Comparison of methotrexate and azathioprine as the first-line steroid-sparing immunosuppressive agents in patients with Takayasu's arteritis.

BACKGROUND: Immunosuppressive (IS) agents are recommended for the first-line treatment of patients with active Takayasu's arteritis (TAK) together with glucocorticoids (GCs). However, there is limited data comparing the efficacy and outcomes of different IS agents for this purpose. OBJECTIVES: In this study, we aimed to compare the outcomes of two most frequently used first-line IS agents, namely methotrexate (MTX) and azathioprine (AZA) in TAK patients. METHODS: TAK patients who received any IS agent in addition to GCs as the initial therapy were included in this multicentre, retrospective cohort study. Clinical, laboratory and imaging data of the patients were assessed. In addition, a matched analysis (cc match) using variables 'age', 'gender' and 'diffuse aortic involvement' was performed between patients who received MTX or AZA as the first-line IS treatment. RESULTS: We recruited 301 patients (F/M: 260/41, mean age: 42.2 ± 13.3 years) from 10 tertiary centres. As the first-line IS agent, 204 (67.8 %) patients received MTX, and 77 (25.6 %) received AZA. Less frequently used IS agents included cyclophosphamide in 17 (5.6 %), leflunomide in 2 (0.5 %) and mycophenolate mofetil in one patient. The remission, relapse, radiographic progression and adverse effect rates were similar between patients who received MTX and AZA as the first-line IS agent. Vascular surgery rate was significantly higher in the AZA group (23% vs. 9 %, p = 0.001), whereas the frequency of patients receiving ≤5 mg/day GCs at the end of the follow-up was significantly higher in the MTX group (76% vs 62 %, p = 0.034). Similarly, the rate of vascular surgery was higher in AZA group in matched analysis. Drug survival was similar between MTX and AZA groups (median 48 months, MTX vs AZA: 32% vs 42 %, p = 0.34). IS therapy was discontinued in 18 (12 MTX, 6 AZA) patients during the follow-up period due to remission. Among those patients, two patients had a relapse at 2 and 6 months, while 16 patients were still on remission at the end of a mean 69.4 (±50.9) months of follow-up. CONCLUSIONS: Remission, relapse, radiographic progression and drug survival rates of AZA and MTX were similar for patients with TAK receiving an IS agent as the first-line f therapy. The rate of vascular surgery was higher and the rate of GC dose reduction was lower with AZA compared to MTX at the end of the follow-up.

Utility of positron emission tomography as a new tool for muscle involvement in patients with idiopathic inflammatory myositis: a controlled study.

OBJECTIVES: Idiopathic inflammatory myositis (IIM) represents a rare group of disease that can affect multiple organs in addition to the muscles. 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is an emerging scanning method that is widely used in diagnosing, staging and response to treatment in patients with cancer. In this study, we aimed to evaluate the muscle involvement in PET/CT which was performed for malignancy screening and its correlation with myositis-specific antibodies (MSA) and/or myositis-associated antibodies (MAA) in patients with IIM. METHODS: IIM patients who fulfilled 2017 EULAR/ACR classification criteria and had PET-CT scans during the active phase of myositis (within two weeks of starting steroids) were included into the study. Age and sex matched participants with history of malignancy (non-IIM patients) were defined as control group. RESULTS: Data of 160 IIM patients were evaluated and 34 patients (of 64.7% female) whose PET/CT results were available, included into the study. Fourteen patients with diagnosis of malignancy without IIM (non-IIM patients) defined as the control group. Sensitivity and specificity of a positive FDG muscle uptake were 37.1% and 100%, 65.7% and 92.9%, 91.4% and 7.1% compared to liver, mediastinum and LTM uptakes, respectively. In multivariate analysis, higher baseline CRP (p=0.017, confidence interval [CI] 95%: 1.03-1.36, OR:1.18) and LDH (p=0.029, CI 95%:1.001-1.017, OR:1.01) levels were associated with muscle PET/CT positivity. CONCLUSIONS: In patients with active IIM, median muscle FDG uptake with PET/CT was higher compared to non-IIM. PET/CT may be used for the evaluation of extent and activity in patients with IIM.

Intracranial granuloma in a patient with granulomatosis with polyangiitis under rituximab maintenance: A case report.

BACKGROUND: Rituximab (RTX) is being used for both induction and maintenance of anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis. However, the efficacy of RTX for the granulomatous findings of granulomatosis with polyangiitis (GPA) has not been demonstrated as clearly as its vasculitic manifestations. CASE SUMMARY: A 46-year-old man was diagnosed in 2019 with GPA with constitutional symptoms, bilateral mastoiditis, prostatic necrosis, nodules in both lungs, pauci-immune necrotizing glomerulonephritis and high level of PR3-ANCA. He reached clinical remission after induction with high-dose corticosteroids and intravenous cyclophosphamide pulses at the 3rd month. Two months following the second cycle of RTX as maintenance, he developed multiple cranial mass lesions, and excisional biopsy revealed necrotizing vasculitis with granuloma formation. Remission was achieved with long-term high-dose corticosteroid therapy after surgical excision. CONCLUSION: We observed a relapse of GPA with intracranial granulomatous lesions in a patient under RTX maintenance. Limited efficacy of RTX should be considered for mainly granulomatous manifestations in patients with GPA.

Characteristics and course of patients with AA amyloidosis: single centre experience with 174 patients from Turkey.

OBJECTIVES: This study aimed to evaluate the clinical, laboratory and genetic characteristics and outcomes of patients with AA amyloidosis. METHODS: Patients followed up in a tertiary referral centre in Turkey with the diagnosis of inflammatory rheumatic diseases and immunohistologically proven AA amyloidosis were included in the study and retrospectively analysed. RESULTS: Among 184 patients with the diagnosis of AA amyloidosis, 174 (83 female, 91 male) were included in the analysis. The most common cause of AA amyloidosis was FMF (78.7%), and 91% of FMF-AA amyloidosis patients were carrying the p.M694V variant (74.1% homozygous). AA amyloidosis was identified earlier in patients with homozygous or compound heterozygous MEFV exon 10 variants compared with the heterozygous patients (27, 30 and 41 years, respectively). Patients with an estimated glomerular filtration rate <60 ml/min at admission had a higher frequency of progression to end-stage renal disease (P < 0.001). The overall mortality rate was 15.3% and it increased gradually in association with the amyloid burden (10% in patients with renal, 15% in renal + gastrointestinal and 43% in those with additional cardiac involvement). Renal findings responded completely to treatment in 31% of the patients, a partial response was observed in 4%, a stable course in 23.6% and progression in 38.5%. Amyloid storm was identified in nine patients and was found to be associated with increased mortality within 1 year. CONCLUSION: FMF patients still constitute the majority of AA amyloidosis patients in Turkey. The MEFV genotype and associated inflammatory load may affect the age of onset of AA amyloidosis, and earlier diagnosis and stricter follow-up and treatment may delay progression of the disease.

Treatment of systemic sclerosis-associated digital ulcers: recommendations of the Turkish Society for Rheumatology.

OBJECTIVES: Digital ulcers (DUs) are associated with a significant burden in systemic sclerosis (SSc) by leading to severe pain, physical disability, and reduced quality of life. This effort aimed to develop recommendations of the Turkish Society for Rheumatology (TRD) on the management of DUs associated with SSc. METHODS: In the first meeting held in December 2020 with the participation of a task force consisting of 23 rheumatologists the scope of the recommendations and research questions were determined. A systematic literature review was conducted by 5 fellows and results were presented to the task force during the second meeting. The Oxford system was used to determine the level of evidence. The preliminary recommendations were discussed, modified, and voted by the task force and then by members of TRD via e-mail invitation allowing personalised access to a web-based questionnaire [SurveyMonkey®]. RESULTS: A total of 23 recommendations under 7 main headings were formulated covering non-pharmacological measures for the prevention of DUs and pharmacological treatments including vasodilators, anti-aggregants, antibiotics, wound care, pain control, and interventions including sympathectomy, botulinum toxin, and surgery. Risk factors, poor prognostic factors, prevention of DU and adverse effects of medical treatments were reported as 4 overarching principles. CONCLUSIONS: These evidence-based recommendations for the management of SSc-associated DUs were developed to provide a useful guide to all physicians who are involved in the care of patients with SSc, as well as to point out unmet needs in this field.

Efficacy and safety of interleukin-1 blockers in kidney transplant recipients with familial Mediterranean fever: a propensity score-matched cohort study.

BACKGROUND: Data on use of interleukin (IL)-1 blockers in kidney transplant recipients (KTRs) with familial Mediterranean fever (FMF) are very limited. We aimed to evaluate the efficacy and safety of anakinra and canakinumab in the transplantation setting. METHODS: In this retrospective cohort study, we included KTRs who suffered from AA amyloidosis caused by FMF and treated with anakinra or canakinumab (study group, n = 36). Using propensity score matching, we selected 36 patients without FMF or amyloidosis from our database of 696 KTRs as the control group. Primary outcomes were patient and graft survival. Biopsy-confirmed graft rejection, changes in estimated glomerular filtration rate (eGFR), high-sensitivity CRP (hsCRP), erythrocyte sedimentation rate (ESR), proteinuria and number of monthly attacks were secondary outcomes. RESULTS: All KTRs with FMF began IL-1 blocker therapy with anakinra and nine (25%) were switched to canakinumab. Overall death was more frequent in the study group (19.4% vs 0%) (P = .005); however, overall graft loss was comparable between study (27.8%) and control groups (36.1%) (P = .448). Five- and 10-year graft survival rates were significantly higher in the study group (94.4% and 83.3%, respectively) than in the control group (77.8% and 63.9%, respectively) (P = .014 and P < .001, respectively). Rejections were numerically lower in study group (8.3% vs 25%), but it did not reach to statistical significance (P = .058). When compared with the pre-treatment period, with IL-1 blockers, the number of attacks per month (P < .001), and eGFR (P = .004), hsCRP (P < .001) and ESR (P = .026) levels were lower throughout the follow-up, whereas proteinuria levels were not. CONCLUSIONS: Anakinra and canakinumab are effective in KTRs suffering from FMF; however, the mortality rate may be of concern.

Course and Prognosis of AA Amyloidosis in Patients with Psoriatic Arthritis: Report of Three Cases from a Single Center Cohort and Review of the Literature.

Objective: Herein, we aimed to evaluate the frequency and clinical features of AA amyloidosis in patients with PsA followed up in our tertiary referral clinic. Methods: We retrospectively evaluated PsA patients classified according to CASPAR classification criteria followed-up in our tertiary referral clinic for AA amyloidosis. The literature search was also done by three independent researchers using the keywords "psoriatic arthritis AND amyloidosis", "spondyloarthritis AND amyloidosis", "AA amyloidosis", "secondary amyloidosis". Results and conclusions: A total of 253 patients were included into the analysis. Two thirds of (n=162; 64%) the patients were women, and the mean age of the patients was 50.6 ± 13.4 (range, 20-90). We identified three patients with AA amyloidosis in 253 patients with PsA (1.2 %). The frequency of PsA-related amyloidosis in our AA amyloidosis cohort (n=165) was 1.8 %. Literature search revealed only a retrospective cohort study and 17 case reports, and we analysed these 31 cases. Nearly half of the cases were male, mean age of the patients was 50.7±15.3 and mean age of amyloidosis diagnosis was 47.2±16.7 years. Most of these patients had both polyarticular and axial involvement (81.3%). AA amyloidosis is a rare in patients with PsA. It should be kept in mind that patients with PsA who have not received appropriate treatment for a long time and/or have refractory disease may develop AA amyloidosis.

A Case of Budd-Chiari Syndrome Associated With Antiphospholipid Syndrome Treated Successfully by Transjugular Intrahepatic Portosystemic Shunt.

Budd Chiari syndrome (BCS) is defined as obstruction of hepatic venous outflow that can be located anywhere from small hepatic venules up to the entrance of inferior vena cava (IVC) into right atrium. Etiologies of BCS include myeloproliferative disorders, congenital, and acquired hypercoagulable states. Anticoagulation is the mainstay of treatment for all cases of BCS with a demonstrable hypercoagulable state. Interventional radiology procedures such as transjugular intrahepatic portosystemic shunting (TIPS) can be utilized to reduce portal hypertension and to improve complications related to portal hypertension. We present a patient with systemic lupus erythematosus who first presented with fever, weight loss, malar rash, alopecia, livedo reticularis, symmetric polyarthritis, pancytopenia, and class IV lupus nephritis when she was 23 years old. After receiving an induction treatment of cyclophosphamide and glucocorticoids, she received a maintenance treatment of azathioprine. She presented with ascites and abdominal pain when she was 36 and the abdominal imaging revealed reduced calibration of hepatic venules and intrahepatic segment of inferior vena cava. Lupus anticoagulant was positive and anti cardiolipin IgM and IgG were positive. Work up for hereditary hypercoagulable states was negative. Thus, the diagnosis was secondary antiphospholipid syndrome where BCS was the first clinical manifestation of the antiphospholipid syndrome. Patient was anticoagulated with warfarin and received diuretics for ascites. After the ascites became refractory to diuretics and the patient had multiple vertebral compression fractures due to volume overload secondary to ascites, she was successfully treated with TIPS. When control imaging was performed, 50% of stenosis was observed in the stent. Balloon dilation of the stent was performed. Interventional radiology techniques like TIPS can be used in BCS patients secondary to APS, in cases when medical treatment is insufficient to control complications of portal hypertension. In BCS patients secondary to APS, TIPS enables clinical improvement but due to the presence of endothelial dysfunction in APS patients, there is a risk of shunt dysfunction secondary to thrombosis or stenosis secondary to intimal hyperplasia. Therefore, strict anticoagulation and regular follow up of patients after TIPS is recommended. In cases with stent stenosis, reintervention may be necessary.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and COVID-19: The Clinical Course and Prognosis of 15 Patients From a Tertiary Care Center.

OBJECTIVE: The aim of this study was to evaluate incidence rates, prognoses, and disease-related factors associated with poor outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) who had coronavirus disease (COVID-19). METHODS: Patients with AAV were questioned for a history of COVID-19 in the outpatient setting. Cumulative clinical findings and treatment history were obtained from the patients' medical records. The clinical, laboratory, and imaging findings of inpatients with COVID-19 were recorded. The data of patients who developed symptomatic COVID-19 and/or died of the disease were used for comparison. RESULTS: Eighty-nine patients (47.2% female; mean age, 56 ± 12.5 years) were included. The diagnosis was granulomatosis with polyangiitis in 56 patients (62.9%) and microscopic polyangiitis in 33 (37.1%). Sixty-one (68.2%) and 21 patients (23.6%) had renal and peripheral nerve involvement, respectively. Ten patients had a history of diffuse alveolar hemorrhage. Fifteen patients (16.9%) had COVID-19, including 9 (60%) with severe pneumonia. Twelve patients (85.7%) were hospitalized, 6 (42.9%) were admitted to the intensive care unit, and 5 (35.7%) died. All deceased patients had hypogammaglobulinemia (IgG levels <700 mg/dL) during hospital admission. Symptomatic COVID-19 was associated with higher disease activity, glucocorticoid and rituximab treatments, and glomerular filtration rate <30 mL/min. A history of peripheral nerve involvement, higher organ damage scores, and hypogammaglobulinemia was associated with mortality. CONCLUSIONS: The prognosis was poor in our patients with AAV who had COVID-19, especially those with severe multisystem involvement. Hypogammaglobulinemia was associated with mortality. Serum IgG level monitoring in patients with AAV would be beneficial during the COVID-19 pandemic.

A Case of Takayasu Arteritis with Thrombotic Microangiopathy Secondary to Malignant Hypertension Due to Bilateral Renal Artery Stenosis.

A 20 year old woman presented with right arm pain. Pulses of right upper extremity were weak, acute phase reactants were elevated and MR angiography demonstrated total occlusion of subclavian artery and right axillary artery with collaterals. The diagnosis was Takayasu arteritis and she was treated with prednisolone, azathioprine and acetylsalicylic acid. During follow up, azathioprine was switched to methotrexate. Three years later, patient presented with elevated blood pressure. CT angiography demonstrated reduced calibration of the aorta and almost total occlusion of the lumen of proximal parts of left and right renal arteries. C-reactive protein was elevated. Steroid dose was increased, methotrexate was discontinued and IV tocilizumab and antihypertensive medications were initiated. One month later, she presented to emergency department with elevated blood pressure and blurred vision in the left eye. Fundoscopic examination revealed bilateral grade 3 hypertensive retinopathy and serous detachment of retina in the left eye. Laboratory results revealed normal CRP, elevated creatinine, elevated lactate dehydrogenase, thrombocytopenia, low hemoglobin and low haptoglobin. Peripheral blood smear revealed 2-3 schistocytes in every field. She was admitted to rheumatology department with the diagnosis of thrombotic microangiopathy secondary to malignant hypertension. IV tocilizumab was administered, and methylprednisolone was maintained at a dose of 20 mg/day. Despite treatment with maximum dose of six antihypertensive medications, her blood pressure was not controlled adequately and she became hypervolemic. After undergoing ultrafiltration, balloon dilation was performed in the left renal artery, and a stent was placed there. After stent placement, creatinine and platelet count normalized, hemoglobin increased and hypertension was controlled. In this case, malignant hypertension which was triggered by bilateral renal artery stenosis due to Takayasu arteritis had caused acute kidney injury and advanced stage hypertensive retinopathy. In addition, unlike other Takayasu arteritis cases with malignant hypertension, thrombotic microangiopathy was also detected.

The relationship between serum A proliferation-inducing ligand and B-cell activating factor levels with disease activity and organ involvement in systemic lupus erythematosus.

OBJECTIVES: We aim to investigate the association between serum B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) levels with disease activity and clinical findings in SLE patients. METHODS: Seventy-nine patients with SLE and 27 healthy controls were included into the study. Serum BAFF and APRIL levels were measured by using ELISA. In 19 patients with active disease at the time of the assessment, BAFF/APRIL levels were reassessed after 6 months of follow-up and disease activity was evaluated by using SLEDAI-2K. The relationship between renal histopathology index scores and lupus nephritis (LN) classes with serum BAFF/APRIL levels was examined in 16 patients who had recent renal involvement and underwent biopsy during the study. RESULTS: Although both BAFF/APRIL levels were higher in patients with SLE compared to the control group (p < 0.001), no correlation was found between BAFF/APRIL levels and SLEDAI scores. Serum BAFF levels were higher in patients with renal disease activity (p = 0.01), and there was a significant correlation between APRIL levels and proteinuria (r = 0.42, p = 0.02). A weak inverse correlation was observed between BAFF and C3 levels (r = 0.25, p = 0.02). No correlation was found between BAFF/APRIL levels and renal SLEDAI scores, renal histopathology, activity, and chronicity index scores. In the active disease group after treatment, there was no significant change in serum BAFF levels, but a significant increase in serum APRIL levels was observed. CONCLUSION: These results suggest that both cytokines are involved in the pathogenesis of SLE and that serum BAFF can be valuable as a biomarker in SLE especially in patients with renal activity.

Chronic oxcarbazepine intoxication in a patient with primary antiphospholipid syndrome on maintenance haemodialysis.

WHAT IS KNOWN AND OBJECTIVE: Oxcarbazepine (OXC) is an antiepileptic drug. Patients suffering from chronic kidney disease with an estimated glomerular filtration rate below 30 ml/min/1.73 m2 require dose adjustments for OXC. CASE SUMMARY: A 31-year-old man was admitted with a history of diplopia, ataxia and dizziness attacks that had disappeared after a regular haemodialysis sessions for three months. Medical history was remarkable for primary antiphospholipid syndrome (APS). However, no signs of new-onset APS-related neurological involvement were present. Then, it was revealed that the patient had been using 2400 mg/day of OXC for four months, despite the prescription of half of this dose. Serum OXC level was 50 mcg/ml (reference: 3-35 mcg/ml) before a regular haemodialysis session. All symptoms disappeared in a few days after reducing to 1200 mg/day and never recurred. WHAT IS NEW AND CONCLUSION: We reported a chronic OXC intoxication in a patient on maintenance haemodialysis. To the best of our knowledge, it is the first chronic OXC intoxication case in the literature. It could be related to episodic removal of OXC and its metabolites via haemodialysis. Consequently, dose modification of drugs is a pivotal point in haemodialysis patients. Chronic drug intoxications must be kept in mind in haemodialysis patients with unexplained symptoms.

Biologic treatments in Takayasu's Arteritis: A comparative study of tumor necrosis factor inhibitors and tocilizumab.

OBJECTIVE: To compare the treatment outcomes of TNF inhibitors and tocilizumab (TCZ) in patients with Takayasu arteritis. METHODS: Takayasu arteritis patients who were refractory to conventional immunosuppressive (IS) drugs and received biologic treatment were included in this multicenter retrospective cohort study. Clinical, laboratory and imaging data during follow-up were recorded. Remission, glucocorticoid (GC) sparing effect, drug survival was compared between TNF inhibitor and TCZ treatments. Also, a subgroup matched comparison was performed between groups. RESULTS: One hundred and eleven (F/M: 98/13) patients were enrolled. A total of 173 biologic treatment courses (77 infliximab, 49 TCZ, 33 adalimumab, 9 certolizumab, 3 rituximab, 1 ustekinumab and 1 anakinra) were given. Tocilizumab was chosen in 23 patients and TNF inhibitors were chosen in 88 patients as first-line biologic agent. Complete/partial remission rates between TCZ and TNF inhibitors were similar at 3rd month and at the end of the follow-up. GC dose decrease (≤4 mg) or discontinuation of GCs was achieved in a similar rate in both groups (TNF inhibitors vs TCZ: 78% vs 59%, p = 0.125). Drug survival rate was 56% in TNF inhibitors and 57% in TCZ group (p = 0.22). The use of concomitant conventional ISs did not affect the drug survival (HR =0.78, 95% CI =0.42-1.43, p = 0.42). The match analysis showed similar results between groups in terms of relapse, decrease in GC dose, surgery need and mortality. CONCLUSION: The efficacy and safety outcomes and drug survival rates seem to be similar for TNF inhibitors and tocilizumab in patients with Takayasu arteritis.

A single center survey study of systemic vasculitis and COVID-19 during the first months of pandemic

Introduction: COVID-19 pandemic created concerns among patients receiving immunosuppressive therapy. Frequency of COVID-19 and impact of lockdown on treatment compliance in patients with vasculitis are largely unknown. Patients and method: Patients with ANCA-associated and large vessel vasculitis that have been followed-up in our clinic were contacted by phone and a questionnaire containing home isolation status, treatment adherence and history of COVID -19 between March 1st and June 30th, 2020 was applied. Results: The survey was applied to 103 patients (F/M: 59/44, mean age: 53.2±12.5). Thirty-three (32%) patients didn?t attend at least one appointment; 98(95.1%) noted that they spent 3 months in home isolation. Five patients (4.8%) received immunosuppressives irregularly and 3(2.9%) developed symptoms due to undertreatment. Four (3.9%) patients admitted to hospital with a suspicion of COVID-19, but none of them had positive PCR or suggestive findings by imaging. COVID-19 diagnosed in a patient with granulomatosis with polyangiitis during hospitalization for disease flare and she died despite treatment. Discussion: Frequency of COVID-19 was low in patients with vasculitis in our single center cohort. Although outpatient appointments were postponed in one-third of our patients, high compliance with treatment and isolation rules ensured patients with vasculitis overcome this period with minimal morbidity and mortality.

A shared motif of hla-dpb1 affecting the susceptibility to pr3-anca positive granulomatosis with polyangiitis: comparative analysis of a Turkish cohort with matched healthy controls.

We aimed to analyse the distribution of HLA Class 2 genotypes which were reported among the genetic risk factors for ANCA-associated vasculitis (AAV) among Turkish patients in comparison with healthy subjects and previously reported data of AAV cohorts. Ninety-eight patients (F/M: 47/51 and mean age: 49 ± 1.14) were enrolled in the study and records of gender and birthplace-matched 196 healthy kidney donors were used as the control group. Patients were classified according to the clinical subgroups and ANCA serotypes (MPO-AAV, PR3-AAV). DNA was isolated from venous blood from all patients, and high-resolution HLA Class 2 genotyping was carried out by using NGS-Omixon Holotype HLA Kit. The frequencies of HLA-DQB1*03:03, - *06:04, and -DPB1*13:01, -*16:01 and -*66:01:00 alleles were significantly higher, and the frequencies of HLA-DQB1*02:02, -DPB1*02:01 and -*04:01 alleles were lower in the PR3-AAV subgroup (n = 53) compared to the controls. Comparison of amino acid sequences of the associated HLA-DPB1 alleles revealed the sequence of D-E-A-V in risk alleles replaced with the G-G-P-M sequence in protective alleles between 84 and 87th positions. Structural analysis of the HLA-DPB1*02:01 showed that this shared position is in the contact area between HLA-DP α and ß chains and within pocket 1 of the antigen-binding groove. First HLA genotyping analysis in Turkish AAV patients revealed a negative correlation between PR3-ANCA positivity and certain HLA-DPB1 alleles contradictory to the results reported from European cohorts. Known functional effects of D-E-A-V sequence on HLA-DPB1 support the importance of our finding, but further studies are needed to reveal its pathogenic mechanisms.

Cancer Risk in a Large Inception Systemic Lupus Erythematosus Cohort: Effects of Demographic Characteristics, Smoking, and Medications.

OBJECTIVE: To assess cancer risk factors in incident systemic lupus erythematosus (SLE). METHODS: Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (overall risk and most common cancers) included demographic characteristics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and the adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 score. RESULTS: Among 1,668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 nonmelanoma skin, 7 lung, 6 hematologic, 6 prostate, 5 melanoma, 3 cervical, 3 renal, 2 each gastric, head and neck, and thyroid, and 1 each rectal, sarcoma, thymoma, and uterine cancers. Half of the cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated that overall cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively associated and antimalarial drugs were negatively associated. Antimalarial drugs and higher disease activity were also negatively associated with nonmelanoma skin cancer risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with nonmelanoma skin cancer risk. CONCLUSION: Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and nonmelanoma skin cancer. Antimalarials were negatively associated with breast cancer and nonmelanoma skin cancer risk. SLE activity was associated positively with hematologic cancer and negatively with nonmelanoma skin cancer. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings.

Monogenic lupus due to spondyloenchondrodysplasia with spastic paraparesis and intracranial calcification: case-based review.

Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia characterized with platyspondyly and metaphyseal lesions of the long bones mimicking enchondromatosis, resulting in short stature. SPENCD often coexists with neurologic disorders and immune dysregulation. Spasticity, developmental delay and intracranial calcification are main neurologic abnormalities. Large spectrum of immunologic abnormalities may be seen in SPENCD, including immune deficiencies and autoimmune disorders with autoimmune thrombocytopenia and systemic lupus erythematosus as the most common phenotypes. SPENCD is caused by loss of tartrate-resistant acid phosphatase (TRAP) activity, due to homozygous mutations in ACP5, playing a role in non-nucleic acid-related stimulation/regulation of the type I interferon pathway. We present two siblings, 13-year-old girl and 25-year-old boy with SPENCD, from consanguineous parents. Both patients had short stature, platyspondyly, metaphyseal changes, spastic paraparesis, mild intellectual disability, and juvenile-onset SLE. The age at disease-onset was 2 years for girl and 19 years for boy. Both had skin and mucosa involvement. The age at diagnosis of SLE was 4 years for girl, and 19 years for boy. The clinical diagnosis of SPENCD was confirmed by sequencing of ACP5 gene, which revealed a homozygous c.155A > C (p.K52T), a variant reported before as pathogenic. Juvenile-onset SLE accounts for about 15-20% of all SLE cases. But, the onset of SLE before 5-years of age and also monogenic SLE are rare. Our case report and the literature review show the importance of multisystemic evaluation in the diagnosis of SPENCD and to remind the necessity of investigating the monogenic etiology in early-onset and familial SLE cases.

Economic Evaluation of Lupus Nephritis in the Systemic Lupus International Collaborating Clinics Inception Cohort Using a Multistate Model Approach.

OBJECTIVE: Little is known about the long-term costs of lupus nephritis (LN). The costs were compared between patients with and without LN using multistate modeling. METHODS: Patients from 32 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics inception cohort within 15 months of diagnosis and provided annual data on renal function, hospitalizations, medications, dialysis, and selected procedures. LN was diagnosed by renal biopsy or the American College of Rheumatology classification criteria. Renal function was assessed annually using the estimated glomerular filtration rate (GFR) or estimated proteinuria. A multistate model was used to predict 10-year cumulative costs by multiplying annual costs associated with each renal state by the expected state duration. RESULTS: A total of 1,545 patients participated; 89.3% were women, the mean ± age at diagnosis was 35.2 ± 13.4 years, 49% were white, and the mean followup duration was 6.3 ± 3.3 years. LN developed in 39.4% of these patients by the end of followup. Ten-year cumulative costs were greater in those with LN and an estimated glomerular filtration rate (GFR) <30 ml/minute ($310,579 2015 Canadian dollars versus $19,987 if no LN and estimated GFR >60 ml/minute) or with LN and estimated proteinuria >3 gm/day ($84,040 versus $20,499 if no LN and estimated proteinuria <0.25 gm/day). CONCLUSION: Patients with estimated GFR <30 ml/minute incurred 10-year costs 15-fold higher than those with normal estimated GFR. By estimating the expected duration in each renal state and incorporating associated annual costs, disease severity at presentation can be used to anticipate future health care costs. This is critical knowledge for cost-effectiveness evaluations of novel therapies.

Multicentric reticulohistiocytosis: Rheumatology perspective.

Multicentric reticulohistiocytosis (MRH) is a rare, multisystemic non-Langerhans cell histiocytosis characterized by skin and articular involvement, and rarely involves various other organs. There are no specific laboratory findings for MRH. Diagnosis is based on clinical findings and skin or synovial biopsy results. There is currently no consensus for the treatment of MRH. Here, we review the differential diagnosis and treatment options of MRH from the rheumatologist's perspective. We also report an index case of MRH associated with Sjögren's syndrome and pulmonary embolism.

Direct and indirect healthcare costs of rheumatoid arthritis patients in Turkey.

OBJECTIVES: To estimate the annual cost of rheumatoid arthritis (RA) in Turkey by obtaining real-world data directly from patients. METHODS: In this cross-sectional study, RA patients from the rheumatology outpatient clinics of 10 university hospitals were interviewed with a standardised questionnaire on RA-related healthcare care costs. RESULTS: The study included 689 RA patients (565 females) with a mean age of 51.2±13.2 years and mean disease duration of 9.4±7.8 years. The mean scores of the Routine Assessment of Patient Index Data 3 and the Health Assessment Questionnaire-Disability Index (5.08±2.34 and 1.08±0.68, respectively) indicated moderate disease activity and severity for the whole group. One-third of the patients were on biologic agents and 12% had co-morbid conditions. The mean number of annual outpatient visits was 11.7±9.6 per patient. Of the patients, 15% required hospitalisation and 4% underwent surgery. The mean annual direct cost was € 4,954 (median, € 1,805), whereas the mean annual indirect cost was € 2,802 (median, € 608). Pharmacy costs accounted for the highest expenditure (mean, € 2,777; median, € 791), followed by the RA-related consultations and expenses (mean, € 1,600; median, € 696). CONCLUSIONS: RA has a substantial economic burden in Turkey, direct costs being higher than indirect costs. Although both direct and indirect costs are lower in Turkey than in Europe with respect to nominal Euro terms, they are higher from the perspectives of purchasing power parity and gross domestic product. Early diagnosis and treatment of RA may positively affect the national economy considering the positive correlation between health care utilisations and increased cost with disease severity.