A multicenter report of biologic agents for the treatment of secondary amyloidosis in Turkish rheumatoid arthritis and ankylosing spondylitis patients.

In this multicenter, retrospective study, we evaluated the efficacy and safety of biologic therapies, including anti-TNFs, in secondary (AA) amyloidosis patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). In addition, the frequency of secondary amyloidosis in RA and AS patients in a single center was estimated. Fifty-one AS (39M, 12F, mean age: 46.7) and 30 RA patients (11M, 19F, mean age: 51.7) with AA amyloidosis from 16 different centers in Turkey were included. Clinical and demographical features of patients were obtained from medical charts. A composite response index (CRI) to biologic therapy-based on creatinine level, proteinuria and disease activity-was used to evaluate the efficacy of treatment. The mean annual incidence of AA amyloidosis in RA and AS patients was 0.23 and 0.42/1000 patients/year, respectively. The point prevalence in RA and AS groups was 4.59 and 7.58/1000, respectively. In RA group with AA amyloidosis, effective response was obtained in 52.2 % of patients according to CRI. RA patients with RF positivity and more initial disease activity tended to have higher response rates to therapy (p values, 0.069 and 0.056). After biologic therapy (median 17 months), two RA patients died and two developed tuberculosis. In AS group, 45.7 % of patients fulfilled the criteria of good response according to CRI. AS patients with higher CRP levels at the time of AA diagnosis and at the beginning of anti-TNF therapy had higher response rates (p values, 0.011 and 0.017). During follow-up after anti-TNF therapy (median 38 months), one patient died and tuberculosis developed in two patients. Biologic therapy seems to be effective in at least half of RA and AS patients with AA amyloidosis. Tuberculosis was the most important safety concern.

Immune thrombocytopenia: epidemiological and clinical features of 216 patients in northwestern Turkey.

We evaluated the clinical features, treatment modalities, treatment responses, and prognosis of our patients with immune thrombocytopenia (ITP). Furthermore, we estimated the frequency of ITP in the Thrace region of Turkey. Two hundred sixteen patients diagnosed with ITP between 2000 and 2012 at our center were retrospectively evaluated. Patients' clinical features, treatments, and responses to treatment modalities were recorded. The mean annual incidence of ITP was 2.92/100,000 (95%CI: 1.57-4.27). The overall prevalence of ITP was 35.1/100,000 (95%CI: 30.3-39.8). The administration of first-line therapy resulted in complete remission (CR) in 76.5 % of patients and partial remission (PR) in 13.6 %. After 5 years, 33 % of patients who were responsive to first-line therapy were still in relapse-free remission. Of patients who were given second-line therapy, CR was obtained in 71.3 % and PR in 14.9 %. The duration of relapse-free remission was longer with splenectomy than with steroids (p < 0.001). Five years after splenectomy, 62 % of patients were in relapse-free remission; contrarily, this was lower with steroids (36 % at 5 years). The annual incidence and prevalence of ITP in northwestern Turkey was similar to data from western countries-at the lower limit for some countries. Effective treatment strategies seem to be steroids as first-line therapy and splenectomy in refractory cases.

Spleen tyrosine kinase (Syk) inhibitor fostamatinib limits tissue damage and fibrosis in a bleomycin-induced scleroderma mouse model.

OBJECTIVES: The pathogenesis of fibrosis in scleroderma (SSc) is unknown. TGF-ß and platelet-derived growth factor are important in the development of fibrosis and tyrosine kinases are involved in these pathways. The possible antifibrotic effects of various kinase inhibitors in SSc have been studied before. Spleen tyro-sine kinase (Syk) is a protein tyrosine kinase which activates intracellular signal transduction pathways; and has been claimed to be involved in the pathogenesis of systemic autoimmune diseases. Inhibition of Syk suppresses IgE- and IgG-associated FcR signal activation in various cell types; and suppresses experimental arthritis and skin and kidney disease in lupus-prone mice. We investigated the ability of a small drug, the Syk inhibitor, fostamatinib, to protect mice from bleomycin-induced SSc. METHODS: Four study groups of BALB/c mice were included into this study: control, bleomycin (administered subcutaneously to BALB/c mice for 21 days), bleomycin and fostamatinib (mice fed with chow containing a Syk inhibitor for 21 days), and fostamatinib alone groups. Skin and lung tissue specimens were obtained and evaluated histologically. RESULTS: Treatment with fostamatinib significantly reduced skin thickness and fibrosis. Mice treated with fostamatinib also displayed less fibrosis and inflammation in the lung tissue. Following fostamatinib treatment, Syk, phospho-Syk, and TGF-ß expression decreased in both skin and lung tissues. CONCLUSIONS: The Syk inhibitor fostamatinib prevented bleomycin-induced fibrosis and inflammation in the skin and in the lung. The anti-fibrotic effect of fostamatinib is linked to reduced Syk phosphorylation and TGF-ß expression. The Syk pathway appears as a potential molecular target for therapeutic intervention in SSc.

Clinical characteristics of haematological malignancy patients diagnosed with leukaemia cutis: Experience of a single centre.

BACKGROUND/OBJECTIVES: We evaluated the clinical characteristics of patients with haematological malignancies at our centre who were diagnosed with leukaemia cutis (LC). In addition, we describe the spectrum of other skin lesions, including, secondary skin malignancies and nonspecific benign skin lesions in haematological malignancy patients. METHODS: We defined 58 skin lesions that developed in 54 inpatients hospitalised in the Department of Haematology, Trakya University Medical Faculty, Turkey. All skin lesions that developed in inpatients between 2006 and 2012 had been evaluated by a dermatologist. The patients' clinical features, skin biopsy results and therapies were obtained from hospital files. The diagnosis of LC was based on clinical features and histopathological examinations of the skin biopsy. RESULTS: There were 11 patients with LC. Six (54.5%) had acute myeloblastic leukaemia. In nine patients (82%), LC was present at the initial presentation. Secondary skin malignancy was detected in 11 patients (five basal cell carcinoma, four Kaposi's sarcoma, one squamous cell carcinoma, one malignant melanoma); and malignancy was present in two patients (18%) at the initial presentation. Nonspecific benign skin lesions, the most frequent of which were drug eruptions, were determined in 32 of our patients. LC had a significantly higher likelihood of being present at initial presentation than other skin lesions (P < 0.01). The median survival in LC patients was quite short (4.5 months). CONCLUSIONS: LC was usually diagnosed at the initial presentation of the patient or during the early course of the disease. Having LC was a poor prognostic factor.

Secondary amyloidosis in ankylosing spondylitis.

We evaluated the frequency of secondary amyloidosis, associated clinical features, and outcomes in ankylosing spondylitis (AS) patients diagnosed in the last decade. The medical records of AS patients diagnosed at single academic medical center were reviewed for clinical evidence of amyloidosis. During routine follow-up, routine urinalysis was performed at each visit; patients with significant proteinuria underwent rectal biopsy. We diagnosed 8 clinically apparent amyloidosis patients (1.1 %) in our cohort of 730 AS patients (508 males, 222 females). Four patients undergoing hemodialysis were diagnosed secondary amyloidosis. Three patients had nephrotic syndrome and renal dysfunction and one patient had non-nephrotic proteinuria. When AS patients with amyloidosis were compared to AS controls, it was observed that the amyloidosis group was older, had longer disease duration, higher initial BASDAI scores, and ESR values, and more frequent peripheral arthritis (p < 0.05). Logistic regression analysis revealed that the initial BASDAI level was an independent predictor for the development of secondary amyloidosis (OR:2.36). Six patients were administered anti-TNF therapy. The clinical findings resolved in these. In 2 patients with nephrotic syndrome and renal dysfunction, in addition to clinical improvement, there was a decrement in proteinuria; renal function improved or remained stable. Anti-TNF therapy is safe and effective in patients with renal failure, and at an earlier stage, appears effective in improving renal function. The development of proteinuria in AS patients should occasion a search for underlying amyloidosis.

Do impaired memory, cognitive dysfunction and distress play a role in methotrexate-related neutropenia in rheumatoid arthritis patients? A comparative study.

We evaluated the roles of sociocultural status, distress and cognitive functions in rheumatoid arthritis (RA) patients who developed methotrexate (MTX)-related neutropenia. The data of 37 RA patients with MTX-related neutropenia who were being followed up at 3 centers were evaluated. The control group included 74 RA patients. The clinical features, biochemical tests and treatment modalities of the patients were obtained from hospital files. The mini-mental state examination (MMSE) test and the Hospital Anxiety and Depression Scale (HADS) were administered for all RA patients with neutropenia as well as the control group. The frequencies of male patients, illiterate patients, patients living alone, patients with serious visual impairment, those with low income, and patients with high creatinine were significantly higher among RA patients with MTX-related neutropenia than in controls (p values <0.05). The RA patients with MTX-related neutropenia had significantly lower MMSE scores, and significantly higher HADS-A and HADS-D scores than controls (p values <0.05). In addition, the proportion of patients with probable dementia was significantly higher in RA patients with MTX-related neutropenia than in controls (p < 0.001). Twenty-six of the 37 patients (70.3 %) developed neutropenia with daily dosing. Patients who used MTX daily were more likely to be living alone than those using weekly dosing (p = 0.011). Multivariate analysis showed that having probable dementia on the MMSE test (OR 52.6), low income level (OR 56.8) and age (OR 1.12) were independent risk factors for the development of MTX-related neutropenia. The presence of probable dementia on MMSE, low socioeconomical status and older age are associated with serious toxicity in RA patients using MTX. Measures should be taken to prevent wrong MTX dosing by the patients. Compliance and patient education is of major importance, in particular, in the patients presented in this study.

Turkish Chronic Myeloid Leukemia Study: Retrospective Sectional Analysis of CML Patients.

OBJECTIVE: here have been tremendous changes in treatment and follow-up of patients with chronic myeloid leukemia (CML) in the last decade. Especially, regular publication and updating of NCCN and ELN guidelines have provided enermous rationale and base for close monitorization of patients with CML. But, it is stil needed to have registry results retrospectively to evaluate daily CML practices. MATERIALS AND METHODS: In this article, we have evaluated 1133 patients' results with CML in terms of demographical features, disease status, response, resistance and use of second-generation TKIs. RESULTS: The response rate has been found relatively high in comparison with previously published articles, and we detected that there was a lack of appropriate and adequate molecular response assessment. CONCLUSION: We concluded that we need to improve registry systems and increase the availability of molecular response assessment to provide high-quality patient care. CONFLICT OF INTEREST: None declared.

Does anti-TNF therapy cause any change in platelet activation in ankylosing spondylitis patients? A comparative study.

Recently, it has been reported that ankylosing spondylitis (AS) was characterised by endothelial dysfunction and the development of atherosclerotic complications. In this study, we evaluated platelet and endothelial activation parameters in AS patients. Fiftynine AS patients and 22 healthy controls were included. The clinical features and acute phase parameters were evaluated. In all patients and healthy controls, platelet-monocyte complexes (PMC), platelet-neutrophil complexes, basal and ADP-stimulated P-selectin (CD62P) expression were determined by flow cytometry; soluble E-selectin (sE-selectin) and soluble CD40L (sCD40L) were determined by ELISA. AS patients were divided into two groups as active and inactive by using BASDAI. In 15 AS patients, the evaluated parameters were assessed before and after 12 weeks of anti-TNF therapy. PMC and sCD40L levels in AS patients were significantly higher than in the control group (P values 0.013 and 0.016). The evaluated variables were similar in active and inactive AS groups (P > 0.05). There were no significant changes in platelet and endothelial activation parameters in AS patients after anti-TNF therapy (P > 0.05). Platelet activation which is reflected by high levels of PMC and sCD40L might be responsible for the increased frequency of atherosclerosis in AS. The platelet activation in our AS patients was not associated with disease activity and did not improve after anti-TNF therapy.

Subclinical atherosclerosis in gouty arthritis patients: a comparative study.

We evaluated the incidence of subclinical atherosclerosis and associated factors in our gouty arthritis patients. We included 55 gouty arthritis patients diagnosed at our center within the last 4 years. The control group included 41 patients with rheumatoid arthritis (RA) and 34 patients with asymptomatic hyperuricemia (AHU). Atherosclerotic risk factors were determined in all subjects. Carotid intima-media thickness (IMT) and the presence of plaques were evaluated by B-mode ultrasonography. The carotid IMT in gouty arthritis patients (0.730 ± 0.19) was significantly higher than in AHU subjects (0.616 ± 0.12) (P = 0.004) and tended to be higher than the RA group (0.669 ± 0.17) (P = 0.1). Atheromatous plaques were significantly more frequent in gouty arthritis patients (16 cases, 29.1%) than in RA patients (5 cases, 12.2%) and AHU subjects (3 cases, 8.8%) (P values, 0.05 and 0.023). Gout patients with plaques were older (P = 0.006) and tended to have tophi more frequently (P = 0.06). Logistic regression analysis showed that age (OR: 1.3, 95% CI: 1.02-1.54) and the presence of tophi (OR: 12.5, 95% CI: 1.2-140) were independent risk factors for the presence of plaques. Gouty arthritis bears a higher risk of atherosclerosis than both RA and AHU.

Patients with iron deficiency anemia have an increased prevalence of gallstones.

We determined the frequency of gallstones (GS) in iron deficiency anemia (IDA) patients and evaluated factors that could affect GS formation-like lipid levels and gallbladder (GB) motilities of the patients. One hundred and eleven IDA patients (88 females, 23 males; median age, 42) and 81 healthy controls (68 females, 13 males; median age, 42) were included into our study. The clinical findings of all IDA patients were recorded down; biochemical values and body mass index (BMI) were determined; and abdominal ultrasonography was performed. In addition, GB emptying was monitored by ultrasound at 30-min intervals for 2 h after a mixed meal in randomly chosen, age-matched 25 IDA patients and 26 controls. Fasting volume (FV), residual volume (RV), and ejection fraction (EF) for all GBs were determined. The frequency of GS plus cholecystectomy was significantly higher in IDA patients (15 cases, 13.5%) than in the control group (five cases, 6.2%, p = 0.048). IDA patients with GS plus cholecystectomy were older than those without GS plus cholecystectomy (p < 0.001). FV and EF did not differ between IDA and control groups (p > 0.05). On the other hand, RV was significantly higher in IDA group than in controls (p = 0.035). The frequency of GS in IDA patients was significantly higher than in controls. The increased prevalence of GS in IDA might be explained with impaired GB motility.

Elevated platelet-monocyte complexes in patients with psoriatic arthritis.

We evaluated platelet and endothelial activation parameters in psoriatic arthritis (PsA), a disease reported to be associated with the development of endothelial dysfunction and increased atherosclerotic complications. Twenty patients with PsA, eight psoriasis and 20 healthy controls were included into the study. The patients' clinical features and acute phase parameters were assessed. In all patients and controls, platelet-monocyte complexes (PMC), platelet-neutrophil complexes (PNC), and basal and ADP-stimulated P-selectin expression were determined with flow cytometry; soluble E-selectin (sE-selectin) and soluble CD40L (sCD40L) were determined with ELISA. Patterns of joint involvement and degrees of skin involvement in PsA patients were assessed. PMC in PsA patients were significantly higher than in the control group (p = 0.02). PNC were not significantly different among the three groups (p values > 0.05). sE-selectin levels in both PsA and psoriasis groups were significantly higher than in healthy controls (p values, respectively, <0.001 and 0.023). Basal and ADP-stimulated CD62P expression and sCD40L level were similar in all groups (p values > 0.05). Polyarticular PsA patients had significantly higher sCD40L than oligoarticular plus spondylitic PsA groups (p = 0.04). sCD40L level was higher in active PsA group than in inactive PsA group (p = 0.03). Groups with limited and extensive skin involvement did not differ significantly in the evaluated parameters. C-reactive protein (CRP) level in PsA patients correlated with sCD40L (r = 0.69, p = 0.012), basal CD62P expression (r = 0.89, p < 0.001) and ADP-stimulated CD62P expression (r = 0.73, p = 0.001). Endothelial activation might be have a role in the pathogenesis of both psoriasis and PsA. Among parameters of platelet activation, only PMC might play a role in the pathogenesis of PsA.

Brucellosis triggering hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency.

OBJECTIVES: To present a case of acute brucellosis triggering acute hemolytic anemia in a subject with glucose-6-phosphate dehydrogenase (G6PD) deficiency. CLINICAL PRESENTATION AND INTERVENTION: A 17-year-old male patient presented with fever, malaise and jaundice. His blood and bone marrow cultures yielded Brucella species. In addition, he was found to have acute hemolytic anemia due to previously undiagnosed G6PD deficiency. He was started on folic acid supplementation and given a combination of doxycycline and rifampicin for 6 weeks. His response to antibiotic therapy was optimal; the hemolytic anemia resolved. There were no further episodes of hemolysis. CONCLUSION: This case showed that the differential diagnosis of acute hemolytic anemia in subjects with G6PD deficiency should include brucellosis, especially in regions where the infection is endemic.

Increased platelet activation markers in rheumatoid arthritis: are they related with subclinical atherosclerosis?

Atherosclerotic cardiovascular mortality is increased in rheumatoid arthritis (RA) patients. We evaluated the association of inflammatory response with platelet, endothelial, coagulation activation parameters; and subclinical atherosclerosis in RA patients. We included 27 RA patients (21 female; six male) and 19 healthy subjects (14 female; five male). Disease activity score (DAS28) in RA patients was calculated; and patients were divided into two groups as active and inactive. Flow cytometry was used to determine platelet CD62P expression, platelet microparticles (PMP), platelet-monocyte (PMC) and platelet-neutrophil complexes (PNC). Plasma E-selectin, thrombin-antithrombin (TAT) complex, and serum sCD40L levels were determined by ELISA. The intima-media thickness (IMT) of carotid arteries was determined by B-mode ultrasonography. In RA patients, platelet CD62P expression (p < 0.001), PMC (p = 0.037) and sCD40L (p < 0.001) levels were increased when compared to the control group. PNC (p = 0.07) and TAT levels (p = 0.1) were non-significantly higher, and PMP level (p = 0.075) was nonsignificantly lower in RA patients. Soluble E-selectin level was significantly higher in the active RA group than in the inactive RA group (p = 0.009). There was no correlation between carotid IMT and activity markers, the evaluated parameters (p > 0.05).The increase in markers of active platelets, CD62P and sCD40L, and PMC levels might be associated with the increased cardiovascular mortality in RA. Nevertheless, none of these parameters were associated with carotid IMT: this suggests that one cross-sectional value might not be a good marker for atherosclerosis

An increased prevalence of fibromyalgia in iron deficiency anemia and thalassemia minor and associated factors.

In this study, we evaluated the prevalence of fibromyalgia (FM) in iron deficiency anemia (IDA) and thalassemia minor (TM) patients and associated factors. In addition, we investigated the prevalence of IDA in outpatients with fibromyalgia, and its effect on clinical findings. The study included 205 IDA, 40 TM patients and 100 healthy controls. FM was diagnosed according to 1990 ACR criteria. Whole blood count, biochemical tests, and serum iron parameters were determined. Pain, fatigue, and FM Impact Questionnaire (FIQ) functional item scores were assessed in FM subjects. In addition, the prevalence of IDA in FM patients diagnosed at the Rheumatology Outpatient Clinic was determined. The prevalences of FM in IDA (17.6%) and TM (20%) groups were higher than in controls (6%; p values 0.006 and 0.025, respectively). When IDA patients with FM were compared to those without FM, it was seen that a higher percentage were females, married, and a higher percentage had history of pica (all p values < 0.05). Serum hemoglobin and iron parameters did not differ between IDA patients with and without FM. IDA was detected in 48 (24.5%) of 196 FM patients. FM patients without IDA had higher sleep disturbance scores (p = 0.012) and longer duration of FM (p = 0.045). FM was a common finding in patients with IDA and TM. FM was associated with female sex and history of pica in IDA patients, and not associated with serum hemoglobin and selected iron parameters. The presence of FM in TM had no association with any of the above-mentioned parameters.

CXCL12 rs18011157 polymorphism in patients with non-Hodgkin's lymphoma: Is it associated with poor outcome?

OBJECTIVE: We studied CXCL12-related rs18011157 polymorphism in non-Hodgkin lymphoma (NHL) patients. We also determined the effect of this polymorphism on clinical features and outcome of NHL. METHODS: We included 90 NHL patients (54 males, 36 females) and 88 healthy controls (54 males, 34 females). CXCL12-related rs18011157 polymorphism was determined by polymerase chain reaction. RESULTS: rs18011157 polymorphism was significantly more frequent in NHL patients with GA genotype than in healthy controls (37.8% vs. 20.5%, P = 0.011). The frequency of patients with initially high lactate dehydrogenase (LDH) level (65.8% vs. 38.5%) and extranodal involvement (61.1% vs. 43.8%) was significantly higher in the GA plus AA genotype groups when considered altogether (P = 0.01 and 0.09). Poor prognostic factors in univariate analysis were the presence of B symptoms, initially high International Prognostic Index (IPI), splenomegaly, nonresponse to first-line therapy, the presence of early relapse, and carrying A allele (GA plus AA genotypes). The independent prognostic factors in multivariate analysis were only early relapse and an initially high IPI score. DISCUSSION: CXCL12 rs1801157 polymorphism which was found to be associated with extranodal involvement and increased LDH in NHL might be a marker of poor prognosis in patients with GA and AA genotypes. CONCLUSIONS: CXCL12-related rs18011517 polymorphism was more frequent in NHL patients: it might be associated with NHL pathogenesis and outcome.

Systemic antineutrophil cytoplasmic antibody vasculitis in a patient with chronic lymphocytic leukemia: quite a rare diagnosis.

There might be rheumatic manifestations of malignant diseases, especially those of the hematological type. Until now, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in chronic lymphocytic leukemia (CLL) has been reported on only very few occasions. Here, we present our patient with Rai stage II CLL who came to us with constitutional symptoms. She turned out to have hematuria with dysmorphic erythrocytes and developed hemoptysis. She had pulmonary-renal syndrome and was diagnosed with p-ANCA positive microscopic polyangiitis. She is currently using prednisolone and cyclophosphamide and undergoing regular hemodialysis. Constitutional symptoms in patients with hematological malignancies should make the physicians consider systemic vasculitis after exclusion of disease-related complications.

Increased circulating platelet-leucocyte complexes in patients with primary Raynaud's phenomenon and Raynaud's phenomenon secondary to systemic sclerosis: a comparative study.

Platelet activation and circulating platelet-leucocyte complexes increase in vascular ischemic events and autoimmune inflammatory diseases. Platelet activation markers and platelet-leucocyte complexes were evaluated in primary Raynaud's phenomenon (RP) and in RP secondary to systemic sclerosis (SSc). Whole-blood flow cytometry was utilized to quantify CD62P, platelet microparticles (PMP), platelet-monocyte complexes (PMC) and platelet-neutrophil complexes (PNC) in primary RP and in SSc patients with secondary RP. SSc patients with secondary RP had significantly higher platelet CD62P expression than primary RP patients and controls (P = 0.017 and 0.004, respectively). Primary and secondary RP patients had higher mean PMC and PNC levels than controls (all P < or = 0.001). PMP level in SSc patients with pulmonary hypertension was significantly higher than in others (P = 0.048). All parameters were similar in SSc patients with and without digital ulcers, aspirin-users and nonusers (P > 0.05). CD62P level decreased significantly after iloprost administration in four patients with digital ulcers (16.1 +/- 17.4 vs 7.4 +/- 3.8%, P = 0.03). Our results suggest there is platelet-leucocyte complex formation in RP, and, despite antithrombotic therapy, platelet activation and platelet-leucocyte interaction are ongoing in SSc. This is important as it might have potential therapeutic implications with respect to using antiplatelet drugs in SSc.

Hemophagocytic syndrome in one patient with adult-onset Still's disease. Presentation with febrile neutropenia.

Macrophage activation syndrome (MAS) is an important complication seen in systemic for juvenile rheumatoid arthritis; until now, it has been reported in only a few cases of adult-onset Still's disease (AOSD). Here, we shall present a 50-year-old female patient who was using steroids and antimalarial drugs for AOSD, and who developed MAS during follow-up. The patient presented with febrile neutropenia, and the neutropenic period lasted for 15 days. The examination of bone marrow aspiration smears demonstrated increased macrophages and findings of hemophagocytosis. Flow cytometric analysis of peripheral blood showed decreased natural killer cells. The patient developed neurologic findings during this period, and during the recovery of neutropenia, she had icterus and liver function test abnormalities. The patient was given granulocyte colony-stimulating factor during neutropenic period, and her neutropenia improved after the administration of high-dose steroids. Our patient was the first AOSD patient who presented with febrile neutropenia during the course of her disease and who was diagnosed to have MAS.