The Effects of Adalimumab in Behçet Disease Patients on Clinical Manifestations and on Pro-Inflammatory Cytokines Milieu: Long-Term Follow-Up.

BACKGROUND: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management. OBJECTIVES: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu. METHODS: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies. RESULTS: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2-6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed. CONCLUSIONS: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.

Hereditary persistence of hemoglobin F is protective against red cell sickling. A case report and brief review.

Fetal hemoglobin (HbF) is a physiologic protein tetramer that is crucial for a developing fetus to survive in utero. Maternal hemoglobin has a relatively lower affinity for oxygen, and thus allows for an efficient transfer of oxygen from maternal to fetal blood. In addition to fulfilling a critical physiologic role, HbF is also known to alleviate symptoms of sickle-cell disease (SCD). The concentration of HbF depends on several factors. HbF is elevated in inherited conditions, such as hereditary persistence of HbF, hereditary spherocytosis, and thalassemia. The level of HbF is also increased in acquired states, such as pregnancy, aplastic anemia, thyrotoxicosis, hepatoma, myeloproliferative disorders, or hypoplastic myelodysplastic syndrome. It has been identified that some genetic loci have significant influence on HbF levels. The XmnI polymorphism, the HMIP locus, and the BCL11A gene are responsible for 45% of variations in HbF levels. Although SCD has been well described in the subpopulations of Africa, it is less common in the subpopulations of India. We describe a case of SCD, in which a patient with high HbF level presented at a very late age (27 years old). We presume the patient's inherently elevated HbF levels were able to compensate for the hypoxic episodes associated with SCD. The onset of symptoms was delayed as a result of elevated HbF levels.

Advancing Understanding of the Aesthetics of Temporal Sequences by Combining Some Principles and Practices in Music and Cuisine With Psychology.

We consider how to optimize remembered aesthetic pleasure resulting from temporal sequences of events such as music and meals. We examine what psychology and music can learn from each other and how this knowledge might be applied to tasting menus and other temporal sequences. Common practices in longer musical works suggest the importance of (a) beginnings and endings, (b) variations in affective intensity over time, (c) repetitions, (d) variations on a theme, and (e) a return to prior material at the end of a piece. Results from psychology suggest that for affective memory, the final and peak experiences are most critical. For example, because a strong positive ending may be important for affective memory, and because return is a major feature of the ending of musical works, it may be an error to end meals with desserts, which are not the favorite courses for most people and typically bear no relation to prior courses (hence no return).

[ULTRASOUND FOR IMAGING OF ACUTE SHOULDER DISEASES].

INTRODUCTION: The shoulder is a complex multi-component structure of the musculoskeletal system with numerous elements within a limited space. These comprise of two joints, synovial sucks (bursa), tendons of rotator cuff, ligaments, multiple muscles, nerves, vessels, fat, bones and skin. Ultrasound (US) investigation of the shoulder enables us to obtain precise information of the anatomy at stasis and motion. Acquired experience and skills in the performance of the US study and knowledge of shoulder structure are a basis for diagnosis of shoulder problems. Analyzing six clinical cases with urgent shoulder diseases, we indicated the importance of US for diagnostic and therapeutic purposes.

[THE INPUT OF MEASURING INFLIXIMAB LEVELS AND LEVELS OF ANTIBODIES TO INFLIXIMAB IN THE MANAGEMENT OF PATIENTS WITH RHEUMATIC DISEASES].

BACKGROUND: High levels of infliximab (IFX) directed antibodies (IFX-Ab) may result in significant reduction in IFX concentration and loss of drug efficacy. OBJECTIVES: To assess the input of measuring serum IFX levels and levels of IFX-Ab in the management of rheumatic diseases. METHODS: Serum levels of IFX and anti-IFX-Ab were measured by ELISA (IFX-Abs were also identified by anti-human lambda chain Ab) and correlated to patients (responders and nonresponders) disease activity scores. RESULTS: A total of 144 tests for IFX were performed in 91 patients (mean age 50.2 years and disease duration 9.9 years). Among responders (57 patients) levels (mean, median) of IFX were significantly higher than in non-responders (34 patients) (4.2 mcg/ml (2.3) versus 1.1 mcg/ml (0.45)); levels of IFX-Ab in responders were significantly lower than in non-responders (4.59 mcg/ml (1.0) versus 13.1 (6.1)). High IFX-Ab levels predicted IFX discontinuation in 8.8% of responders and 55.9% among non-responders. In non-responders with low IFX levels and low IFX-Ab, the shortening of re-treatment intervals lead to significant improvement. In about 28% of patients, results of blood tests influenced treatment decisions. CONCLUSIONS: Assessment of immunogenicity of anti-TNF monoclonal antibodies proved useful information for guiding the therapy in rheumatic diseases with suboptimal clinical response. Patients with low IFX levels and low levels of IFXAb may benefit from increasing the drug dose or decreasing of re-treatment intervals. In patients with negligible serum levels of IFX and high levels of IFX-Ab, the therapy should be switched to another biological agent, probably with a different mechanism of action.

Diffuse Large B Cell Lymphoma Mimicking Granulomatosis with Polyangiitis.

In a patient with systemic multiorgan disease with overlapping features, the differential diagnosis included infectious diseases, malignancies, and systemic autoimmune or inflammatory diseases. We present an unusual case of a young male with B cell lymphoma who presented with symptoms mimicking systemic vasculitis and review the existing literature.

Long-term follow-up of patients with scleroderma interstitial lung disease treated with intravenous cyclophosphamide pulse therapy: a single-center experience.

BACKGROUND: Scleroderma lung disease (ILD-SSc) is treated mainly with cyclophosphamide (CYC). The effectiveness of CYC was judged after 12-24 months in most reports. OBJECTIVES: To analyze the effect of monthly intravenous CYC on pulmonary function tests including forced vital capacity (FVC) and diffusing lung capacity (DLCO), as well as Rodnan skin score (mRSS), during long-term follow-up. METHODS: We retrospectively collected the data on 26 ILD-SSc patients who began CYC treatments before 2007. Changes in FVC, DLCO and mRSS before treatment, and at 1,4 and 7 years after completion of at least six monthly intravenous CYC treatments for ILD-SSc were analyzed. RESULTS: Mean cumulative CYC dose was 8.91 ± 3.25 G. More than 30% reduction in FVC (0%, 8%, and 31% of patients), DLCO (15%, 23%, 31%), and mRSS (31%, 54%, 62%) at years 1, 4 and 7 was registered. During the years 0-4 and 4-7, annual changes in FVC, DLCO and mRSS were 3.2 vs. 0.42% (P < 0.040), 4.6 vs. 0.89% (P < 0.001), and 1.8 vs. 0.2 (P = 0.002). The greatest annual FVC and DLCO reduction over the first 4 years correlated with mortality (P = 0.022). There were no differences in the main variables regarding doses of CYC (< 6 G and > 6 G). CONCLUSIONS: In patients with ILD-SSc, CYC stabilized the reduction of FVC during treatment, but this effect was not persistent. The vascular characteristic of ILD-SSc (DLCO) was not affected by CYC treatment. CYC rapidly improved the mRSS. This effect could be achieved with at least 6 G of CYC. Higher rates of annual reduction in FVC and DLCO in the first 4 years indicate the narrow window of opportunity and raise the question regarding ongoing immunosuppression following CYC infusions.

Ultrasound investigation of the glenohumeral joint by anterior access in patients with rheumatoid arthritis and healthy controls.

BACKGROUND: The aim of this study was to measure glenohumeral joint (GHJ) parameters via the anterior access through ultrasound and to compare to data from posterior and inferior accesses. MATERIAL AND METHODS: Twenty healthy controls (M: F=15: 5, aged 45.1±11.2 years) and 16 patients (M: F=5: 11, aged 54.6±14.7 years) with active rheumatoid arthritis (RA) (DAS 28 4.6±1.2) were investigated (SonoSite-Titan). To make the GHJ visible on the anterior access, we used the original GHJ opening maneuver. The GHJ width was measured for every transducer position at 2 points. The positions were: posterior transversal, inferior longitudinal, anterior longitudinal along the articular line, anterior transversal upper, middle and lower. The joint width included thickness of cartilage plus synovial fluid/pannus. Rotator interval (RI) width and height (upper biceps channel) were measured. RESULTS: Our normal GHJ values by posterior and inferior accesses were within previously estimated values (<2 mm and <3 mm, respectively). We acquired the first values of GHJ width from the anterior access. The last were within a range of 0.7-1.7 mm for healthy controls. Patients with RA showed significantly enlarged joint cavities. RI was not inflamed. Posterior and inferior data of GHJ width were significantly correlated (p=0.01). The data did not correlate with anterior values (p=+0.44, p=-0.56). Synovitis was much more prominent in posterior, upper anterior transversal, and anterior longitudinal accesses. CONCLUSIONS: The GHJ may be visualized by anterior access using a special maneuver. Synovitis in the anterior region of the GHJ may develop at an independent rate. Anterior GHJ sonography may be complementary to the classic access.

Early repolarization: innocent or dangerous?

Electrocardiographic (ECG) findings of wide QRS complexes in right precordial leads with saddle ST elevation in patients with polyarthritis, palpitations and family history of syncope urged us to review early repolarization syndrome (ERS). ERS is commonly seen in young men. The main ECG features are as follows: wide spread concave ST-segment elevation, more in the precordial leads (usually V2-V4); notching or irregular contour of J point and prominent concordant T waves with large amplitude. ERS was historically considered as a benign ECG variant. In recent years, it has emerged as a marker for increased risk of sudden cardiac death. The purpose of this review was to describe the ECG manifestations of this syndrome and to review the literature concerning its arrhythmogenic potential. The authors found it important not only discussing the rate of ERS life threatening but also to reemphasize its differences from other syndromes. Some of the last are much more dangerous: acute myocardial infarction and Brugada syndrome. The tables will be helpful for physicians to distinguish ERS from other syndromes in patients with chest pain and ST elevation.

Trends of SAPHO therapy: should we be content?

The interventional studies with bone biopsy of the SAPHO lesions and microbiological investigation are a significant addition to a long range of publications showing an association of SAPHO with Propionibacterium acnes. Infectious agents isolated from SAPHO patients have merited special attention for many years. Their possible etiological role is supported by the pathogen isolation from different sites: anterior chest wall, spine, synovial fluid, bone tissue, and skin pustules. A range of pathogens have been found, including Staphylococcus aureus, Hemophilusparainfluenzae, actinomyces, and even Treponemapallidum. P. acnes is a much more frequent pathogen and plays a particular role. The article focus is to emphasize limited use of interventional method to verify infection ethology of SAPHO in publications last two years. Successful therapy may be really effective and eradicative on a basis of the pathogen identification.Randomized control studies are needed to confirm the effects of antibiotic therapy.

Rituximab: rescue therapy in life-threatening complications or refractory autoimmune diseases: a single center experience.

Rituximab (RTX) is a chimeric anti-CD20 antibody, approved for rheumatoid arthritis (RA) patients who failed anti-Tumor Necrosis Factor therapy. It has been used occasionally for life-threatening autoimmune diseases (AID). We report our center experience in the use of RTX in life-threatening complications or refractory AID. Clinical charts of patients treated with RTX at our center were reviewed, cases treated for life-threatening complications or refractory AID were analyzed. Acute damage to vital organs such as lung, heart, kidney, nervous system with severe functional impairment were defined as life-threatening complications; treatment failure with high-dose corticosteroids, cyclophosphamide, IVIG, plasmapheresis was defined as refractory autoimmune disease. During the years 2003-2009, 117 patients were treated with RTX, most of them for RA. Nine patients (6 females, mean age 51.5 years, mean disease duration 6.3 years) answered the criteria. The indications were as follows: pulmonary hemorrhage (1 patient with cryoglobulinemic vasculitis, 1 with systemic sclerosis, 1 with ANCA-associated vasculitis), catastrophic anti-phospholipid syndrome (2 SLE patients), non-bacterial endocarditis and pulmonary hypertension (1 patient with mixed connective tissue disease), vasculitis and feet necrosis (1 patient with systemic lupus erythematosus), severe lupus demyelinative neuropathy and acute renal failure (1 patient), and severe rheumatoid lung disease with recurrent empyema and pneumothorax (1 patient). B cell depletion was achieved in all patients. The median time since starting of complications to RTX administration was 3 weeks (range 2-15 weeks). Complete remission (suppression of the hazardous situation and return to previous stable state) was seen in 7 out of 9 patients. Partial remission (significant improvement) was achieved in the remained. The median time to response was 3 weeks (range 1-8 weeks), mean follow-up 47.2 months (range 6-60 months). A rapid tapering off of steroids was achieved in all patients. Two patients relapsed and were successfully retreated with RTX: the patient with severe RA lung relapsed after 3 years, one of the patients with ANCA-associated pulmonary alveolar hemorrhage relapsed after 10 months. There were no side effects during RTX infusion. Two episodes of serious infections were registered: fatal Gram-negative sepsis 6 months after RTX treatment, and septic discitis 4 months after receiving RTX. RTX serves as a safe, efficient, and prompt rescue therapy in certain life-threatening conditions and resistant to aggressive immunosuppression AID. RTX when administrated at an earlier stage, prevented irreversible vital organ damage, and allowed rapid steroid tapering off in already severe immunodepressed patients.

Pulmonary arteries involvement in Takayasu's arteritis: two cases and literature review.

OBJECTIVES: To review pulmonary arteritis (PA) complicated by pulmonary arterial hypertension (PAH) in Takayasu's arteritis (TA). METHODS: Two cases of PA and PAH in TA patients and similar cases published in the Medline database from 1975 to 2009 were reviewed. RESULTS: Forty-six cases (females 89.1%, Asians 65%, mean age 34.6 years) were analyzed, 42.2% of which had PAH. Isolated PA was reported in 31.8%. Respiratory symptoms were presented as dyspnea (75.5%), chest pain (48.9%), hemoptysis (42.2%), and cough (17.7%). Hypertension, vascular bruits, and diminished/absent pulses were reported in 48.9% of patients. A diagnosis of PA was based on abnormal uptake on pulmonary perfusion scan and a finding of stenosis, narrowing, occlusion, and irregularity on computed tomography or magnetic resonance imaging, and/or pulmonary angiography. Patients were treated with glucocorticoids (77.5%), disease-modified antirheumatic drugs (35%), and warfarin (20%); only a few were treated with biological agents. Vascular procedures were performed in 52.5% of cases, on pulmonary arteries in 37.5% with good results. The outcome was death in 20.5% of PA patient and 33.3% in PAH patients. CONCLUSIONS: TA may be complicated by life-threatening PA and PAH. Clinical signs are not specific and may be masked by involvement of the aorta and its branches. Treatment with glucocorticoids and disease-modified antirheumatic drugs has only partial effect, which may be intensified by biological agents. Invasive procedures on pulmonary arteries may be a complementary option. PA and PAH in TA patients should be recognized early and treated promptly for prevention of irreversible vascular damage.

Large leg ulcers due to autoimmune diseases.

BACKGROUND: Large leg ulcers (LLU) may complicate autoimmune diseases. They pose a therapeutic challenge and are often resistant to treatment. To report three cases of autoimmune diseases complicated with LLU. CASE REPORT: Case 1. A 55-year old woman presented with long-standing painful LLU due to mixed connective tissue disease (MCTD). Biopsy from the ulcer edge showed small vessel vasculitis. IV methylprednisolone (MethP) 1 G/day, prednisolone (PR) 1mg/kg, monthly IV cyclophosphamide (CYC), cyclosporine (CyA) 100mg/day, IVIG 125G, ciprofloxacin+IV Iloprost+enoxaparin+aspirin (AAVAA), hyperbaric oxygen therapy (HO), maggot debridement and autologous skin transplantation were performed and the LLU healed. Case 2. A 45-year old women with MCTD developed multiple LLU's with non-specific inflammation by biopsy. MethP, PR, hydroxychloroquine (HCQ), azathioprine (AZA), CYC, IVIG, AAVAA failed. Treatment for underlying the LLU tibial osteomyelitis and addition of CyA was followed by the LLU healing. Case 3. A 20-year-old man with history of polyarteritis nodosa (PAN) developed painful LLU's due to small vessel vasculitis (biopsy). MethP, PR 1 mg/kg, CYC, CyA 100 mg/d, AAVAA failed. MRSA sepsis and relapse of systemic PAN developed. IV vancomycin, followed by ciprofloxacin, monthly IVIG (150 g/for 5 days) and infliximab (5 mg/kg) were instituted and the LLU's healed. CONCLUSIONS: LLU are extremely resistant to therapy. Combined use of multiple medications and services are needed for healing of LLU due to autoimmune diseases.

Sacroiliitis and severe disability due to isotretinoin therapy.

We report a case of acute sacroiliitis with severe disability after only 3 weeks of isotretinoin therapy with graduate reduction of pain, limitation and muscle incompetence after discontinuation of the drug and ACTH-depo injection and Ethodolac therapy. Naranjo probability scale indicated a probable relationship between isotretinoin therapy and bilateral sacroiliitis. We discussed possible mechanisms of sacroiliitis and disability due to isotretinoin treatment.

Arterio-venous shunts or low oxygen utilization?

An idea of arteriovenous shunts (AVS) was proposed for explanation of dynamic regulation of oxygenation and venous hyperoxia. A formula enabling calculation of AVS and real CO2 production has recently been derived by comparing data of arterial and venous blood gases. Regarding venous hyperoxia, there is a need to differentiate capillary to tissue transport defect (low oxygen utilisation-LOU) from AVS, which may exist simultaneously. The AVS may be associated with normal or relatively high oxygen utilization from the capillary vessels and increased CO2 production. AVS is proposed to carry protective and 'stealing' properties including renal, cardiac, and pulmonary hemodynamic. Calculations of the AVS may be important for dynamic assessment of vascular and metabolic status and in emergency medicine.

SAPHO syndrome: is a range of pathogen-associated rheumatic diseases extended?

SAPHO syndrome, representing a constellation of synovitis, acne, palmo-plantar pustulosis, hyperostosis, and osteitis, is now recognized as a distinct medical entity: a reactive infectious osteitis. Genetic, immunological, and bacterial mechanisms are implicated in the development of the disease. Diagnostic problems may arise due to non-complete manifestations of SAPHO: either acne and arthritis or acne and anterior wall osteitis with an unclear pustulosis history. The interventional study of Assmann et al. is a significant addition to a long range of publications showing an association of SAPHO with Propionibacterium acnes. Randomized control studies are needed to confirm the effects of antibiotic therapy.