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Background: Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status., Objectives: To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc)., Methods: The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed., Results: Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often 'other antibodies' (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset., Conclusions: These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose: To assess the diagnostic accuracy of contrast material-enhanced magnetic resonance (MR) imaging of superficial cranial arteries in the initial diagnosis of giant cell arteritis ( GCA giant cell arteritis )., Materials and Methods: Following institutional review board approval and informed consent, 185 patients suspected of having GCA giant cell arteritis were included in a prospective three-university medical center trial. GCA giant cell arteritis was diagnosed or excluded clinically in all patients (reference standard [final clinical diagnosis]). In 53.0% of patients (98 of 185), temporal artery biopsy ( TAB temporal artery biopsy ) was performed (diagnostic standard [ TAB temporal artery biopsy ]). Two observers independently evaluated contrast-enhanced T1-weighted MR images of superficial cranial arteries by using a four-point scale. Diagnostic accuracy, involvement pattern, and systemic corticosteroid ( sCS systemic corticosteroid ) therapy effects were assessed in comparison with the reference standard (total study cohort) and separately in comparison with the diagnostic standard TAB temporal artery biopsy ( TAB temporal artery biopsy subcohort). Statistical analysis included diagnostic accuracy parameters, interobserver agreement, and receiver operating characteristic analysis., Results: Sensitivity of MR imaging was 78.4% and specificity was 90.4% for the total study cohort, and sensitivity was 88.7% and specificity was 75.0% for the TAB temporal artery biopsy subcohort (first observer). Diagnostic accuracy was comparable for both observers, with good interobserver agreement ( TAB temporal artery biopsy subcohort, κ = 0.718; total study cohort, κ = 0.676). MR imaging scores were significantly higher in patients with GCA giant cell arteritis -positive results than in patients with GCA giant cell arteritis -negative results ( TAB temporal artery biopsy subcohort and total study cohort, P < .001). Diagnostic accuracy of MR imaging was high in patients without and with sCS systemic corticosteroid therapy for 5 days or fewer (area under the curve, ≥0.9) and was decreased in patients receiving sCS systemic corticosteroid therapy for 6-14 days. In 56.5% of patients with TAB temporal artery biopsy -positive results (35 of 62), MR imaging displayed symmetrical and simultaneous inflammation of arterial segments., Conclusion: MR imaging of superficial cranial arteries is accurate in the initial diagnosis of GCA giant cell arteritis . Sensitivity probably decreases after more than 5 days of sCS systemic corticosteroid therapy; thus, imaging should not be delayed. Clinical trial registration no. DRKS00000594 ., (© RSNA, 2014.)

Purpose: To assess deep temporal artery and temporalis muscle involvement in patients with giant cell arteritis (GCA)., Material and Methods: Ninety-nine patients who received magnetic resonance imaging (MRI) and superficial temporal artery biopsy (TAB) were included in this study. Patients with positive TAB (n = 61) were defined as GCA patients, those with negative TAB (n = 38) as the GCA-negative reference group. Contrast-enhanced T1w-images were acquired utilizing 1.5 T and 3 T MRI. Two radiologists assessed the images. Mural contrast-hyperenhancement and wall thickening of the deep temporal artery and hyperenhancement of the muscle were defined as inflammation. MRI results were correlated with jaw claudication in 70 patients., Results: The two observers found temporalis muscle involvement in 19.7 % (n = 12) and 21.3 % (n = 13) of GCA patients. It occurred bilaterally in 100 %. Specificities were 92/97 % and sensitivities were 20/21 %. Deep temporal artery involvement was found in 34.4 % (n = 21) and 49.2 % (n = 30) and occurred bilaterally in 80/90.5 %. Specificities were 84/95 % and sensitivities were 34/49 %. Both structures were affected simultaneously in 18/21.3 %. Jaw claudication correlated moderately with inflammation of the temporalis muscle (r = 0.31; p < 0.05) and the deep temporal artery (r = 0.38; p = 0.01)., Conclusion: MRI visualizes changes in the temporalis muscle and the deep temporal artery in GCA. Moderate correlation of clinical symptoms with MRI results was observed., Key Points: • Approximately 20 % of GCA patients presented with temporalis muscle inflammation. • A total of 34-49 % of GCA patients presented with vasculitis of the deep temporal artery. • In approximately 20 % of GCA patients, both structures were simultaneously involved. • Involvement of both structures correlated moderately with presence of jaw claudication. • MRI is a suitable tool for the assessment of vasculitis and muscle inflammation.

The aim of this study was to evaluate the diagnostic value of a 32-channel head coil for the characterization of mural inflammation patterns in the superficial cranial arteries in patients with giant cell arteritis (GCA) compared to a standard 12-channel coil at 3T MRI. 55 patients with suspected GCA underwent high resolution T1-weighted post-contrast MRI at 3T to detect inflammation related vessel wall enhancement using both coils. To account for different time delays between contrast agent injection and sequence acquisition, the patients were divided into two cohorts: 27 patients were examined with the 32-channel coil first and 28 patients with the 12-channel coil first. Images were evaluated by two blinded readers with regard to image quality, artifact level and arteries' inflammation according to a standardized ranking scale; furthermore signal-to-noise ratio (SNR) measurements were performed at three locations. Identification of arteries' inflammation was achieved with both coils with excellent inter-observer agreement (κ=0.89 for 12-channel and κ=0.96 for 32-channel coil). Regarding image grading, the inter-observer variability was moderate for the 12-channel (κ=0.5) and substantial for the 32-channel coil (κ=0.63). Significantly higher SNR and improved image quality (p<0.01) were obtained with the 32-channel coil in either coil order. Image quality for depiction of the superficial cranial arteries was superior for the 32-channel coil. For standardized GCA diagnosis, the 12-channel coil was sufficient., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Primary fibromyalgia syndrome (FMS) is associated with substantial psychiatric comorbidity. The aim of the present study was to investigate the interrelationship between self-reported symptoms of depression and pain in FMS compared with rheumatoid arthritis (RA)., Methods: In a cross-sectional study, 100 patients with FMS and 50 patients with RA were compared with regard to depression and psychopathology using the Symptom Check List (SCL-27). Group comparisons were calculated by parametric and non-parametric tests. The association between pain intensity and depression was determined by correlation analyses and multivariate statistical procedures (CATREG)., Results: Pain intensity was significantly higher in FMS compared with RA. FMS patients also scored significantly higher on all subscales of the SCL-27 including the depression scale and the General Symptom Index (GSI) (P < 0.001). These group differences remained stable even after correcting for pain intensity. Correlation analyses revealed an association between pain intensity and depression in FMS but not in RA (R = 0.419, P < 0.001)., Conclusion: FMS patients in tertiary referral centers suffer from higher levels of pain intensity than RA patients. Depression predicts levels of pain in FMS but not in RA and is therefore an important target of intervention.

Objective: To compare the impact of initial corticosteroid treatment on high-resolution MRI and colour-coded duplex sonography (CCDS) findings in patients with GCA (temporal)., Methods: Sensitivity and specificity of CCDS and high-resolution contrast-enhanced MRI studies of 59 patients with suspected GCA were retrospectively analysed. Patients were grouped according to the duration of steroid treatment before imaging: 0-1 day, 2-4 days and >4 days. In 41 patients, imaging results were compared with findings of temporal artery biopsy (TAB)., Results: Sixty-one per cent (36/59) of patients were diagnosed with GCA. TAB findings were positive in 59% (24/41). The compared results of TAB sensitivity of CCDS and MRI under steroid treatment of 0-1 day were 92% and 90%, 2-4 days 80% and 78% and >4 days 50% and 80%, respectively. The compared results of the final clinical diagnosis sensitivity of CCDS and MRI under steroid treatment of 0-1 day was 88% and 85%, 2-4 days 50% and 64% and >4 days 50% and 56%, respectively., Conclusion: Sensitivity of a first-time CCDS or an MRI for detection of GCA rapidly decreases under corticosteroid treatment. Therefore imaging of patients with suspected GCA should be performed as soon as possible, preferably within the first days of treatment.

Objectives: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are relatively common inflammatory disorders. Establishing the diagnosis however may be difficult, since so far no specific biomarkers of the disorders are available., Methods: As a screening procedure, the authors used protein arrays for the detection of new autoantigens in GCA and PMR. The results of the protein array were confirmed by different ELISAs detecting IgG antibodies against the human ferritin heavy chain, N-terminal 27 amino acids of the human ferritin heavy chain or the homologous peptide of Staphylococcus epidermidis. Sera of patients with only GCA (n=64), only PMR (n=47) and both PMR and GCA (n=31) were used., Results: In the ELISA using the human ferritin peptide, the sensitivity of IgG antibodies against ferritin was 92% in 36 GCA and/or PMR patients before initiation of treatment, 22/32 (69%) in patients with disease flares and 64/117 (55%) in the total cohort including treated and inactive patients. In controls, the false positive rate was 11/38 (29%) in systemic lupus erythematosus, 1/36 (3%) in rheumatoid arthritis, 0/31 (0%) in late onset rheumatoid arthritis, 3/46 (6.5%) in B-non-Hodgkin's lymphoma and 1/100 (1%) in blood donors. In the ELISA using the ferritin peptide of S epidermidis, 89% of 27 patients with untreated GCA and PMR were positive., Conclusion: Antibodies against the ferritin peptide were present in up to 92% of untreated, active GCA and PMR patients. They can be useful as a diagnostic marker of PMR and GCA.

Objectives: To retrospectively analyse inflammatory involvement of the ophthalmic arteries in patients with GCA utilizing high-resolution MRI., Methods: A cohort of 50 patients with GCA who had been examined by 1.5 or 3T high-field MRI was analysed retrospectively in a consensus reading for possible involvement of the ophthalmic arteries. In 43 patients, entire orbits were within the field of view. In all cases, the superficial cranial arteries displayed mural inflammation in post-contrast T1-weighted spin-echo (SE) images. MRI results were compared with ophthalmological findings, subjective visual symptoms and laboratory values, i.e. CRP and ESR., Results: We observed mural contrast enhancement of the ophthalmic arteries in 20/43 patients (46%). Bilateral involvement was seen in 14, unilateral enhancement in six cases. Fifteen patients had ophthalmic vascular diseases: nine had anterior ischaemic optic neuropathy (AION), one posterior ischaemic optic neuropathy (PION), four revealed central retinal artery occlusion (CRAO) and one patient presented with narrowing of the retinal arteries. Funduscopy detected no arteritis-related changes in 22 cases. Of those patients who were MRI positive, seven had ophthalmological disease. Twenty-six patients complained of visual symptoms including amaurosis fugax, vision loss, diplopia or eye pain., Conclusions: High-resolution MRI detects mural contrast enhancement consistent with inflammatory changes in the superficial cranial and extracranial arteries and additionally in the ophthalmic arteries. This provides insight in vasculitic orbital involvement during one single investigation.

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.

Objective: The functional variant C77G (rs17612648) of PTPRC (CD45) was described to confer risk for systemic sclerosis (SSc) in German Caucasians. We analyzed this association in an independent, larger German cohort., Methods: We genotyped 171 cases and 179 controls. Cases were subgrouped according to sex, autoantibody profiles, or clinical subsets., Results: No association of SSc with C77G was detected in the whole dataset, in subgroups, or in combined analyses with a previous study., Conclusion: The results do not confirm PTPRC C77G as a general and independent risk factor for development of SSc.

Objective: To compare the diagnostic performance of high-resolution magnetic resonance imaging (MRI) and color-coded duplex sonography (CCDS) in patients with giant cell (temporal) arteritis (GCA)., Methods: Results of high-resolution MRI and CCDS in 59 patients with suspected GCA were compared with the final clinical diagnosis (based on the American College of Rheumatology GCA criteria and a 6-month followup study). Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each method. In 41 of the patients, imaging results were also compared with the findings of a temporal artery (TA) biopsy., Results: Thirty-six of the 59 patients (61%) were ultimately diagnosed as having GCA. Sensitivity of high-resolution MRI and CCDS was 69% and 67%, respectively, specificity was 91% and 91%, PPV was 93% and 92%, and NPV was 66% and 64%, respectively. TA biopsy findings were positive in 24 of the 41 biopsied patients (59%). Sensitivity of high-resolution MRI and CCDS compared with TA biopsy was 83% and 79%, respectively, specificity was 71% and 59%, PPV was 80% and 73%, and NPV was 75% and 67%, respectively. The differences between high-resolution MRI and CCDS were not significant., Conclusion: The diagnostic power of high-resolution MRI and CCDS in detecting GCA was comparable. Either of these noninvasive techniques may have value in the evaluation of patients with suspected GCA, and decisions regarding which technique to use may depend on the clinical setting.

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.

Background: Giant cell arteritis (GCA) is often diagnosed very late, variable "facets" of the disease exist render the diagnosis more difficult., Methods/patients: Follow-up observations of five very old patients are reported in whom diagnosis was made too late, resulting in blindness of both eyes., Results: Five patients (age 76-84 years, 4 women, one man) with GCA became blind in both eyes because diagnosis had been delayed (two patients) or onset of therapy was too late (three patients). In two patients who also had arterial hypertension, the symptom "headache" had been misleading. Symptoms of accompanying general diseases masked the real diagnosis, particularly in the second patient who had renal insufficiency, coronary artery disease, and unilateral obstruction of the internal carotid artery. Symptoms that failed to lead to the correct diagnosis were: muscle or chewing pain (three patients), circumscribed numbness around the mouth (second patient), and persistent headache despite normalization of blood pressure. Normal findings from cranial CTAs (two patients) led to the wrong reassurance of the patient. Swelling of the optic disk (two patients) was misdiagnosed by ophthalmologists, as was a retinal branch arterial occlusion (first patient). Three patients, afraid of possible side effects caused by glucocorticoids, took ineffective alternative medications. Poor vigilance led to blindness of the fifth patient with long-standing polymyalgia rheumatica., Conclusions: Targeted examinations at the onset of symptoms are necessary. GCA-symptoms were mis-constructed by additional diseases that disguised the correct diagnosis. The danger of bilateral blindness is particularly great in patients of great age.

Objective: To noninvasively determine the involvement pattern of the cranial arteries in giant cell arteritis (GCA), with high-resolution magnetic resonance imaging (MRI)., Methods: The superficial cranial arteries of 21 patients with suspected GCA were examined using a 3T high-field MRI scanner. Postcontrast T1-weighted spin-echo images were acquired with submillimeter spatial resolution, to assess mural thickness and lumen diameter of the major cranial arteries on both sides of the head. In all cases, MRI results were compared with findings of clinical examination and laboratory tests. In addition, temporal artery biopsy specimens from 10 patients were examined by histology., Results: MRI sharply revealed all of the major superficial cranial arteries, allowing for an evaluation of their lumen and vessel wall. Nine of the 21 patients were diagnosed as having GCA according to the criteria of the American College of Rheumatology. In all of these patients with clinically diagnosed GCA, multiple cranial arteries showed signs of inflammation on MRI. In 1 patient, the occipital arteries were inflamed, while the temporal arteries were spared., Conclusion: Postcontrast high-resolution MRI visualizes the major cranial arteries on both sides of the head within a single examination. The cranial involvement pattern in GCA can be assessed precisely and noninvasively. In the majority of GCA patients, several cranial arteries were affected simultaneously, with a predominance of involvement of the frontal branch of the superficial temporal artery. Inflammation of the occipital arteries, with sparing of the temporal arteries, was also encountered.

Background: Retroperitoneal fibrosis (RPF) and inflammatory aneurysm of the abdominal aorta (IAAA) are regarded as two manifestations of the same disease, termed "chronic periaortitis"., Objective: To determine the optimal therapeutic and diagnostic approaches to IAAA., Methods: The outcome of medical immunosuppressive and surgical treatment of 20 patients was examined. Measurements of the C reactive protein (CRP) were compared with contrast enhanced imaging studies in the follow up of the patients., Results: The diameter of the periaortic mantle and its contrast enhancement improved in 13/15 (87%) patients given immunosuppressive treatment for a period of more than 6 months. Strong contrast enhancement was associated with a substantial rise in CRP, but no correlation between the CRP value and thickness of the fibrotic mass was found, even at intraindividual follow up., Conclusions: Immunosuppressive treatment should be included in the first line treatment of patients with RPF and should be maintained long term. Imaging studies are better than CRP measurements in the evaluation of response to treatment.

Purpose: To validate and extend the US case definition for the Multiple Chemical Sensitivity Syndrome (MCS) from 1999 by a systematic literature-review., Data Source: MEDLINE-research from 1997 to August 2003, research in the Cochrane-Library in August 2003, earlier reviews since 1997., Study Selection: Headings and abstracts were screened by one reviewer. All references dealing with multiple chemical sensitivities (MCS) which covered topics of interest such as symptom-profiles, differential diagnostic procedures, etc. were included in the analysis., Data Extraction and Synthesis: Topic-specific data extraction and synthesis was done by one reviewer. Data interpretation was discussed by all other authors., Results: Out of 1429 references 36 publications proved to be suitable for the review. The results can be summarized as follows: exposure-related symptoms associated with self-reported multiple chemical sensitivities can be divided into non-specific complaints of the central nervous system--CNS (main characteristics) and functional disturbances in other organ systems (optional complaints). There is a significant overlap of MCS, CFS and fibromyalgie. At present no standards for a diagnostic procedure based on the criteria outlined above are existing, Conclusions: MCS should only be diagnosed in patients who are mainly suffering from exposure-related non-specific complaints of the Central nervous system. The suggested diagnostic procedure follows the guidelines for CFS which are extended by diagnostic clarification of functional disturbances in other organ systems.

In the case of inflammatory disease of the joints, the first diagnostic step is to determine whether the patient has monoarthritis, oligoarthritis or polyarthritis. After excluding a septic or a crystal-related process by joint puncture and synovial fluid analysis, further laboratory investigations including immunological and bacteriological tests can contribute to the diagnosis, and imaging procedures may also be useful. Primary therapy can be provided with NSAIDs or easy-on-the-stomach coxibs. Where indicated, antibiotics or, if warranted by the diagnosis and in the presence of persistent effusion, corticosteroids.

Immunoglobulins undergoing cold-dependent precipitation are known as cryoglobulins. A type I cryoglobulin after Brouet et al. from serum of a patient with severe cutaneous vasculitis and membranoproliferative glomerulonephritis was purified by reversible temperature-dependent precipitation and analyzed using FPLC, Western blotting and peptide sequencing. The isolated cryoglobulin consisted of a single complex of a molecular weight of above 210kDa observed under non-reducing conditions in SDS-polyacrylamide gel electrophoresis (PAGE). Under reducing conditions, this complex resolved into three bands, two of which were reminiscent of Ig heavy (HC) chains and one of Ig-light chains (LC). The FPLC-purified type I cryoglobulin showed reversible precipitation analyzed by spectrophotometry. Delineation of the peptides involved in complex formation by immunoblot analysis and peptide sequencing revealed IgG3-V(H)4/Igkappa-VkappaIII/JkappaII and IgG1/V(H)3 molecules with evidence of somatic mutation. Coomassie blue-staining suggested that molar amounts of the IgG3-heavy chain were much higher than that of the IgG1-heavy chain. Treatment with SDS and boiling did not disrupt the unusually high molecular weight Ig complex. Pre-treatment of the cryoglobulin in 6M guadinium hydrochloride followed by gel filtration chromatography suggested covalent association of the IgG3, IgG1 and Igkappa molecules. Therefore, it might be that the cryoglobulin was produced by a single plasma B cell clone which passed immunological check-points in terms of B cell selection in the bone marrow in the absence of allelic exclusion, class switching and affinity maturation by somatic mutation.

Background: Immunosuppressive treatment of rheumatic diseases may be associated with several opportunistic infections of the brain. The differentiation between primary central nervous system (CNS) involvement and CNS infection may be difficult, leading to delayed diagnosis., Objective: To differentiate between CNS involvement and CNS infection in systemic rheumatic diseases., Methods and Results: Three patients with either longstanding or suspected systemic rheumatic diseases (systemic lupus erythematodes, Wegener's granulomatosis, and cerebral vasculitis) who presented with various neuropsychiatric symptoms are described. All three patients were pretreated with different immunosuppressive drugs (leflunomide, methotrexate, cyclophosphamide) in combination with corticosteroids. Magnetic resonance imaging of the brain was suggestive of infectious disease, which was confirmed by cerebrospinal fluid analysis or stereotactic brain biopsy (progressive multifocal leucoencephalopathy (PML) in two and nocardiosis in one patient)., Discussion: More than 20 cases of PML or cerebral nocardiosis in patients receiving corticosteroids and cytotoxic drugs for rheumatic disease have been reported. The clinical aspects of opportunistic CNS infections and the role of brain imaging, cerebrospinal fluid analysis and stereotactic brain biopsy in the differential diagnosis are reviewed.

Background: Syphilis has distinctly increased in the last decades. It is necessary to know the different eye changes in syphilis., Patients: In four patients, between 34 and 71 years of age, typical as well as unusual syphilitic eye changes were found. In three patients diagnosis was made due to the inflammatory eye changes., Results: An iritis was found in two patients (62 and 34 years old). In addition, the 62-year-old patient showed the unusual fundus picture of both vasculitis and neuroretinitis, with macular exudates and swelling of the optic disk. A venous occlusion, a rare sign in syphilis, was diagnosed in a 55-year-old patient. A 71-year-old patient revealed the characteristic finding of a placoid chorioretinitis. All four patients showed a swelling of the optic disk., Conclusion: Syphilis should be suspected even in older patients with an uncertain origin of uveitis, optic nerve disease, pupillary changes, or eye motility disturbances giving rise to carry out serologic tests in patients with the suspected diagnosis.

Objectives: Hyperprolactinaemia has been associated with the active phase of human systemic lupus erythematosus and rheumatoid arthritis. In the present study, we investigated the role of prolactin (PRL) in relation to the number of typical symptoms and serum markers of systemic inflammation in patients with polymyalgia rheumatica (PMR)., Methods: One hundred and two PMR patients presented with typical symptoms such as adynamia, bilateral muscular pain in shoulders, upper arms or neck, bilateral muscular pain in the pelvic girdle, headache, morning stiffness, arthralgia, symptoms of depression, fever, initial weight loss (>4 kg/month), and transient visual symptoms. If one of the mentioned symptoms was present, the corresponding item was scored with one point (maximum unweighted item points=10). PRL, interleukin-2 (IL-2), IL-6, IL-1 receptor antagonist (IL-1ra), tumour necrosis factor (TNF), soluble IL-2 receptor (sIL-2R), and soluble vascular cell adhesion molecule (sVCAM) were measured by enzyme-linked immunosorbent assay in patients and 31 age-matched healthy controls., Results: Fifteen PMR patients with elevated PRL had a higher number of symptoms as compared with patients with normal levels (P=0.003). PRL was correlated with the number of symptoms (all PMR patients: r(rank)=+0.380, P<0.001) and duration of morning stiffness (all PMR patients: r(rank)=+0.335, P=0.002) irrespective of prior corticosteroid treatment. However, PRL did not correlate with markers of systemic inflammation such as erythrocyte sedimentation rate, C-reactive protein, serum IL-1ra, IL-2, sIL-2R, IL-6, TNF, and sVCAM., Conclusion: The number of symptoms in PMR patients was positively correlated with PRL, but PRL was not correlated with serum markers of inflammation. This indicates that PRL is not a pro-inflammatory stimulus in patients with PMR. The inter-relationship between PRL and symptoms or duration of morning stiffness may be more a sign of central nervous system involvement, as it can be observed in people with depressed mood or under psychological stress.

A previous case report described the formation of a complex between a monoclonal IgA with cryolabile properties and C-reactive protein (CRP). Our study provides the first evidence for the frequent occurrence of CRP in cryoglobulins (Cg) of all three types according to Brouet's classification. We performed a systematic immunochemical analysis of cryoglobulins from 18 patients by Western blotting and in 15 of 18 cryoprecipitates a single band (23 KD), immunoreactive with anti-CRP antibody, was demonstrable irrespective of the clonal composition of the cryoglobulins. This band was detectable in 4/5 of type I, in 6/8 of type II, and in 5/5 of type III cryoprecipitates, classified according to Brouet et al. In addition, the complement proteins C1q and C3 were present in nearly all CRP-containing cryoglobulins, presumably reflecting previous activation of the classical complement pathway at least. All three CRP-negative cryoprecipitates were derived from sera with low cryoglobulin content (1-2 g/l). Longitudinal investigation of 23 cryoprecipitates from seven patients confirmed that successful detection of CRP by Western blotting depends on the protein concentration of the cryoglobulins. Since complexed CRP was previously shown to be an effective activator of complement, via C1q binding, CRP may modulate pathophysiologic effects mediated by cryoglobulins in vivo.

The causes for the high frequency of cardiovascular disease in dialysis patients are multifactorial in origin. Disturbances in the carbohydrate and lipid metabolism, the balance between oxidants and antioxidants and the immuno-inflammatory system are thought to play a role. Chronic uremia is characterized by the accumulation of advanced glycation end products (AGEs) and advanced oxidation products (AOPP) as well as activation of the acute phase response. High serum levels of these products and acute phase reactants such as C-reactive protein (CRP), fibrinogen and serum amyloid A can be found. CRP has been shown to predict cardiovascular and overall mortality in hemodialysis patients. Whether CRP is involved causally in atherosclerosis or merely represents a marker of disease is as yet unknown. Since CRP has been detected in colocalization with modified apolipoproteins or complement components in atherosclerotic lesions, a pathophysiological role seems very likely. AGEs as well have been detected in aortas of hemodialysis patients. Incubation of endothelial cells with AGEs induced expression of adhesion molecules with consecutive attraction of monocytes to the vessel wall. Thus far, clinical studies investigating the predictive effects of AGEs on cardiovascular mortality in hemodialysis patients are lacking. There is considerable debate about what factors turn on the acute phase response in this population. Proinflammatory effects of AGEs mediated through one receptor for AGEs, RAGE, have been described. We hypothesize that there may be a link between increased hepatic CRP production and the accumulation of AGEs in uremia. AGEs may stimulate CRP production in hepatocytes either directly or indirectly via interaction with monocytes.

Background: Ocular involvement in panarteritis nodosa (PAN) has been reported to occur in 10 to 20% of patients. In 3 patients with acute visual disturbance we point out unusual findings., Patients: Case 1. A 40-year-old man initially presented with papilledema together with partial optic atrophy in both eyes, later polyneuropathy, gangrene of the toes and myalgic pains developed. Caliber changes in the small arteries in the liver were seen angiographically and recognized as signs of PAN. Under treatment with cyclophosphamide und prednisone no relapse occurred during a follow-up of 2 years. Case 2. In a 67-year-old man who suffered from arterial hypertension and coronary heart disease, central retinal artery occlusion occurred, at first in the left and then later in the right eye. The clinically suspected diagnosis of PAN (arterial hypertension, myalgia, polyneuropathy) was confirmed by a muscle biopsy. During a follow-up of 4 years--including treatment with prednisone and cyclophosphamide--no relapse occurred. Case 3. A 16-year-old adolescent with throbbing headaches and a thickened right temporal artery reported visual disturbances. These were due to an inflammation of choroidal vessels of the right eye appearing as an initial sign of PAN. Histology revealed a necrotising arteritis of the temporal artery. He presented with signs of Raynaud's disease, cachexia and arterial hypertension. Multiple vasculitic changes were detected by aorto-arteriography. Five months after the visual deterioration an anterior spinal artery syndrome with quadriplegia developed. After a follow-up of 2 years and treatment with prednisone und cyclophosphamide, he still had paralysis of both legs. The visual acuity was 1.0 in each eye., Conclusion: PAN should be considered in differential diagnosis in patients with acute inflammatory signs of the optic nerve head, the choroid and/or the retina together with general signs of the disease. If the disease is suspected, a muscle biopsy is indicated.

Patients: Five patients (mean age 81.6 years) developed bilateral blindness and 3 additional patients suffered cerebral strokes (mean age 58 years) due to temporal arteritis. Bilateral blindness and strokes occurred despite corticosteroid treatment., Results: In all patients with temporal arteritis, the diagnosis was made too late. Patients with bilateral blindness were referred to the Eye Hospital when one eye had already become blind. The delay between the first symptoms and blindness in one eye was (average) 7 weeks. The interval between blindness of the first and second eyes was (average) 5 days in 3 patients, and simultaneous blindness in both eyes occurred in 2 patients. The other eye also became blind despite mega-doses of prednisone in 3 patients. Three additional patients already showed neurological signs and symptoms at the beginning of the temporal headache. All 3 patients developed strokes after some weeks or months. The wrong diagnosis was made in the first examination(s) by the physician with patients having prodromal signs or symptoms, but who also showed signs of other vascular diseases (diabetes mellitus, hypertension or occlusion of the internal carotid artery) which masked the inflammatory disease of temporal arteritis., Conclusions: Early diagnosis is essential to prevent severe complications. In patients with a cerebral stroke the early neurological deficits are warning signs which means that one must observe the patient regularly at short intervals. After the diagnosis has been settled, treatment of the patients for several months with a high dosage of corticosteroids is mandatory.

Objectives: To determine the correlation between inflammatory cytokines and adrenal hormones in patients with polymyalgia rheumatica (PMR) and to compare the ratio of serum cortisol and androstenedione (ASD) or dehydroepiandrosterone sulphate (DHEAS) in normal subjects with PMR patients., Methods: In 102 patients with PMR (32 beginning and 70 chronic disease) and 31 age-matched and sex-matched healthy subjects, ASD, cortisol, DHEAS, interleukin-6 (IL-6), and tumour necrosis factor (TNF) were measured by immunometric assays., Results: Serum levels of IL-6 were elevated in patients with PMR as compared with normal subjects (10.0 +/- 1.6 vs 2.1 +/- 0.1 pg/ml, P = 0.01), which was not found for TNF. In PMR patients, serum levels of IL-6 were positively correlated with serum levels of ASD (P < 0.001), cortisol (P < 0.001), and DHEAS (P = 0. 038) irrespective of corticosteroid treatment. Serum levels of cortisol in relation to IL-6 were significantly lower in patients with chronic disease and long-standing corticosteroid administration as compared with patients with recent onset of the disease and without corticosteroid therapy (P < 0.01)., Conclusions: In PMR, as expected, there was an increase in IL-6 serum levels that was associated with elevated serum levels of ASD, DHEAS, and cortisol which was more marked in patients with recent-onset disease and without corticosteroids. However, serum levels of cortisol in patients with and without corticosteroids were lower than expected by considering the inflammatory status (increased IL-6). This may indicate a change in the hypothalamic-pituitary-adrenal (HPA) axis responsiveness to inflammatory stimuli such as IL-6 during chronic disease. Furthermore, there seems to be a shift of biosynthesis to cortisol in relation to DHEAS or ASD in chronic disease.

Objective: To determine the relationship between the antiinflammatory molecule interleukin 10 (IL-10) and disease symptoms, IL-1beta, tumor necrosis factor (TNF), and IL-1 receptor antagonist (IL-1ra) in patients with polymyalgia rheumatica (PMR)., Methods: In 102 patients with PMR, we determined the severity of the disease by the presence of typical clinical symptoms (symptom score with a maximum of 10 points). IL-10, IL-1beta, TNF, and IL-1ra were measured in all patients and 31 age matched healthy controls by enzyme immunometric assays., Results: Compared to patients with elevated serum levels, patients with normal serum levels of IL-10 (below the mean + 3 SD of controls, 7.79 pg/ml) more often had adynamia (p = 0.045), bilateral muscular pain in shoulders, upper arms or neck (p = 0.045), bilateral muscular pain in the pelvic girdle (p < 0.001), headache (p = 0.014), morning stiffness (p < 0.001), symptoms of depression (p = 0.013), and initial weight loss (p = 0.011), and had a higher symptom score (5.5+/-0.4 vs 3.7+/-0.3; p < 0.001). The overall symptom score correlated negatively with IL-10 serum levels (Rrank = -0.421, p < 0.001). IL-10 correlated negatively with IL-1beta (p = 0.013) and TNF-alpha (p = 0.039). The association between elevated serum levels of IL-10 and low serum levels of IL-1beta and TNF was observed only in patients with corticosteroid treatment. In these patients, elevated serum levels of IL-10 were positively associated with an increased ratio of IL-1ra to IL-1beta., Conclusion: Elevated serum levels of IL-10 were associated with a more mild form of PMR. This study indicates a favorable role of IL-10 in patients with PMR.

Our objective was to study the value of 99mtechnetium-pyrophosphate (99mTc-PYP) muscle scintigraphy and magnetic resonance imaging (MRI) in detecting areas of likely muscle inflammation and in increasing the rate of positive muscle biopsies in patients with suspected myositis. The results showed that in 13 out of 13 patients with clinical and/or signs of inflammatory muscle disease, increased 99mTc-PYP uptake was demonstrated at different muscle sites 3 h after isotope injection. Subsequent MRI of symmetric muscle areas with enhanced 99mTc-PYP uptake revealed signal patterns suggesting inflammation in all cases. Biopsy of these targeted muscles demonstrated characteristic histopathologic signs of muscle inflammation in 9 out of 13 patients. Four of these 9 patients had clinically atypical disease or did not show elevated creatine phosphokinase levels. Seven of these 9 patients had not been pretreated with corticosteroids. In 4 patients only muscle fiber atrophy and/or necrosis without cellular infiltrations was seen. These 4 patients had received either high doses of corticosteroids or low doses over longer periods of time before muscle biopsy. In conclusion, the combination of 99mTc-PYP muscle scintigraphy and MRI demonstrated muscle areas with maximum inflammatory signal patterns. Targeting of muscles by MRI only will probably yield reliable results of muscle biopsy in cases of clinically and serologically characteristic myositis. 99mTc-PYP muscle scintigraphy may provide useful initial information about localization of inflamed muscle tissue, especially in atypical disease. Treatment with corticosteroids prior to histologic diagnosis may abolish inflammatory infiltrations in affected muscle tissue.

Psychiatric symptoms may be caused by systemic autoimmune diseases. Quite often, mental disorders are an early symptom during the course of an autoimmune disease and sometimes they may even be the presenting symptom. This article reviews psychiatric and neurologic symptoms in systemic lupus erythematodes, Sjögren syndrome, primary vasculitides and other immunopathies such as the primary antiphospholipid syndrome and Sneddon's syndrome. The article also discusses diagnostic aspects and therapeutic options if an autoimmune disease as cause of a psychiatric or neurologic symptom is suspected. An increased awareness of psychiatrists and neurologists will make it possible that systemic autoimmune diseases are early identified as a possible cause of psychiatric symptoms and may then be treated adequately.

Objective: Sacroiliitis is often difficult to diagnose in the absence of radiographic alterations. For the diagnosis of active sacroiliitis, plain radiography, scintigraphy, and contrast enhanced magnetic resonance imaging (MRI) were evaluated in a prospective study., Methods: In 44 consecutive patients with complete clinical and laboratory evaluation, plain radiographs, quantitative sacroiliac (SI) scintigraphy, and MRI were performed to evaluate the contribution of these imaging techniques to the diagnosis of active sacroiliitis. Scintiscanning and MRI were done in 20 control subjects to define the normal range of imaging findings. We determined the sensitivity and specificity for each imaging method using a reference standard based on clinical symptoms of inflammatory low back pain with or without laboratory signs, and on clinical and radiographic followup during 1.5-2.5 years to confirm diagnosis., Results: MRI was most sensitive (95%) and superior to quantitative SI scintigraphy (48%) or conventional radiography (19%) for the detection and confirmation of active sacroiliitis. For the assessment of inflammatory signs, MRI had higher specificity (100%) than scintigraphy (97%) or plain radiography (47%). At repeat MRI after 2-30 months, there was persistent pathologic signal intensity in the subchondral bone area despite clinically successful antiinflammatory drug therapy., Conclusion: For the assessment of active changes in the synovial portion and the subchondral bone marrow, contrast enhanced MRI is superior to quantitative SI scintigraphy or conventional radiography. MRI picks up an additional 75% of early cases not diagnosed by plain radiography. Scintigraphy is only of limited value. Persistent pathologic signal intensity in the subchondral bone marrow seems to be closely associated with previous inflammatory episodes, thus limiting specificity of MRI for active sacroiliitis. Based on our findings we suggest an algorithm for the evaluation of patients with suspected active sacroiliitis.

The complement (C) activation by C-reactive protein (CRP) in acute-phase sera is routinely tested in our laboratory by means of an indirect immunofluorescence method (C3-IFT) on rat kidney sections. This C3-IFT assay is based on the binding of CRP to the renal tissue followed by the fixation of C4 and C3 components to distinct vessel-associated medullary structures as a result of CRP-mediated C activation in vitro. While the activation cascade leading to the deposition of C4 and C3 could previously be deduced experimentally, we were unable as yet to visualize CRP and the components of the C1 complex on kidney sections when testing patients' sera by indirect immunofluorescence. In an attempt to analyze the mechanisms of unexpectedly negative C3-IFT results (e.g. bacterial endocarditis) we employed monolayers of fixed HEp-2 cells which have previously been shown to be a suitable substrate for CRP binding. By incubating purified native CRP supplemented with normal human serum as a source of C we detected the C components Clq, Clr, Cls, C4 and C3 in the same speckled immunofluorescent pattern on HEp-2 cell nuclei as described characteristically for CRP binding. The serial activation steps from CRP up to C3 could also be followed on HEp-2 cells using C3-IFT-positive acute-phase sera. However, certain C3-IFT-negative acute-phase sera showed an arrest between Cls and C4 of the CRP-mediated C activation cascade. HEp-2 cells can thus be used to monitor the process of autologous C activation initiated by endogeneous CRP in patients' sera. In contrast to native CRP, urea-modified CRP (mCRP) did not bind to HEp-2 cell nuclei, but was detected in association with distinct filamentous cytoplasmic structures. Unlike its native counterpart, binding of mCRP was not followed by a deposition of C components.

Background: The utility of cytomegalovirus (CMV) urine cultures was checked in patients with HIV (a) to identify those at risk for CMV retinitis and (b) to guide clinical decisions on treatment and prophylaxis of CMV retinitis., Methods: HIV infected patients were tested for CMVuria by shell vial cell cultures. The prevalence of CMVuria was related to CD4 count, HIV risk group, and time before and after diagnosis of CMV retinitis., Results: A total of 639 shell vial cell cultures were obtained from 266 HIV infected ophthalmic patients. Only 4% of all patients with a CD4 count > 400 x 10(6)/l shed CMV in their urine compared with 42% with a CD4 count < or = 50 x 10(6)/l. Twenty three of 25 patients with CMV retinitis had a CD4 count < or = 50 x 10(6)/l. Among 130 patients with a CD4 count < or = 50 x 10(6)/l (a) those who were CMVuric had a nearly sevenfold risk (p < 0.0001) of developing CMV retinitis (35%) compared with those who did not shed CMV in their urine (5%), and (b) CMVuria and CMV retinitis were more frequent in homosexuals (58%/25%) than in intravenous drug users (23%/15%). More than 1 year before diagnosis of CMV retinitis 18% of patients were CMVuric compared with 83% of patients who were CMV culture positive in the last 3 months. CMVuria under virustatic maintenance therapy is associated with worsening of retinitis in two thirds of cases., Conclusion: Ophthalmic screening of patients with HIV should include those with a CD4 count < or = 50 x 10(6)/l and focus on the subgroup with additional CMVuria. Screening of other patients can be dropped without undue risk in order to spare AIDS patients unnecessary hospital visits. CMVuria as a single finding, however, does not justify antiviral prophylaxis of CMV retinitis.

Glycoprotein B (gB) is involved in cell to cell transmission of human cytomegalovirus (HCMV) and may be a critical factor in tissue tropism and viral pathogenesis. We analyzed the distribution of the four known gB genotypes of HCMV in 99 HIV-positive patients. 29 patients had HCMV retinitis, and 70 patients had asymptomatic HCMV infection. DNA was isolated from blood, urine, and aqueous humor, and gB genotypes were determined by PCR and restriction analysis. Infections with gB type 1 were less frequent in patients with retinitis than in patients with asymptomatic HCMV infection (17% versus 37%; p = 0.05). Furthermore, the gB type was correlated with dissemination of infection. In patients with HCMV detected in only one compartment (blood or urine) the gB type 1 was found more frequently than in patients with HCMV detected in at least two compartments (p = 0.01). The data show that gB genotypes differ in their association with clinical disease, and indicate that the gB genotype may contribute to the course of HCMV infection.

We present a case of Sneddon's syndrome with high titers of antiphospholipid antibodies (APLA), in which the leading symptom was an incapacitating memory defect. MRI revealed vasculitic lesions of the central nervous system (CNS). Therefore immunosuppressive therapy was started with steroids and cyclophosphamide pulses. The transient beneficial effects of such a therapy will be discussed.

A case of Takayasu's arteritis is reported. Ventilation-perfusion lung scans and exercise thallium scintigraphy clearly showed pulmonary and coronary arterial involvement, respectively. Clinical examination and angiography revealed no other abnormal vascular findings. This case points out the difficulty in attempting to diagnose Takayasu's disease if only atypical vascular involvement is present.

In two patients with primary antiphospholipid antibody syndrome and acute cerebrovascular ischemic events, local intraarterial fibrinolysis and intravenous heparin therapy, respectively, resulted in a limitation of persisting neurological deficits. On the basis of the 35 case reports available a combination of anticoagulation with warfarin, plus immunosuppression with steroids and/or cyclophosphamide or azathioprine, appears to be the best treatment to prevent further cerebral ischemic events. The therapeutic options are reviewed and discussed.