[An update on Behçet's syndrome]. / Neues zum Behçet-Syndrom.

Behçet's syndrome (BS, synonym: Behçet's disease, or Adamantiades-Behçet's disease, ABD) is classified as a vasculitis of variable vessel size and can manifest itself in both arterial and venous vessels. Its extensive and at the same time interindividually very different clinical picture is not uncommon a challenge, both with regard to the diagnosis of this rheumatic systemic disease, which is rather rare in our latitudes, and its therapeutic options. In addition to the four cardinal symptoms of recurrent oral aphthae, genital aphthae, skin and eye lesions, the clinical picture offers numerous other manifestations which often require interdisciplinary cooperation. In addition to the above mentioned ocular involvement, which can still lead to blindness if inadequately treated, this is especially true for intestinal and cerebral manifestations as well as for large vessel vasculitis.A final revision of the European League Against Rheumatism recommendations for the management of Behcet's syndrome (EULAR) was made in 2018, and the recommendations are now established internationally as an important treatment guide. Therapy is based on the leading organ involvement. After adalimumab received approval for the treatment of posterior ocular involvement in 2016, another agent, apremilast, became available in 2020. The drug is recommended for the treatment of recurrent oral aphthae in adult Behçet's patients requiring systemic therapy. Nevertheless, there is a further need for new drugs.This article aims to highlight recent findings in the areas of epidemiology, immunopathogenesis & genetics, clinical findings, and therapy, with an emphasis on clinical relevance.

[An update on Behçet's syndrome]. / Neues zum Behçet-Syndrom.

Behçet's syndrome (BS, synonym: Behçet's disease, or Adamantiades-Behçet's disease, ABD) is classified as a vasculitis of variable vessel size and can manifest itself in both arterial and venous vessels. Its extensive and at the same time interindividually very different clinical picture is not uncommon a challenge, both with regard to the diagnosis of this rheumatic systemic disease, which is rather rare in our latitudes, and its therapeutic options. In addition to the four cardinal symptoms of recurrent oral aphthae, genital aphthae, skin and eye lesions, the clinical picture offers numerous other manifestations which often require interdisciplinary cooperation. In addition to the above mentioned ocular involvement, which can still lead to blindness if inadequately treated, this is especially true for intestinal and cerebral manifestations as well as for large vessel vasculitis.A final revision of the European League Against Rheumatism recommendations for the management of Behcet's syndrome (EULAR) was made in 2018, and the recommendations are now established internationally as an important treatment guide. Therapy is based on the leading organ involvement. After adalimumab received approval for the treatment of posterior ocular involvement in 2016, another agent, apremilast, became available in 2020. The drug is recommended for the treatment of recurrent oral aphthae in adult Behçet's patients requiring systemic therapy. Nevertheless, there is a further need for new drugs.This article aims to highlight recent findings in the areas of epidemiology, immunopathogenesis & genetics, clinical findings, and therapy, with an emphasis on clinical relevance.

Tocilizumab for the Treatment of Familial Mediterranean Fever-A Randomized, Double-Blind, Placebo-Controlled Phase II Study.

Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician's global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be >2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of ≤2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial.

Sexual dysfunction and depression in Behçet's disease in comparison to healthy controls.

Behçet's disease (BD) can affect the genital system and is more common in Middle Eastern countries and Asia but also occurs in Caucasian people. Aim of this study was to evaluate the prevalence of sexual dysfunction (SD) and depression in patients with BD compared to a healthy control group (HCG). In addition, differences with regard to depression and patients' origin were evaluated. This prospective, monocentric study included 106 consecutive patients from our specialized BD outpatient clinic. Patients were asked to fill out the paper based standardized and validated questionnaires International Index of Erectile Function (IIEF), the Female Sexual Function Index (FSFI) and the Beck Depression Inventory (BDI). In addition, 206 healthy controls were asked to fill out the questionnaires. 106 patients with BD were evaluated and 206 participants in the HCG. The mean age in BD group was 40.5 years as compared to 44.4 years in the HCG. Half of the patients had Middle Eastern and half Caucasian origin. SD was found in 24.5% of all subjects. Only 6.9% of male patients showed signs of SD, while half of the women's group was suffering from SD. The prevalence for SD was significantly higher in women with Middle Eastern ethnic origin compared to women with Caucasian origin (75 vs. 33.3%, p = 0.024). Erectile Dysfunction occurred in 55% of all male patients which was not statistical different from the HCG. Genital ulcers affected 73.6% of all patients. Depression was found in 36.7% of all subjects as compared to 6.25% in the HCG (p < 0.001). Both, SD and depression correlated positively in males (p = 0.017) and females (p = 0.013). SD and depression are very common problems in BD and should be addressed by the treating physician. Both manifestations are intensifying each other. Depression especially is more prevalent compared to the healthy population.

Erectile function and connective tissue diseases. Prevalence of erectile dysfunction in German men with systemic sclerosis compared to other connective tissue diseases and healthy subjects.

OBJECTIVES: Women are more frequently affected by connective tissue diseases like systemic sclerosis (SSc). Therefore, few studies exist on male-specific complaints. This study aimed to investigate the prevalence and associated factors of erectile dysfunction (ED) in SSc compared with other connective tissue diseases (CTD) and healthy controls. METHODS: 64 patients were analysed and compared with 123 age-matched HC. The 15-item International Index for Erectile Function (IIEF) questionnaire was used to assess sexual function. The prevalence of depression was quantified by using the validated Beck Depression Inventory (BDI). RESULTS: Mean age was 52.3 years (SD 10.75) for SSc, 52.9 years (SD 11.01) for patients with other CTD and 52.6 (SD 12.37) for HC. Mean IIEF-15 score was 13.6 for SSc, 11.7 for other CTD and 23.6 for HC. ED was significantly more frequent in patients with SSc (55.0%) and other CTD (54.4%) than in HC (12.7%) (p<0.001) and correlated with diseases severity. The mean BDI score was 10.8 for SSc/CTD and 5.4 for HC (p<0.001). With 36.6%, SSc patients suffered more often from a depression than patients with other CTD (17.4%) and HC (6.3%). We found a significant correlation between the IIEF-15 and depression classified by BDI (r= -0.527; p<0.001). CONCLUSIONS: This is the first study to show increased prevalence of ED, especially severe ED, in men with SSc compared to other CTD and age-matched HC. Physicians should be aware of this influence on sexual health and its correlation to depression and disease severity.

Shear Wave Elastography for Assessment of Muscular Abnormalities Related to Systemic Sclerosis.

RATIONALE AND OBJECTIVES: To assess muscular abnormalities related to systemic sclerosis (SSc) using shear wave elastography and correlate results with those of clinical tests. MATERIALS AND METHODS: We evaluated 55 patients (mean age: 50.4 years; range: 18-88; 34 female) with SSc before treatment and choose muscle groups based on cutaneous involvement and functional impairment [forearms (9); thighs (41); thenar/hypothenar (5)]. We performed shear wave elastography in two orientations to access heterogeneity using virtual touch IQ and mean shear wave velocity values (SWV) and measured skin and fascia thickness. We compared SWVs to the modified Rodnan skin score (mRSS). Twenty-two healthy controls (mean age: 52.0; range: 19-88; 7 female) underwent the same protocol. RESULTS: SWV pattern analysis (homogeneous vs heterogeneous) detected SSc with sensitivity/specificity/negative predictive value/positive predictive value0.79/0.81/0.91/0.62 in transverse and 0.75/0.18/0.91/0.56 in longitudinal orientation. In patients we found poor correlation between SWVs and mRSS but a cutoff of mRSSE = 20 separated them significantly (p < 0.01). Skin and muscle fascia were significantly thicker in patients vs. controls (p < 0.001). CONCLUSION: SSc involves more than increased skin and fascial thickness which is not fully represented by mRSS. Elasticity differs in muscles with and without SSc. The former shows higher SWV and increased heterogeneity in transversal planes of muscular fibers.

[Behçet's Syndrome]. / Behçet-Syndrom.

Behçet's syndrome (BS) is classified as a variable vessel vasculitis. The clinical picture is very diverse and usually requires interdisciplinary collaboration. Pathogenetically, BS seems to take a middle position between a polygenic autoinflammatory disease and an autoimmune disease. New EULAR recommendations were issued in 2018. The therapy depends on which organs are most affected. Since 2016, adalimumab has been approved for the treatment of posterior ocular involvement. Infliximab, interferon a2a, interleukin-1 antagonists and apremilast may be alternative therapies.

Intermetatarsal bursitis as first disease manifestation in different rheumatological disorders and related MR-imaging findings.

Metatarsalgia defined as pain at the plantar aspect of the forefoot. Intermetatarsal bursitis is considered one potential soft-tissue cause of metatarsalgia that is presumably under-estimated, under-investigated, and, consequently, often misdiagnosed. To assess the role of MRI in the elucidation of the cause of metatarsalgia in patients with different autoimmune disorders presenting primarily with this symptom and to present the accompanying clinical and radiological findings of intermetatarsal bursitis. Retrospective evaluation of the medical records of patients with different rheumatological conditions claiming primarily of pedal pains suggests metatarsalgia and who underwent, therefore, all magnetic resonance imaging between March 2010 and April 2018. Of them, six patients fulfilled these criteria and were diagnosed subsequently with intermetatarsal bursitis. Several underlying autoimmune conditions were diagnosed. All patients were clinically assessed by the squeeze test and radiologically investigated with MRI; three patients underwent additional sonography. All patients presented intermetatarsal bursitis as first disease manifestation. The number of involved bursae ranged from one to three on one side. The main MR findings were distension of the intermetatarsal bursa with increased signal intensity on T2-weighted and post-contrast fat saturation T1-weighted images. Most frequent locations were the second and third intermetatarsal spaces. The size of the intermetatarsal bursitis and its plantar extension were correlated in all patients. Intermetatarsal bursitis can potentially be the first manifestation of different rheumatological diseases. Awareness of this potential association as well as cognizance of its imaging findings can help for making a more accurate and prompt earlier diagnosis of the underlying disease changing also the therapeutic approach.

Tocilizumab in Uveitic Macular Edema Refractory to Previous Immunomodulatory Treatment.

PURPOSE: To analyze the efficacy of tocilizumab in uveitic macular edema (ME) resistant to various immunomodulatory drugs. METHODS: Patients received tocilizumab every 4 weeks intravenously. Central foveal thickness (CFT) was assessed by optical coherence tomography (OCT). RESULTS: Five patients (8 eyes) who were ineffectively pretreated with systemic prednisolone, at least one immunosuppressive drug, and at least one biologic drug for uveitic macular edema were included in the study. At 3 months, a response of ME (≥25% reduction in CFT) was observed in 6 eyes (75.0%) of 5 patients. During follow-up, complete resolution of ME was achieved in 5 eyes (62.5%) of 4 patients. Improvement of BCVA was observed in 3 eyes of 3 patients, and stabilization in 3 eyes of 3 patients. Tocilizumab was well tolerated, and no severe side effects occurred. CONCLUSIONS: Treatment with tocilizumab can be considered in chronic uveitic macular edema even if previous immunomodulatory therapy has failed.

Monitoring Disease Activity in Patients with Aortitis and Chronic Periaortitis Undergoing Immunosuppressive Therapy by Perfusion CT.

RATIONALE AND OBJECTIVES: To evaluate the role of perfusion CT for monitoring inflammatory activity in patients with aortitis and chronic periaortitis undergoing immunosuppressive therapy. MATERIALS AND METHODS: Seventeen symptomatic patients (median age 68.5 years) who underwent perfusion-based computed tomography (CT) monitoring after diagnostic contrast-enhanced CT were retrospectively included in this study. Blood flow (BF), blood volume (BV), volume transfer constant (k-trans), time to peak, and mean transit time were determined by setting circular regions of interest in prominently thickened parts of the vessel wall or perfused surrounding tissue at sites where the perfusion CT color maps showed a maximum BF value. Differences in CT perfusion and, morphological parameters, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were tested for significance during therapy. RESULTS: In all patients BF and BV dropped at second perfusion CT (P < 0.05). In aortitis patients, CRP dropped from 3.86 ± 5.31 mg/dL to 0.9 ± 1.37 mg/dL and in periaortitis patients from 1.78 ± 2.25 mg/dL to 0.79 ± 1.55 mg/dL, whereas ESR dropped from 45.71 ± 37.59 seconds to 8.57 ± 3.1 seconds and 36.78 ± 34.67 seconds to 17.22 ± 21.82 seconds in aortitis and in periaortitis, respectively. CONCLUSIONS: The course of perfusion CT parameters in aortitis and chronic periaortitis undergoing immunosuppressive therapy dropped at different extent after therapy.

MRI parametric monitoring of biological therapies in primary large vessel vasculitides: a pilot study.

OBJECTIVE: To evaluate the development of characteristic MRI changes in patients with primary large-vessel vasculitis (LVV) when treated with biological therapies. METHODS: 12 patients with primary LVV (8 patients with Takayasu arteritis and 4 patients with giant-cell arteritis) received biological therapy with tumour necrosis factor-α blockers (n = 9) or an interleukin-6 inhibitor (n = 3). MRI investigations were performed at baseline (pre-treatment) and follow-up. All patients underwent the same MRI/MR angiography (MRA) protocol. Laboratory parameters (C-reactive protein and erythrocyte sedimentation rate) and clinical response (Birmingham Vasculitis Activity Score) were assessed. RESULTS: Wall thickness was 4.2 ± 0.3 mm pre-treatment and significantly decreased to 3.2 ± 0.3 mm post treatment in 9/12 patients. Mural enhancement was increased in all 12/12 patients with LVV, and subsided with therapy in 5/12 patients. Mural oedema or ill-defined contour were less prevalent but also improved with biological treatment. C-reactive protein and erythrocyte sedimentation rate levels decreased, and clinical assessment revealed a significant improvement from pre-treatment to post-treatment. However, the course of imaging characteristics often did not parallel that of laboratory or clinical parameters. In all three patients receiving interleukin-6 blockade, laboratory markers and clinical scores normalized despite persistent vascular inflammation in one patient which was disclosed by MRI. CONCLUSION: Contrast-enhanced MRI/MRA may be useful when evaluating the development of disease activity in primary LVV under biological therapies. A high degree of suspicion and regular imaging follow-up is needed to detect persistent inflammation. ADVANCES IN KNOWLEDGE: This is the first study investigating the applicability of different MRI/MRA parameters for monitoring biological therapy in patients with primary LVV.

Whole Exome Sequencing Identifies Rare Protein-Coding Variants in Behçet's Disease.

OBJECTIVE: Behçet's disease (BD) is a systemic inflammatory disease with an incompletely understood etiology. Despite the identification of multiple common genetic variants associated with BD, rare genetic variants have been less explored. We undertook this study to investigate the role of rare variants in BD by performing whole exome sequencing in BD patients of European descent. METHODS: Whole exome sequencing was performed in a discovery set comprising 14 German BD patients of European descent. For replication and validation, Sanger sequencing and Sequenom genotyping were performed in the discovery set and in 2 additional independent sets of 49 German BD patients and 129 Italian BD patients of European descent. Genetic association analysis was then performed in BD patients and 503 controls of European descent. Functional effects of associated genetic variants were assessed using bioinformatic approaches. RESULTS: Using whole exome sequencing, we identified 77 rare variants (in 74 genes) with predicted protein-damaging effects in BD. These variants were genotyped in 2 additional patient sets and then analyzed to reveal significant associations with BD at 2 genetic variants detected in all 3 patient sets that remained significant after Bonferroni correction. We detected genetic association between BD and LIMK2 (rs149034313), involved in regulating cytoskeletal reorganization, and between BD and NEIL1 (rs5745908), involved in base excision DNA repair (P = 3.22 × 10(-4) and P = 5.16 × 10(-4) , respectively). The LIMK2 association is a missense variant with predicted protein damage that may influence functional interactions with proteins involved in cytoskeletal regulation by Rho GTPase, inflammation mediated by chemokine and cytokine signaling pathways, T cell activation, and angiogenesis (Bonferroni-corrected P = 5.63 × 10(-14) , P = 7.29 × 10(-6) , P = 1.15 × 10(-5) , and P = 6.40 × 10(-3) , respectively). The genetic association in NEIL1 is a predicted splice donor variant that may introduce a deleterious intron retention and result in a noncoding transcript variant. CONCLUSION: We used whole exome sequencing in BD for the first time and identified 2 rare putative protein-damaging genetic variants associated with this disease. These genetic variants might influence cytoskeletal regulation and DNA repair mechanisms in BD and might provide further insight into increased leukocyte tissue infiltration and the role of oxidative stress in BD.

Perfusion-based assessment of disease activity in untreated and treated patients with aortitis and chronic periaortitis: correlation with CT morphological, clinical and serological data.

OBJECTIVE: To evaluate the role of perfusion-based assessment of inflammatory activity in patients with treated and untreated aortitis and chronic periaortitis as compared with clinical and serological markers. METHODS: 35 patients (20 females; median age 66 years) with (peri) aortitis were retrospectively evaluated. All patients had clinical symptoms prompting at the time of imaging. All patients first underwent whole-body contrast-enhanced CT and subsequently segmental volume perfusion CT for assessment of the degree of vascularization of (peri) aortitis as a surrogate marker for inflammatory activity. Blood flow, blood volume, volume transfer constant (k-trans), time to peak and mean transit time were determined. The thickness of the increased connective tissue formation was measured. Perfusion data were correlated with clinical symptoms and acute-phase inflammatory parameters such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and leukocyte number. RESULTS: 21 of 35 patients were untreated and 14 of 35 had previous/ongoing immunosuppression. The interobserver agreement was good (κ = 0.78) for all perfusion parameters. Average values of perfusion parameters were higher in untreated patients but remained abnormally elevated in treated patients as well. Perfusion data and ESR and CRP correlated well both in aortitis (p < 0.05) and in periaortitis (p < 0.05). In periaortitis, perfusion parameters agreed well with ESR and CRP values (p < 0.05) only in untreated patients. CONCLUSION: Perfusion CT parameters in untreated aortitis and chronic periaortitis correlate well with serological markers with respect to disease activity assessment. However, in treated periaortitis, correlations were weak, suggesting an increased role for (perfusion-based) imaging. ADVANCES IN KNOWLEDGE: Volume perfusion CT may be used for diagnosis of aortitis/periaortitis.

Ovarian reserve alterations in premenopausal women with chronic inflammatory rheumatic diseases: impact of rheumatoid arthritis, Behçet's disease and spondyloarthritis on anti-Müllerian hormone levels.

OBJECTIVE: Recent publications have shown a negative influence of SLE on female ovarian reserve. Other authors have not found a significant impact of Crohn's disease or early RA on anti-Müllerian hormone (AMH) levels. This study aimed to investigate the potential effect of Behçet's disease (BD), RA and SpA on ovarian reserve as reflected by serum AMH levels. METHODS: Serum samples from 33 RA, 32 SpA and 30 BD patients without previous cytotoxic treatment were analysed and compared with age-matched, healthy controls. AMH was quantified using a standard ELISA with a standard value of 1-8 ng/ml; values <1 ng/ml defined a reduced ovarian reserve. RESULTS: Median age was 26, 28.5 and 33 years and median disease duration was 6, 5.9 and 7 years for RA, SpA and BD patients, respectively. Compared with healthy controls, patients had significantly reduced AMH levels, with a median value for RA of 1.8 ng/ml (control 2.4 ng/ml; P = 0.009), for SpA of 1.5 ng/ml (control 2.3 ng/ml; P = 0.013) and for BD of 1.1 ng/ml (control 1.9 ng/ml; P = 0.007). HLA-B27 had a negative influence on ovarian reserve in SpA patients, whereas other serological parameters did not in the other diseases. CONCLUSION: This is the first study to show a reduced ovarian reserve in patients with RA, SpA or BD. Together with our findings in SLE, we conclude a negative influence of chronic rheumatic diseases on ovarian reserve.