[The rich diversity of Whipple's disease]. / Facettenreichtum des Morbus Whipple.

Whipple's disease (WD) is a rare, chronic multiorgan disease which can caused by Tropheryma whipplei, a ubiquitous gram positive bacterium. Detection of T. whipplei is mostly performed histologically using periodic acid-Schiff (PAS) staining in affected tissues to visualize characteristic PAS-positive macrophages and by the polymerase chain reaction (PCR). Clinically, WD is often characterized by gastrointestinal symptoms (diarrhea, colic-like abdominal pain and weight loss). Arthritis is a common presentation of WS, often leading to a misdiagnosis of seronegative rheumatoid arthritis and as a consequence to immunosuppressive therapy. The clinical presentation of WD is highly polymorphic affecting different organ systems (e. g. cardiac or neurological manifestation) and making an appropriate clinical diagnosis and even the diagnostic process itself difficult. This article reports on three cases presenting with completely different leading symptoms (initially misdiagnosed as seronegative rheumatoid arthritis, spondyloarthritis and adult onset of Still's disease, respectively) that illustrate the rich diversity of WD. The cases were chosen to draw attention to the fact that although WD is mainly associated with the field of gastroenterology and gastrointestinal (GI) involvement is common, it may appear without GI symptoms. In cases of a clinical suspicion of WD, diagnostic efforts should be made to detect the bacterium in the affected organ. The German S2k guidelines on GI infections and WD published in January 2015 summarized the current state of the art for WD. The currently recommended primary treatment is antibiotics that can infiltrate the cerebrospinal fluid, e. g. ceftriaxone, followed by cotrimoxazole, which should be maintained over several months.

[Multimodal rheumatologic complex treatment of rheumatoid arthritis-a monocentric retrospective analysis]. / Multimodale rheumatologische Komplexbehandlung bei rheumatoider Arthritis ­ eine monozentrische Retrospektivanalyse.

BACKGROUND: Multimodal rheumatologic complex treatment (MRCT, operation and procedures classification system, OPS code 8­983) is a specific concept of acute inpatient care (DRG I97Z) for treatment of patients with rheumatic diseases, degenerative diseases and/or chronic pain syndromes suffering from exacerbated pain and functional impairment. OBJECTIVE: A monocentric retrospective analysis of the effects of MRCT on pain and functional status in patients with rheumatoid arthritis (RA) was conducted. METHODS: A total of 103 treatment episodes in 75 patients with proven RA who received MRCT between 2014 and 2017 were included in the analysis. The changes in pain intensity were evaluated using a numerical rating scale (NRS), the functional limitations as assessed by the Hanover function questionnaire (FFbH) and the health assessment questionnaire (HAQ) and the disease activity (disease activity score of 28 joints, DAS28) before and after MRCT episodes. In addition, the patient characteristics and the course of the disease were documented and a univariate analysis of the influence of these factors on the parameters activity and function was performed. RESULTS: In patients with RA, the MRCT resulted in a significant amelioration of pain (p < 0.0001), a significant improvement of functional capacity (FFbH p = 0.0013, HAQ p = 0.1396) and a significant reduction of disease activity (DAS28 p < 0.0001). Different aspects of the disease and its previous course (e. g. disease duration, type and number of previous anti-rheumatic drugs, current medication) did not have a significant effect on the response. CONCLUSION: This retrospective monocentric analysis proved the efficacy of MRCT with respect to the inpatient treatment period in a large cohort of RA patients. This treatment concept not only improved pain and function (FFbH) but also significantly reduced the disease activity.

[Molecular effects of physical therapy. What's new?]. / Molekulare Wirkungen physikalischer Therapiemaßnahmen. Was gibt es Neues?

Modern molecular medicine offers the possibility to investigate the potential influences of different methods of physical therapy on pivotal mechanisms and mediators of the inflammatory processes of rheumatic diseases and interactions between cells of the immune system and bone. Based on recent studies, it could be shown that modulation of these regulatory systems can be achieved by various physiotherapeutics.

[Modern disease-modifying antirheumatic drugs]. / Moderne Antirheumatika.

The term modern disease-modifying antirheumatic drugs (DMARD) includes not only the constantly growing family of DMARDs for chronic inflammatory rheumatic diseases but also the repositioning of established drugs in updated and novel algorithms of the different entities. The usual precursor for these developments is rheumatoid arthritis for which completely revised and updated guidelines have been published not only in Germany but also on the European level. In addition, label extensions to existing drugs have been granted for connective tissue diseases and vasculitides, e.g. anti-CD20 antibodies for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides and belimumab for systemic lupus erythematosus. Moreover, several novel drugs, especially of the biologics class, have been either introduced in clinical rheumatology or are close to being licensed and include ustekinumab for psoriatic arthritis, granulocyte growth inhibitors and janus kinase inhibitors for rheumatoid arthritis and atacicept for systemic lupus erythematosus. With the termination of the patent for several biologics, a new momentum also took place: the approval of the so-called biosimilars which has already initiated intensive discussions not only with respect to "similar" effects and side effects but also with respect to their potential impact on economical aspects.

[Evidence-based recommendations for the management of undifferentiated peripheral inflammatory arthritis (UPIA). The German perspective on the international 3e initiative]. / Evidenzbasierte Empfehlungen zum Management einer undifferenzierten peripheren entzündlichen Arthritis (UPIA). Die deutsche Perspektive zur internationalen 3e-Initiative.

INTRODUCTION: Peripheral arthritis is the most common presenting complaint in clinical rheumatology. Unequivocal identification of the underlying entity can be difficult, particularly at an early stage. Such cases are commonly referred to as undifferentiated peripheral inflammatory arthritis (UPIA). Since evidence-based recommendations for the clinical management of UPIA are lacking, this international 3e initiative convened 697 rheumatologists from 17 countries to develop appropriate recommendations. METHODS: Based on a systematic literature research in Medline, EMBASE, Cochrane Library, and the ACR/EULAR abstracts of 2007/2008, 10 multinational recommendations were developed by 3 rounds of a Delphi process. In Germany, a national group of experts worked on 3 additional recommendations using the same method. The recommendations were discussed among the members of the 3e initiative and the degree of consensus was analyzed as well as the potential impact of the recommendations on clinical practice. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed for the development of 10 multinational recommendations concerning differential diagnosis, diagnostic and prognostic value of clinical assessments, laboratory tests and imaging techniques, and monitoring of UPIA. In addition, 3 national recommendations on the diagnostic and prognostic value of a response to anti-inflammatory therapy on the analysis of synovial fluid and on enthesitis were developed by the German experts based on 35 out of 5542 references. CONCLUSIONS: The article translates the 2011 published original paper of the international 3e initiative (Machado et al., Ann Rheum Dis 70:15-24, 2011) and reports the methods and results of the national vote and the additional 3 national recommendations.

Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: association with the functional IRAK1 196Phe/532Ser haplotype.

OBJECTIVE: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Phe functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. METHODS: We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). RESULTS: An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 × 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 × 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 × 10(-4), respectively). CONCLUSION: Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.

Association of the CD226 Ser(307) variant with systemic sclerosis: evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis.

OBJECTIVE: The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. METHODS: CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. RESULTS: The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 × 10(-5) . The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 × 10(-6) , OR 1.82 (95% CI 1.38-2.40), P = 2.16 × 10(-5) , and OR 1.61 (95% CI 1.25-2.08), P = 2.73 × 10(-4) , respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. CONCLUSION: Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

[In-vitro study on dissection of inflamed synovial tissue by hydro-jet cutting]. / In-vitro-Untersuchungen zur Dissektion der entzündlichen Synovialis mittels Hochdruck-Flüssigkeitsstrahl (Hydro-Jet-Cutting).

Surgical synovectomy is a useful therapeutic option for rheumatoid arthritis patients with ongoing active synovitis despite optimal medical therapy. The present experimental study evaluated the novel, minimally invasive surgical technique of hydro-jet cutting in vitro using synovial biopsies. Depending on the selected water pressure (30-100 bar) it is possible to achieve precise and selective dissection of the synovial membrane. It was found that application of a water jet at 60 bar for 15 s is ideal for dissecting the stratum synoviale from the stratum fibrosum without any alteration of the joint capsule. This finding was confirmed by histological analyses. This novel and precise dissection technique promises to be an excellent alternative to the established techniques of synovectomy in the near future.

Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group.

OBJECTIVE: To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc). METHODS: A list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores. RESULTS: Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily); vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting. CONCLUSION: The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.

NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis.

BACKGROUND: Recent evidence has highlighted a potential role of interleukin 1ß (IL-1ß) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1ß. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders. OBJECTIVE: /st> To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population. METHODS: NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin. RESULTS: Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA. CONCLUSIONS: Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

Association of a KCNA5 gene polymorphism with systemic sclerosis-associated pulmonary arterial hypertension in the European Caucasian population.

OBJECTIVE: Pulmonary arterial hypertension (PAH) has emerged as a leading cause of death in systemic sclerosis (SSc). The genetic basis of PAH has been unraveled in recent years, with a major role played by transforming growth factor ß receptors; however, some other candidate genes have also been advocated, including potassium voltage-gated channel, shaker-related subfamily, member 5 (KCNA5). We undertook this study to determine whether KCNA5 polymorphisms confer susceptibility to SSc and its vascular phenotype, including PAH. METHODS: Four KCNA5 single-nucleotide polymorphisms (SNPs), rs10744676, rs1860420, rs3741930, and rs2284136, were genotyped in a discovery set of 638 SSc patients and 469 controls. In addition, rs10744676 was genotyped in an independent replication sample (938 SSc patients and 564 controls) and in a cohort of 168 patients with different PAH subtypes. RESULTS: The KCNA5 rs10744676 variant was found to be associated with SSc in the discovery sample, with an odds ratio (OR) of 0.62 (95% confidence interval [95% CI] 0.48-0.79, adjusted P = 0.0003) in comparison with controls (C allele frequency 11.4% versus 17.2%). When subphenotypes were investigated, an association was found solely for PAH associated with SSc (OR 0.31 [95% CI 0.13-0.71], adjusted P = 0.04). The other KCNA5 SNPs tested were not associated with any SSc subset. The above association with PAH associated with SSc was replicated in the second set. In the combined population, rs10744676 was strongly associated with PAH associated with SSc in comparison with controls (OR 0.36 [95% CI 0.21-0.63], P = 0.0002). In the independent cohort of patients with PAH, after investigating PAH subtypes, only rs10744676 showed an association with PAH associated with SSc. CONCLUSION: Our results provide the first evidence for an association between the KCNA5 rs10744676 variant and PAH associated with SSc.

[Biologics and cardiovascular risk]. / Biologika und kardiovaskuläres Risiko.

Over the course of the last decade, biologic response modifiers (biologics) have significantly broadened the therapeutic armamentarium in clinical rheumatology. In addition to their impressive efficacy, they have also received considerable attention regarding their adverse effects. In contrast to the risk of severe infections and malignancies, the cardiovascular risk of these drugs has provoked less vigilance. This article reviews the current data on the cardiovascular effects and adverse effects of biologics.

[Detection of psoriasis arthritis with the GEPARD patient questionnaire in a dermatologic outpatient setting]. / GEPARD-Patientenfragebogen: Erfassung von Patienten mit Psoriasisarthritis aus einem ambulanten dermatologischen Patientenpool.

BACKGROUND: Diagnosis of psoriasis arthritis (PsA) is often delayed in an outpatient dermatological setting. Therefore, we compiled a patient questionnaire (GEPARD, GErman Psoriasis ARthritis Diagnostic questionnaire) to detect PsA in psoriasis outpatients. PATIENTS AND METHODS: Initially, between 2005 and 2007, we evaluated GEPARD in the outpatient setting of our Department of Dermatology with the Vasey and Espinoza criteria. In May 2008, the questionnaire was distributed to practices in the Regensburg area, Germany. Patients who filled out the GEPARD questionnaire were invited for a rheumatological work-up and, where indicated, arthrosonography, conventional X-ray, MRI, and scintigraphy examinations were performed. PsA was classified on the basis of the CASPAR criteria. RESULTS: We calculated a sum cut-off score of >or= 4 positive answers in the first cohort. Of all 54 patients examined 63% could be diagnosed with PsA according to the CASPAR criteria. After a complete work-up with all diagnostic means 79.6% (43 patients) could be detected with inflammatory joint manifestations. CONCLUSION: It is possible to detect PsA patients in a dermatologic outpatient setting with the GEPARD questionnaire.

Use of vasoactive/vasodilating drugs for systemic sclerosis (SSc)-related digital ulcers (DUs) in expert tertiary centres: results from the analysis of the observational real-life DeSScipher study.

INTRODUCTION: DeSScipher is the first European multicentre study on management of systemic sclerosis (SSc), and its observational trial 1 (OT1) evaluated the efficacy of different drugs for digital ulcer (DU) prevention and healing. The aim of this study was to assess current use of vasoactive/vasodilating agents for SSc-related DU in the expert centres by analysing the baseline data of the DeSScipher OT1. METHOD: Baseline characteristics of patients enrolled in the OT1 and data regarding DU were analysed. RESULTS: The most commonly used drugs, in both patients with and without DU, were calcium channel blockers (CCBs) (71.6%), followed by intravenous iloprost (20.8%), endothelin receptor antagonists (ERAs) (20.4%) and phosphodiesterase 5 (PDE-5) inhibitors (16.5%). Of patients, 32.6% with DU and 12.8% without DU received two drugs (p < 0.001), while 11.5% with DU and 1.9% without DU were treated with a combination of three or more agents (p < 0.001). Sixty-five percent of the patients with recurrent DU were treated with bosentan and/or sildenafil. However, 64 out of 277 patients with current DU (23.1%) and 101 (23.6%) patients with recurrent DU were on CCBs alone. CONCLUSIONS: Our study shows that CCBs are still the most commonly used agents for DU management in SSc. The proportion of patients on combination therapy was low, even in patients with recurrent DU: almost one out of four patients with current and recurrent DU was on CCBs alone. Prospective analysis is planned to investigate the efficacy of different drugs/drug combinations on DU healing and prevention. Key Points • The analysis of DeSScipher, the first European multicentre study on management of SSc, has shown that the most commonly used vasoactive/vasodilating drugs for DU were CCBs, followed by intravenous Iloprost, ERAs and PDE-5 inhibitors. • More than half of the patients with recurrent DU received bosentan and/or sildenafil. • However, the proportion of patients on combination therapy of more than one vasoactive/vasodilating drug was low and almost one out of four patients with current and recurrent DU was on CCBs alone.

[Novel B-cell directed strategies for the treatment of rheumatic diseases]. / Neue Anti-B-Zell-Strategien für die Therapie rheumatischer Erkrankungen.

The clinical success of B-cell depletion using the anti-CD20 antibody rituximab has sparked a new era in the therapy of rheumatic diseases. A large variety of novel B-cell directed biologic agents has been developed recently. The new strategies not only aim at depleting B-cells (ocrelizumab, veltuzumab, ofatumumab, TRU-015) but also target essential survival and proliferation factors such as BAFF (belimumab, atacicept, briobacept), and are directed at modulating B-cell function via CD22 (epratuzumab), inhibition of costimulation (abatacept) and induction of tolerance (abetimus). Thus far, clinical trials indicate high efficacy comparable to rituximab as well as a good safety profile. This review summarizes the therapeutic mechanisms of the novel B-cell directed agents and the current status of clinical trials in rheumatic diseases.

Classification, categorization and essential items for digital ulcer evaluation in systemic sclerosis: a DeSScipher/European Scleroderma Trials and Research group (EUSTAR) survey.

BACKGROUND: A consensus on digital ulcer (DU) definition in systemic sclerosis (SSc) has been recently reached (Suliman et al., J Scleroderma Relat Disord 2:115-20, 2017), while for their evaluation, classification and categorisation, it is still missing. The aims of this study were to identify a set of essential items for digital ulcer (DU) evaluation, to assess if the existing DU classification was useful and feasible in clinical practice and to investigate if the new categorisation was preferred to the simple distinction of DU in recurrent and not recurrent, in patients with systemic sclerosis (SSc). METHODS: DeSScipher is the largest European multicentre study on SSc. It consists of five observational trials (OTs), and one of them, OT1, is focused on DU management. The DeSScipher OT1 items on DU that reached ≥ 60% of completion rate were administered to EUSTAR (European Scleroderma Trials and Research group) centres via online survey. Questions about feasibility and usefulness of the existing DU classification (DU due to digital pitting scars, to loss of tissue, derived from calcinosis and gangrene) and newly proposed categorisation (episodic, recurrent and chronic) were also asked. RESULTS: A total of 84/148 (56.8%) EUSTAR centres completed the questionnaire. DeSScipher items scored by ≥ 70% of the participants as essential and feasible for DU evaluation were the number of DU defined as a loss of tissue (level of agreement 92%), recurrent DU (84%) and number of new DU (74%). For 65% of the centres, the proposed classification of DU was considered useful and feasible in clinical practice. Moreover, 80% of the centres preferred the categorisation of DU in episodic, recurrent and chronic to simple distinction in recurrent/not recurrent DU. CONCLUSIONS: For clinical practice, EUSTAR centres identified only three essential items for DU evaluation and considered the proposed classification and categorisation as useful and feasible. The set of items needs to be validated while further implementation of DU classification and categorisation is warranted. TRIAL REGISTRATION: Observational trial on DU (OT1) is one of the five trials of the DeSScipher project (ClinicalTrials.gov; OT1 Identifier: NCT01836263 , posted on April 19, 2013).

Antigen-specific T cell-mediated gene therapy in collagen-induced arthritis.

Autoantigen-specific T cells have tissue-specific homing properties, suggesting that these cells may be ideal vehicles for the local delivery of immunoregulatory molecules. We tested this hypothesis by using type II collagen-specific (CII-specific) CD4(+) T hybridomas or primary CD4(+) T cells after gene transfer, as vehicles to deliver an immunoregulatory protein for the treatment of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). CII-specific T cells or hybridomas were transduced using retroviral vectors to constitutively express the IL-12 antagonist, IL-12 p40. Transfer of engineered CD4(+) T cells after immunization significantly inhibited the development of CIA, while cells transduced with vector control had no effect. The beneficial effect on CIA of IL-12 p40-transduced T cells required TCR specificity against CII, since transfer of T cells specific for another antigen producing equivalent amounts of IL-12 p40 had no effect. In vivo cell detection using bioluminescent labels and RT-PCR showed that transferred CII-reactive T-cell hybridomas accumulated in inflamed joints in mice with CIA. These results indicate that the local delivery of IL-12 p40 by T cells inhibited CIA by suppressing autoimmune responses at the site of inflammation. Modifying antigen-specific T cells by retroviral transduction for local expression of immunoregulatory proteins thus offers a promising strategy for treating RA.

Gene therapy in autoimmune disease.

Recent work on gene therapies for autoimmune disease has continued to provide insight into the pathogenesis of autoimmunity. Reliable, effective and targeted gene therapy applications have been achieved by using transduced dendritic cells and antigen-specific T cells as delivery vehicles. Bioluminescence imaging has been implemented to visualize cell trafficking and homing in vivo. As a first step into human gene therapy, a phase I clinical trial for assessing the feasibility and safety of gene transfer has been completed in a group of rheumatoid arthritis patients.

Vasculitis of the aortic arch and cardiac valves as the cause of relapsing fever of unknown origin in an elderly, white man.

Here, we report the case of fever of unknown origin (FUO) in a 77-year-old white man. The patient presented with a 3-week history of fever (between 38.5 and 39 degrees C) and general malaise. These symptoms had occurred about five to seven times during the past 30 years, and despite repeated hospitalizations, no diagnosis was made. Physical examination did not reveal any specific signs of infection nor did the patient fulfill the criteria for any rheumatic disease including vasculitides. Blood chemistry showed a greatly elevated C-reactive protein (CRP; 158.2 mg/l) and an erythrocyte sedimentation rate >100 mm, indicating an active inflammatory process, and leukocytes were significantly elevated (20,000/mul). Rheumatological parameters showed only nonspecific changes. Finally, a 2-[(18)F]-fluoro-2-deoxy-D: -glucose-positron emission tomography was performed, revealing a markedly enhanced glucose uptake in the ascending aorta and the cardiac valves, indicating vasculitis as the cause of FUO in this patient. Based on this finding, treatment was started with corticosteroids, and 2 days after the initiation of treatment, the patient had normal body temperature, and after 5 days, CRP values had returned to normal. After tapering and final complete removal of steroid treatment, the patient was still free of symptoms, hence no disease-modifying antirheumatic drug therapy was necessary.