to warrant CMV screening before starting a biological agent.

[Molecular diagnosis of collagen vascular diseases and vasculitides]. / Molekulare Diagnostik der Kollagenosen und Vaskulitiden.

Collagen vascular diseases and vasculitides comprise various diseases, which may affect virtually every organ system. Therefore, their diagnosis and management is often an interdisciplinary challenge. Because of the heterogeneous symptoms, these diseases have significant overlap, which interferes with the clinical diagnosis and may require additional investigation. Therefore, a rational and comprehensive diagnostic work-up should be performed at the initial presentation before initiation of therapy. The detection of antinuclear (ANA) or anticell antibodies by indirect immunofluorescence microscopy on Hep2 cells is used to screen for autoantibodies in collagen vascular diseases. The molecular specificity of autoantibodies should be further characterized using immunoassays with recombinant or purified protein. When systemic autoimmune disease is suspected, the function of the frequently affected organs should be evaluated. The immunopathological findings should always be interpreted in the context of clinical, histological, and imaging data. The detection of autoantibodies is helpful for the initial diagnosis, provides prognostic information, may indicate involvement of organs or systems and some parameters may also be used for disease monitoring. The clinical significance of autoantibodies is emphasized by the fact that their detection constitutes diagnostic criteria for most collagen vascular diseases and several vasculitides. The screening for ANCA may be performed using immunoassays with recombinant myeloperoxidase and proteinase 3 or by indirect immunofluorescence microscopy on granulocytes. In this article, the current diagnostic tools and their relevance for the diagnosis and monitoring of systemic autoimmune diseases with primary skin involvement are reviewed.

[B-cell-directed therapy in patients with connective tissue diseases]. / Anti-B-Zelltherapie bei Kollagenosen.

B cells are able to present antigen, secrete cytokines and differentiate into (auto)antibody secreting cells and are therefore considered as an important therapeutic target in patients with autoantibody-mediated autoimmune disease. Benefits and limitations of B-cell-directed therapies and unmet medical needs are discussed in this minireview. B cell targeting broadens our armamentarium available to treat SLE and other connective tissue diseases. But further research addressing unmet medical needs is required and refractory patients receiving B cell-directed off-label therapeutics should be enrolled in registries to collect information on the value and safety of these drugs in rare autoimmune diseases.

NK cell populations in collagen vascular disease.

OBJECTIVES: Pulmonary involvement of varying etiology is common in collagen vascular diseases (CVDs). Bronchoalveolar lavage fluid (BALF) cell differentials reveal information on the immune mechanisms involved in the CVDs. The aim of the present study was to evaluate BALF cell populations in CVD-associated ILD and to investigate possible correlation with pulmonary function. METHODS: Fifty-seven patients (26 male and 31 female, mean age ± SD: 54.68±12.18 years) with CVD-associated interstitial lung disease were studied. Patients were divided into 6 groups based on underlying CVD. The study population also included a group of 10 healthy controls. BALF was examined in all individuals. Cell density, total cell number and differential cell count were recorded. BALF lymphocyte subsets were analysed by dual flow cytometry. Pulmonary function was assessed in all patients. RESULTS: BALF differential cell count did not differ significantly among the different groups. Scleroderma patients showed the highest percentage of CD19 cells (p<0.001). The NK and NKT cell percentages were significantly higher in systemic lupus erythematosus and in Sjögren, respectively, compared to other CVDs and controls (p=0.001 and p<0.001). Also BALF neutrophil percentage correlated negatively with FVC (r=-0.356, p=0.011) and FEV1 (r=-0.336, p=0.017) and BALF NKT cell percentage correlated negatively with pO2 (r=-0.415, p=0.003). CONCLUSIONS: Important variations observed in BALF cell populations suggest the implication of NK and NKT cells in the pathogenesis of lung involvement in CVDs.

[Non-specific interstitial pneumonia (NSIP)]. / Nicht spezifische interstitielle Pneumonie.

Non-specific interstitial pneumonia (NSIP) belongs to the group of idiopathic interstitial pneumonias (IIP). However, NSIP can also be found in several other diseases. For example, the NSIP pattern is most commonly found in interstitial lung disease due to connective tissue disease. In this review, the definition and classification, aetiology, pathogenesis and histology, clinical symptoms, serological markers, lung function parameters, radiographic signs, treatment, and prognosis of NSIP are presented. Idiopathic NSIP as a distinct form of NSIP will be discussed separately.

Identification of α-tubulin as an autoantigen recognized by sera from patients with neuropsychiatric systemic lupus erythematosus.

In a previous study we found in 50% of patients with neuropsychiatric manifestations of systemic lupus erythematosus (NP-SLE) organ specific antibodies to 45-56 kD proteins in a 100,000 g supernatant (SN) from bovine brain mitochondria. Aim of the present study was to identify the corresponding target antigen. A 100,000 g SN from bovine brain mitochondria was applied to SDS-gel electrophoresis. A 50 kD band recognized by sera from patients with NP-SLE in the Western blot (WB) was excised from the gels and applied to mass spectrometry. The identified protein was expressed in Escherichia coli and retested against sera from eleven patients with NP-SLE (severe symptoms n=6, mild symptoms n=5), 26 SLE-patients without NP manifestations and 53 controls (patients with multiple sclerosis, epilepsy, healthy blood donors). Mass spectrometry of the 50 kD band revealed the presence of α-tubulin. Applying the recombinant α-tubulin in the WB, four of the eleven NP-SLE patients (36%), one of the 26 patients with SLE without NP manifestations (4%) and none of the 53 controls reacted with α-tubulin. The antibodies were more frequently found in patients with severe (50%) than with mild NP-SLE (20%). α-tubulin may be a novel marker autoantigen for a neuropsychiatric manifestation at least in a subgroup of patients with SLE. Whether anti-α-tubulin antibodies are of pathogenetic relevance has still to be clarified.

Allogeneic disparities in immunoglobulin-like transcript 5 induce potent antibody responses in hematopoietic stem cell transplant recipients.

In hematopoietic stem cell transplant (HSCT) recipients, the recognition of polymorphic antigens by the donor-derived immune system is an important mechanism underlying both graft-versus-host disease and graft-versus-leukemia (GVL) effect. Here we show that a subset of HSCT recipients (13.9%, n = 108) have antibodies directed to surface molecules of dendritic cells. We have used one such serum in conjunction with retroviral expression cloning to identify the highly polymorphic surface molecule immunoglobulin-like transcript 5 (ILT5) as one of the targets of dendritic cell-reactive antibodies. ILT5 reactive antibodies were found in 5.4% of HSCT patients but not in solid organ transplantation recipients, patients with collagen diseases, multiparous women, or polytransfused or healthy persons. We show that ILT5-specific antibodies can mediate killing of ILT5-bearing cells and furthermore demonstrate ILT5 expression in some leukemic cells, indicating that it might be a target for GVL effects. Thus, our results represent the first description of potent allogeneic antibody responses to a non-major histocompatibility complex cell surface molecule in hematopoietic stem cell transplanted patients and warrant further studies to elucidate the role of antibodies to polymorphic cell surface molecules in GVL and graft-versus-host responses.

[Anti-B-cell strategies in vasculitides and collagenoses]. / Anti-B-Zell-Strategien bei Vaskulitiden und Kollagenosen.

B-cells play a central role in the pathogenesis of autoimmune diseases. As already discussed in other articles, besides the production of potentially pathogenic autoantibodies, B-cells may function as antigen-presenting cells, may induce T-cell activation and produce various cytokines. The feasibility of targeting B-cells in patients with severe and refractory autoimmune disorders, especially in patients with vasculitis or connective tissue diseases, has met growing interest among rheumatologists in recent years. The use of rituximab as a monoclonal antibody directed against CD20 positive B-cells has been reported in case reports and small patient series; however, these are hard to compare as different diseases are described and different doses and schedules of rituximab were used. It has to be considered that positive reports are more likely to be reported than patients who do not improve or experience side effects. Data on only a few indications from randomized, double-blind studies are available; however, even these results should be evaluated critically.

Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease.

INTRODUCTION: Previous studies of interstitial lung disease (ILD) suggest that prognosis and therapeutic response are influenced by the presence of underlying collagen vascular disease (CVD). Yet, what proportion of patients presenting with ILD have CVD is largely unknown. We sought to determine the frequency of a new CVD diagnosis in an ILD referral population. MATERIALS/PATIENTS AND METHODS: We retrospectively studied 114 consecutive patients evaluated at the Johns Hopkins Interstitial Lung Disease Clinic for the development of CVD. RESULTS: In this retrospective cohort, nearly one-third of the 114 patients with confirmed ILD satisfied published criteria for a CVD diagnosis. Seventeen (15%) patients were diagnosed with a new CVD as a direct consequence of their ILD evaluation. Patients with new CVD diagnosis were younger than those without new CVD diagnosis: 51.4years (95% CI 45-58years) and 60years (95% CI 57-63), respectively (p=0.01). Moreover, an ANA>or=1:640 (p=0.03) and elevated levels of creatine phosphokinase (CPK) or aldolase (p<0.001) were associated with a new CVD diagnosis. CONCLUSIONS: Unrecognized collagen vascular disease may be more common than previously appreciated among patients referred with ILD. High titer ANA and an elevated CPK or aldolase are associated with a CVD diagnosis in this referral population.