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1.  Switching from allopurinol to febuxostat for the treatment of hyperuricemia and renal function in patients with chronic kidney disease 
Clinical Rheumatology  2014;33(11):1643-1648.
Hyperuricemia is a frequent complication of chronic kidney disease (CKD). Febuxostat is a novel xanthine oxidase inhibitor that is metabolized by many metabolic pathways in the kidney and the liver. We performed a 1-year cohort study of 73 hyperuricemic patients who had an estimated glomerular filtration rate (eGFR) below 45 ml/min and were being treated with urate-lowering therapy. In 51 patients, treatment was changed from allopurinol to febuxostat, and the other 22 patients were continued on allopurinol. The serum levels of uric acid (UA) level, creatinine, and other biochemical parameters were measured at baseline and after 3, 6, 9, and 12 months of treatment. The serum UA levels significantly decreased from 6.1 ± 1.0 to 5.7 ± 1.2 mg/dl in the febuxostat group and significantly increased from 6.2 ± 1.1 to 6.6 ± 1.1 mg/dl in the allopurinol group. The eGFR decreased 27.3 to 25.7 ml/min in the febuxostat group and from 26.1 to 19.9 ml/min in the allopurinol group. The switch from allopurinol to febuxostat was significantly associated with the changes in eGFR according to a multiple regression analysis (β = −0.22145, P < 0.05). Febuxostat reduced the serum UA levels and slowed the progression of renal disease in our CKD cohort in comparison with allopurinol.
PMCID: PMC4192559  PMID: 25048744
Allopurinol; Chronic kidney disease; eGFR; Febuxostat; Hyperuricemia; Uric acid
2.  Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA 
Clinical rheumatology  2009;28(5):611-613.
The purpose of this study was to identify rheumatoid arthritis (RA)-related autoantibodies in subjects with interstitial lung disease (ILD) and no articular findings of RA, supporting the hypothesis that RA-related autoimmunity may be generated in non-articular sites, such as the lung. This was a retrospective chart review utilizing clinic databases of patients with ILD to identify cases with lung disease, RA-related autoantibody positivity, and no clinical evidence of articular RA. Four patients with ILD, RF, and anti-CCP positivity and no articular findings of RA were identified. All four patients were male with a mean age at time of diagnosis of ILD of 70 years old. All had a history of smoking. Three patients died within 2 years of diagnosis of ILD and never developed articular symptoms consistent with RA; the final case met full criteria for articular RA several months after stopping immunosuppressive treatment for ILD. RF and anti-CCP can be present in smokers with ILD without clinical evidence of articular RA and in one case symptomatic ILD and autoantibody positivity preceded the development of articular RA. These findings suggest that RA-specific autoimmunity may be generated due to immunologic interactions in the lung and may be related to environmental factors such as smoking.
PMCID: PMC4084723  PMID: 19252818
Anti-cyclic citrullinated peptide (anti-CCP) antibodies; Interstitial lung disease; Rheumatoid arthritis; Rheumatoid arthritis pathogenesis; Rheumatoid factor (RF)
3.  Clinical efficacy of abatacept, tocilizumab, and etanercept in Japanese rheumatoid arthritis patients with inadequate response to anti-TNF monoclonal antibodies 
Clinical Rheumatology  2014;33(9):1247-1254.
The aim of this study was to compare the efficacy and retention rates of three biologics (abatacept, tocilizumab, and etanercept) after switching from first-course anti-TNF monoclonal antibody therapy. We performed a retrospective multicenter study of 89 patients who underwent second-course biologic therapy for 52 weeks after switching from first-course anti-TNF monoclonal antibody therapy. Patients at baseline had a mean age of 58.7 years, mean disease duration of 9.8 years, and mean clinical disease activity index (CDAI) of 22.4. There was no significant difference between the three drugs, except in rheumatoid factor positivity. Retention rates for abatacept, tocilizumab, and etanercept treatment at 52 weeks were 72.0, 89.5 and 84.6 %, respectively. The evaluation of CDAI indicated no significant difference at 52 weeks among the three drugs. Discontinuation due to all unfavorable causes did not significantly differ among the three drugs in hazard ratio-based evaluations. Our results show that patients treated with abatacept, tocilizumab, and etanercept achieved a high response rate with no significant differences in drug retention rates and clinical efficacy. These drugs represent good therapeutic options for patients with RA who are refractory to anti-TNF monoclonal antibody therapy.
PMCID: PMC4138439  PMID: 24970596
Abatacept; Etanercept; Rheumatoid arthritis; Switching medications; Tocilizumab
4.  Impact of Managed Care Health Insurance System for Indigent Patients with Rheumatoid Arthritis in Puerto Rico 
Clinical rheumatology  2013;32(6):763-769.
The aim of this study was to determine the clinical outcome among indigent patients with rheumatoid arthritis (RA) in Puerto Rico receiving their healthcare in a managed care system, as compared to non-indigent patients treated in fee-for-service settings. A cross-sectional study was conducted in 214 Puerto Ricans with RA (per American College of Rheumatology classification criteria). Demographic features, health-related behaviors, cumulative clinical manifestations, disease activity (per Disease Activity Score 28), comorbid conditions, functional status (per Health Assessment Questionnaire, HAQ), and pharmacologic profile were determined. Data were examined using univariable and multivariable (logistic regression) analyses. The mean (standard deviation [SD]) age of the study population was 56.6 (13.5) years; 180 (84.1%) were women. The mean (SD) disease duration was 10.8 (9.6) years. Sixty-seven patients were treated in the managed care setting and 147 patients received their healthcare in fee-for-service settings. In the multivariable analyses RA patients treated in the managed care setting had more joint deformities, extra-articular manifestations, arterial hypertension, type 2 diabetes mellitus, cardiovascular events, fibromyalgia syndrome, and poorer functional status, while having a lower exposure to biologic agents than those treated in fee-for-service settings. Efforts should be undertaken to curtail the gap of health disparities among these Hispanic patients in order to improve their long term outcomes.
PMCID: PMC3780563  PMID: 23314687
Rheumatoid arthritis; medically-indigent patients; Hispanics; Puerto Ricans; healthcare; managed care system; fee-for-service system
5.  Predictors of medication non-adherence for vasculitis patients 
Clinical rheumatology  2013;32(5):649-657.
The primary purpose of this article is to document whether demographic, clinical, regimen-related, intrapersonal, and interpersonal factors predict medication non-adherence for vasculitis patients. A secondary purpose is to explore whether adherence varies by medication type and whether patients experienced drug-related side effects. Vasculitis patients (n=228) completed online baseline and 3-month follow-up surveys. Demographic (age, gender, education, race, marital status, and insurance status), clinical (perceived vasculitis severity, disease duration, vasculitis type, and relapse/remission status), regimen-related (experience of side effects), intrapersonal (depressive symptoms), and interpersonal (adherence-related support from family and friends) factors were measured at baseline. Medication non-adherence was assessed at follow-up using the Vasculitis Self-Management Survey medication adherence sub-scale (α=0.89). Variables that significantly correlated (p<0.05) with non-adherence were included in a linear regression model to predict non-adherence. Younger age (r=−0.23, p<0.001), female sex (r=0.16, p<0.05), experience of side effects (r=0.15, p<0.05), and more depressive symptoms (r=0.22, p< 0.001) were associated with more medication non-adherence, In the regression model, younger age (β=−0.01, p=0.01) and more depressive symptoms (β=0.01 p=0.02) predicted worse adherence. For six out of eight vasculitis medication types, patients who experienced side effects were less adherent than patients who did not experience side effects. Multiple factors are associated with medication non-adherence for vasculitis patients. Providers should discuss medication adherence and drug-related side effects with vasculitis patients. Providers may want to particularly target younger patients and patients with clinical signs of depression.
PMCID: PMC3743237  PMID: 23314654
Depression; Medication adherence; Side effects; Social support; Vasculitis
6.  Progress made towards enhancement of rheumatology education and practice in Zambia: review of an ILAR-supported project 
Clinical Rheumatology  2014;33(10):1367-1372.
The burden of non-communicable diseases such as musculoskeletal diseases in the developing world is often overshadowed by the more prevalent infectious diseases. Generally, there is gross underestimation of the burden of rheumatologic disease in the backdrop of scanty or indeed non-existent rheumatology services in these countries. Local studies conducted in the last two decades in Zambia have documented the increasing burden of rheumatologic conditions in the country. There are unfortunately negligible rheumatology services in the country both at tertiary or primary health-care facility levels. There is thus an urgent need to build capacity for these services so as to improve the care and management of rheumatic conditions. Here, we review progress made by an International League of Associations for Rheumatology (ILAR)-supported project that has run for the past 2 years (2012–2013) with the objective of enhancing paediatric and adult rheumatology education and practice so as to stimulate positive change in practice and related care services in Zambia. During this short time of the project, substantial progress has been made in the areas of paediatric and adult rheumatology services enhancement at the University Teaching Hospital, Lusaka: streamlining of referrals and follow-ups of rheumatology patients, laying foundations for short- and long-term medical education in rheumatology and raising public awareness of rheumatic diseases. The progress made by this grant underscores the suitability of the ILAR mission statement “think global, act local” demonstrating that even with minimum resources and networking, improvement of rheumatology care in developing countries is attainable.
PMCID: PMC4161929  PMID: 24752350
EPAREP; ILAR; Rheumatology education; Rheumatology in developing countries
7.  The use of TNF-α blockers in psoriatic arthritis patients with latent tuberculosis infection 
Clinical Rheumatology  2014;33(4):543-547.
Psoriatic arthritis (PsA) is an inflammatory arthropathy associated with skin and/or nail psoriasis. TNF-α is an essential cytokine for the host defense, and its depletion by treatment may facilitate the risk of infections or their reactivation. The aim of this study was to evaluate the efficacy and safety of TNF-α blockers in patients with PsA and concomitant latent tuberculosis infection (LTBI) comparing their outcome with non-infected PsA patients. This is a retrospective study in 321 patients with PsA, attending the Psoriatic Arthritis Clinic at the University Federico II of Naples, who had an inadequate response to DMARDs and started therapy with TNF-α blockers. We identified 40 patients with LTBI, who were included in this study along with 40 not infected PsA patients as control group. At baseline (T0) and every 3 months for 2 years (T2), data concerning PsA activity were registered. All patients underwent chest X-ray every 6 months (or 12 if appropriate). In each group, 22 patients were on etanercept therapy, 14 on adalimumab, and 4 on infliximab. Anti-TNF-α therapy was effective in both group of patients, and no statistically significant differences were found in the analysis of the study variables between the two groups from T0 to T2. No serious adverse events occurred in both groups, and no patient was withdrawn from therapy. Our experience suggests that anti-TNF-α treatment is effective and safe in PsA patients with concomitant LTBI. Therefore, neither LTBI nor chemoprophylaxis seems to influence the course of anti-TNF-α therapy.
PMCID: PMC3962579  PMID: 24554385
Anti-TNF-α; IGRA; LTBI; PsA; TST; Tuberculosis
8.  Deterioration of cutaneous microcirculatory status of Kawasaki disease 
Clinical rheumatology  2012;31(5):847-852.
Kawasaki disease (KD) is associated with generalized vasculitis with a predilection for coronary artery leading to ectasia and aneurysm in some cases. The aim of this study was to noninvasively assess the cutaneous microcirculation and correlate it with the coronary artery diameter in these patients. Laser Doppler flowmetry and dynamic capillaroscopy were performed at the nailbeds to assess total cutaneous blood flow and microcirculation in children with KD, both in the afebrile phase (after the resolution of fever) and convalescent phases, in comparison to controls. The 100 subjects analyzed in this study included 64 patients with KD (33 in afebrile phase and 31 in convalescent phase) and 36 normal controls. In KD, the capillary morphology was abnormal when compared to controls, with a larger diameter of the arterial and venous limbs, a higher intercapillary distance and a decrease in the loop numbers. Significantly decreased capillary blood cell velocity was noted in afebrile phase but not in convalescent phase. In the afebrile phase, a decreased capillary blood cell velocity significantly correlated with an increased coronary artery diameter. In conclusion, KD patients, both in the afebrile and convalescent phases, exhibited morphologic alterations in the microcirculation when compared to the controls. The results indicate the potential role of dynamic capillaroscopy for the noninvasive survey of microcirculation abnormalities in patients with KD.
PMCID: PMC3929954  PMID: 22311621
Capillary blood cell velocity; Dynamic capillaroscopy; Kawasaki disease; Microcirculation
9.  The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain 
Clinical Rheumatology  2014;33(4):451-459.
Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone’s better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.
PMCID: PMC3962576  PMID: 24526250
Anti-inflammatory; Chronic pain; Fibromyalgia; Glial cell modulators; Low-dose naltrexone; Microglia
10.  Risk factors for severe bacterial infections in patients with systemic autoimmune diseases receiving rituximab 
Clinical Rheumatology  2014;33(6):799-805.
The risk of serious bacterial infectious events (SIEs) after an RTX course used in severe and refractory cases of systemic autoimmune diseases (SAID) is well known. Risk factors for SIEs merit investigation. For this case–control study, data were collected in a single centre of internal medicine and included all patients who received rituximab (RTX) for SAID between 2005 and 2011 (rheumatoid arthritis was excluded). Sixty-nine patients with SAID received a total of 87 RTX courses. Thirteen SIEs were reported in 12 patients leading to death in 5 patients. Patients with a history of SIE were significantly older (63.6 ± 18.8 vs 48.8 ± 16.7; p = 0.0091), suffered most frequently of diabetes mellitus (33.3 % vs 5.3 %, p = 0.015), had a lower CD19 count (1.0 ± 1.2/mm3 vs 3.9 ± 7.2/mm3) and had most frequently a prednisone dose >15 mg/day (91.7 % vs 47.7 %) at the start of the first RTX course. The SIE rate was 18.7 per 100 patient-years. At the initiation of the RTX course, risk factors for SIEs were lower IgG levels (OR = 0.87, 95%CI = 0.77–0.99, p = 0.03), lower CD19 count (OR = 0.85, 95%CI = 0.73–1.00) and creatinine clearance ≤ 45 ml/min (OR = 7.78, 95%CI = 1.36–44.38, p = 0.002). Conversely history of pneumococcal vaccination significantly decreased the risk of SIEs (OR = 0.11, 95%CI = 0.03–0.41, p = 0.0009). Concomitant treatment with prednisone at a dose >15 mg/day significantly increased the SIE risk (OR = 8.07, 95%CI = 1.94–33.59, p = 0.0004). SIEs are frequent in SAID treated with RTX, particularly in patients receiving high-dose corticosteroids, in patients with renal insufficiency and in patients with low IgG levels or a low CD19 count.
PMCID: PMC4058071  PMID: 24487486
Infectious risk; Rituximab; Systemic autoimmune diseases; Systemic lupus erythematosus; Vasculitis
11.  Safety, effectiveness, and pharmacokinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years 
Clinical Rheumatology  2014;33(10):1433-1441.
The objective of this study was to assess the safety of adalimumab in patients aged 2 to <4 years old or ≥4 years old weighing <15 kg with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA). Clinical effectiveness and pharmacokinetics (PK) of adalimumab were also evaluated. This was an international, multicenter, open-label, phase 3b study in 32 patients with active JIA that were treated with adalimumab 24 mg/m2 (maximum = 20 mg/dose) every other week up to 120 weeks, with or without concomitant methotrexate. Adverse events (AEs) were summarized for completed visits. Efficacy endpoints included American College of Rheumatology pediatric (PedACR) 30/50/70/90 responses and JIA core components. Adalimumab serum trough concentrations were measured in a subset of patients. Among the patients, 88 % were female. Baseline mean age, weight, and JIA duration were 3 years, 13 kg, and 12 months, respectively; 39 % had elevated C-reactive protein. AE incidence rates included any AEs (29/32, 91 %), serious AEs (5/32, 16 %), infectious AEs (25/32, 78 %), and serious infections (3/32, 9 %). No deaths, malignancies, or opportunistic infections were reported. Growth was not adversely impacted. At week 96, 92 % of patients achieved PedACR30, and 77 % achieved PedACR70. Improvements in JIA core components were observed. Mean steady-state serum adalimumab trough concentrations were 7–8 μg/mL at weeks 12 and 24. Adalimumab was well tolerated in JIA patients aged 2 to <4 years old or ≥4 years old weighing <15 kg. The efficacy and PK of adalimumab were comparable to those seen in older JIA patients.
PMCID: PMC4161937  PMID: 24487484
Adalimumab; Polyarticular juvenile idiopathic arthritis; Safety
12.  Hepatitis reactivation in patients with rheumatic diseases after immunosuppressive therapy—a report of long-term follow-up of serial cases and literature review 
Clinical Rheumatology  2013;33(4):577-586.
The aims of this paper are to report hepatitis B virus reactivation in 12 patients with rheumatic disease undergoing immunosuppressive therapy and to evaluate whether pre-emptive antiviral therapy is necessary in patients receiving disease-modifying anti-rheumatic drugs. From January 2008 to March 2012, a total of 12 HBV-infected patients with rheumatic diseases were consecutively enrolled in the long-term follow-up. Liver function, HBV DNA, and serum aminotransferase level were tested during the follow-up. We also reviewed the published reports and summarized the clinical characteristics of HBV reactivation during immunosuppressive therapy in patients with rheumatic diseases. The medium duration of follow-up was 41 months (range 16–48). Patients were treated with prednisone, disease-modifying anti-rheumatic drugs (DMARDs) or tumor necrosis factor-alpha-blocking agents (TNFBA). HBV reactivation was only documented in two patients treated with prednisone without pre-emptive antiviral therapy. One hundred patients from literature review were identified as having HBV reactivation; 20.8 % of the patients receiving prednisone experienced HBV reactivation compared to only 4.46 and 9.52 % of patients treated with DMARDs or TNFBA, respectively. This long-term follow-up of serial cases suggests that pre-emptive antiviral therapy should be administered in patients receiving prednisone therapy for rheumatic disease. In contrast, DMARDs and TNFBA are relatively safe to HBV-infected patients with rheumatic diseases. Close monitoring of HBV DNA and ALT levels is necessary in the management of HBV reactivation.
PMCID: PMC3962582  PMID: 24343455
Disease-modifying anti-rheumatic drugs; Hepatitis B; Rheumatic disease; Steroid; Tumor necrosis factor-alpha-blocking agent
13.  Attenuated osteoarticular phenotype of type VI mucopolysaccharidosis: a report of four patients and a review of the literature 
Clinical Rheumatology  2013;33(5):725-731.
Mucopolysaccharidosis type VI (Maroteaux–Lamy syndrome, MPS VI, OMIM 253200) is caused by mutations in the gene coding for N-acetylgalactosamine-4-sulfatase (4-sulfatase, arylsulfatase B, ARSB, EC, a lysosomal enzyme involved in the degradation of dermatan sulfate (DS). The clinical presentation of MPS VI varies greatly with respect to age of onset and rate of disease progression. This report focuses on the attenuated form of MPS VI, which can go unrecognized for years and often presents with atypical signs or symptoms. We described a cohort of MPS VI patients (n = 4) heterozygous for the p.Y210C mutation who had a significant osteoarticular involvement at the onset of their disease and who were diagnosed years or even decades later. We have also reviewed the literature (n = 36). Two types of attenuated MPS VI phenotypes could be distinguished: osteoarticular and cardiac. The majority of MPS VI patients reported so far as relatively attenuated presented with an essentially osteoarticular phenotype associated with the p.Y210C mutation. Patients homozygous for the p.R152W mutation presented with a cardiac phenotype, which, despite fulfilling the generally used criteria for attenuated phenotype, may lead to fast disease progression and abrupt death. The knowledge of natural history and genotype–phenotype correlation may help in developing a tailored therapy potentially using enzyme replacement therapy with substrate reduction therapy or chaperones.
PMCID: PMC4000421  PMID: 24221504
Attenuated phenotype; Cardiac phenotype; Genotype–phenotype analysis; Maroteaux–Lamy syndrome; Mucopolysaccharidosis type VI; Osteoarticular phenotype
14.  Methotrexate-induced nausea and vomiting in adolescent and young adult patients 
Clinical Rheumatology  2013;33(3):403-407.
This study aims to determine the prevalence of methotrexate-induced nausea and vomiting in both adolescent and adult patients with inflammatory arthritis. A survey of methotrexate side effects was conducted on patients with inflammatory arthritis. We provided a brief questionnaire to unselected patients with inflammatory arthritis being treated with methotrexate attending adolescent and adult rheumatology clinics. The questions related to the presence, absence, and severity of nausea and vomiting, the temporal relationship with methotrexate and whether anti-emetics had been prescribed. A total of 106 patients from the age of 13 years and above—57 adults (over 20 years) and 49 adolescents (13–19 years) were included in this study. The median age for those experiencing nausea was 19 years (interquartile range (IQR) 7) and for those with no nausea 55 years (IQR 46) (p < 0.001). Thirty-six out of 49 adolescent patients reported nausea (73 %) compared to only 20/57 adults (35 %) (p < 0.001). Multiple logistic regression analysis showed that the nausea group had a significantly higher proportion of adolescents (p = 0.0002), patients taking subcutaneous (SC) methotrexate MTX (p = 0.002), and patients with duration of MTX of more than 1 year (p = 0.049). Adolescents were estimated to have over 6 times higher odds of nausea compared to adults (OR 6.31, 95 % CI 2.38 to 16.75, p = 0.0002) after adjusting for SC MTX and duration of MTX. Only 22 % of adolescents and 10 % of adults were prescribed anti-emetics. There is a higher prevalence of MTX-induced nausea and vomiting in adolescents and younger adult patients with inflammatory arthritis compared to older adults. The role of anti-emetics in the treatment of these symptoms is unclear.
PMCID: PMC3937539  PMID: 24108504
Adolescents; Inflammatory arthritis; Methotrexate; Nausea
15.  Clinical efficacy of abatacept compared to adalimumab and tocilizumab in rheumatoid arthritis patients with high disease activity 
Clinical Rheumatology  2013;33(1):39-47.
Favourable clinical results in rheumatoid arthritis (RA) patients with high disease activity (HDA) are difficult to achieve. This study evaluated the clinical efficacy of abatacept according to baseline disease activity compared to adalimumab and tocilizumab. This study included all patients registered in a Japanese multicenter registry treated with abatacept (n = 214), adalimumab (n = 175), or tocilizumab (n = 143) for 24 weeks. Clinical efficacy of abatacept in patients with HDA (DAS28-CRP > 4.1) and low and moderate disease activity was compared. Clinical efficacy of abatacept, adalimumab, and tocilizumab was compared in patients with HDA at baseline. In patients treated with abatacept, multivariate logistic regression identified HDA at baseline as an independent predictor for achieving low disease activity (LDA; DAS28-CRP < 2.7) [OR 0.26, 95 % CI 0.14–0.50] or remission (DAS28-CRP < 2.3) [OR 0.26, 95 % CI 0.12–0.56] at 24 weeks. In patients with HDA at baseline, logistic regression did not identify treatment with adalimumab or tocilizumab as independent predictors of LDA or remission compared to abatacept. Retention rates based on insufficient efficacy were significantly higher in patients treated with abatacept compared to adalimumab and lower than tocilizumab. Retention rates based on adverse events in patients treated with abatacept were significantly lower compared to tocilizumab. Clinical efficacy of abatacept was affected by baseline disease activity. There were no significant differences between the three different classes of biologics regarding clinical efficacy for treating RA patients with HDA, although definitive conclusions regarding long-term efficacy will require further research.
PMCID: PMC3890049  PMID: 24057092
Abatacept; Adalimumab; High disease activity; Japanese multicenter registry system; Rheumatoid arthritis; Tocilizumab
16.  Efficacy and safety of rituximab as maintenance therapy for relapsing granulomatosis with polyangiitis—a case series 
Clinical Rheumatology  2013;33(6):841-848.
The objective of this work was to study the efficacy and safety of pre-emptive rituximab (RTX) in a series of patients with severe relapsing granulomatosis with polyangiitis (GPA). GPA is a systemic vasculitis with a high relapse rate despite successful remission induction. Drug toxicity with repeated induction treatments and long-standing immunosuppression poses a problem. Based on the findings in reports on RTX for rheumatoid arthritis, we treated patients with severe relapsing GPA with pre-emptive RTX, 1,000 mg 2 weeks apart every 6 months, aiming at achieving sustainable remission. All patients at one centre with relapsing GPA in spite of traditional maintenance treatment, who had received more than or equal to three cycles of RTX as regularly repeated pre-emptive maintenance therapy every 6 months, were included in this retrospective study. Information on disease manifestations and activity, treatments, lab parameters and adverse events was extracted from the medical files. Of the 12 included patients, all with a positive proteinase 3–anti-neutrophil cytoplasmic antibodies, generalised disease and a median disease duration of 35 months (21–270), 92 % (11/12) achieved sustainable remission during a median follow-up time of 32 months (range 21–111) from first RTX treatment. Concomitant immunosuppressants were reduced. Infections were the most common adverse events, but infections were an issue also before the start of RTX. RTX administered every 6 months seems to be an effective maintenance treatment in a population with severe, relapsing long-standing GPA. Granulomatous as well as vasculitic manifestations responded equally well. Infections are a problem in this patient group but no new safety problems were identified.
PMCID: PMC4058072  PMID: 23959445
Granulomatosis with polyangiitis; Infections; Maintenance therapy; Rituximab; Safety
17.  Clinical features and prognostic factors of thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus: a literature review of 105 cases from 1999 to 2011 
Clinical Rheumatology  2013;33(3):419-427.
This study aims to review clinical features, treatments, and prognostic factors of thrombotic thrombocytopenic purpura (TTP) associated with systemic lupus erythematosus patients (sTTP). The case reports of sTTP published in world literature from 1999 to 2011 were collected, and 105 cases were divided into death group and survival group. The epidemiologic characteristics, clinical manifestations, laboratory examinations, treatments, and prognostic factors were analyzed. We found that coexistence of renal and neurological impairments were significantly frequent in the death group (100 %) than in the survival group (56.5 %) (P = 0.002). Type IV was predominant in 57.7 % of renal pathological damage, followed by type V (11.5 %), type II (5.8 %), and thrombotic microangiopathy (TMA) (5.8 %). TMA appeared more frequently (50 %) in the death group than in the survival group (6.25 %) (P = 0.042). End-stage renal disease occurred in nine cases with type IV in five (55.6 %), type TMA in one (11.1 %), and unspecified in three cases (33.3 %). Of 32 cases, 40.6 % showed severe ADAMTS13 deficiency and returned to normal or mildly deficient after remission. The total mortality rate of sTTP was 12.4 % and the mortality rate of patients with infection (27.3 %) was significantly higher than those without infection (8.4 %) (P = 0.028). Plasma exchange and glucocorticoids were administrated in over 80 % of cases with 65.7 % remission rate, while additional cytotoxics or rituximab was mostly used in refractory sTTP and achieved over 90 % of remission rate. Above all, coexistence of renal and neurological impairments, infection, and renal damage with type IV or TMA might denote a poor prognosis of sTTP.
PMCID: PMC3937538  PMID: 23954922
ADAMTS13; Infection; Prognostic factors; Systemic lupus erythematosus; Thrombotic thrombocytopenic purpura
18.  Serum endothelin-1 and NT-proBNP, but not ADMA, endoglin and TIMP-1 levels, reflect impaired right ventricular function in patients with systemic sclerosis 
Clinical Rheumatology  2013;33(1):83-89.
Heart and pulmonary involvement is a leading cause of systemic sclerosis (SSc)-related deaths.
The aim of our study was to assess if biochemical markers of right ventricular (RV) overload, endothelial function and collagen metabolism can predict RV dysfunction assessed by Doppler echocardiography in SSc patients.
We prospectively studied 111 consecutive patients (101 F, 10 M, age 54.2 ± 13.8 years) with diagnosed SSc (mean disease duration 9.4 ± 11.4 years) and a group of 21 age-matched subjects (18 F, 3 M, age 49.3 + 10.5 years). We performed transthoracic echocardiography (Phillips iE 33) and measured serum endothelin-1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), asymmetric dimethylarginine (ADMA), endoglin and human tissue inhibitor of matrix metalloproteinase (TIMP-1) concentration.
Median serum NT-proBNP level in SSc patients was 133.5 (range 21.86–17,670 pg/ml) and was significantly higher than in controls (p = 0.0002). Moreover, the median serum ET-1 level of 1.49 (range 0.26–8.75 pg/ml) was higher in SSc patients (p = 0.002). However, no significant differences in ADMA, TIMP-1 and endoglin serum concentration between SSc patients and controls were observed. Serum NT-proBNP concentration correlated positively with echocardiographic signs of RV overload: tricuspid regurgitation pressure gradient (r = 0.38, p = 0.0004) and RV Tei index (r = 0.25, p = 0.01). ET-1 serum level correlated negatively with tricuspid annular plane systolic excursion (r = −0.4, p = 0.01) and positively with inferior vena cava diameter measured at expiration (r = 0.38, p = 0.0002). The echocardiographic signs of RV overload were significantly more pronounced in the highest NT-proBNP tertile (>195 pg/ml) group than in the lowest one (<88 pg/ml).
Serum ET-1 and NT-proBNP, but not endoglin, ADMA and TIMP-1 levels correlating with the echocardiographic parameters of RV overload, can be considered as noninvasive indicators of RV dysfunction in SSc patients.
PMCID: PMC3890053  PMID: 23942766
Biomarkers; Echocardiography; Pulmonary hypertension; Systemic sclerosis
19.  Clinical and serological features of systemic sclerosis in a Chinese cohort 
Clinical rheumatology  2012;32(5):617-621.
Our goal was to study the prevalence of systemic sclerosis (SSc) subtypes, autoantibody profile, and pulmonary fibrosis in a large group of Han Chinese. Chinese SSc patients (n=419) were recruited from a multicenter study including hospitals and outpatient clinics in China. All patients met the American College of Rheumatology classification criteria for SSc. Anti-topoisomerase (ATA), anti-centromere (ACA), anti- RNA polymerase III (anti-RNAP3), and anti-U1- ribonucleoprotein (anti-U1RNP) were detected utilizing commercially available kits. The clinical and autoantibody information in Chinese patients was compared to that in the US Caucasian patients (n=834), recruited from the Genetics versus Environment in Scleroderma Outcome Study and Scleroderma Family Registry. Chi-square test was utilized for the abovementioned comparisons. Chinese patients showed 40.3 % limited (lcSSc) and 59.7 % diffuse (dcSSc) forms of SSc. ATA was found in 59.9 %, ACA in 13.4 %, anti-RNAP3 in 1.3 %, and anti-U1RNP in 18 % of Chinese SSc patients. Compared to US patients (65.1 % lcSSc, 34.9 % dcSSc, ATA in 18.7 %, ACA in 32.4 %, anti-RNAP3 in 17.4 %, and anti-U1RNP in 2.8 %), Chinese SSc patients are significantly higher in dcSSc and the frequencies of ATA and anti-U1RNP, but lower in ACA and anti-RNAP3. In addition, pulmonary fibrosis was observed in 78 % Chinese SSc patients and was strongly associated with the presence of ATA. The present study represents the first report of SSc features in a large group of Chinese patients. Clinical subtypes and the frequencies of SSc-related autoantibodies in Chinese SSc patients are significantly different from those in SSc patients of the US Caucasian descent.
PMCID: PMC3734856  PMID: 23271609
Anti-centromere antibody; Anti-topoisomerase antibody; Autoantibodies; Pulmonary fibrosis; Systemic sclerosis
20.  Performance of Global Assessments of Hip, Knee, and Back Symptom Change 
Clinical rheumatology  2010;30(3):331-338.
To compare patients’ global assessments of change in knee, hip, and back symptoms with actual changes over time in pain, function, and radiographic severity.
Participants (n=894, 80% female, mean age=66 years) completed two assessments (mean of 4 years apart) as part of a study on the genetics of generalized osteoarthritis. At both assessments, participants completed the Western Ontario and McMaster Universities OA Index (WOMAC), and radiographic severity was assessed for knees, hips, and low back. At the second assessment, participants described changes in knee, hip, and low back symptoms as Worse, Better, Same, or Never Had Symptoms. Analysis of covariance models examined mean changes in WOMAC scores and radiographic severity according to categories of the global assessment measures. Statistical significance was examined for linear trend.
Mean WOMAC total, pain, and function scores decreased (indicating improvement) among participants who indicated joint symptoms were Better; showed little change among those who reported symptoms were the Same/Never Had Symptoms; and increased among those who reported symptoms were Worse. For all analyses except the comparison of WOMAC pain change according to global assessment of low back symptom change, there was a statistically significant linear trend (p<0.05). Patterns were similar for changes in radiographic severity, but the tests of linear trend were not statistically significant.
Results support the concordance of these global assessments of joint symptom change with actual changes in self-reported symptoms. These global assessments may be useful for assessing change over time when baseline data are unavailable.
PMCID: PMC3731381  PMID: 20683742
Osteoarthritis; Knee; Hip; Back; Pain; Function; Psychometrics
21.  The effectiveness of tofacitinib, a novel Janus kinase inhibitor, in the treatment of rheumatoid arthritis: a systematic review and meta-analysis 
Clinical Rheumatology  2013;32(10):1415-1424.
The aim of the present study was to conduct a meta-analysis of the effectiveness of tofacitinib, a novel oral Janus kinase inhibitor, recently approved for the treatment of active rheumatoid arthritis in patients who have failed previous treatment with methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). A systematic literature search was conducted in PubMed, EMBASE, Cochrane Library, and other databases till 3 May 2013. All included studies were analyzed with the use of the Review Manager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. Nine randomized controlled trials (RCTs) comparing tofacitinib with placebo were identified. Two of them additionally provided the comparison with adalimumab. However, only eight RCTs met the inclusion criteria for the meta-analysis. The overall results of the meta-analysis showed that tofacitinib provided a statistically significant improvement according to the response criteria (ACR20/50/70) after 12 weeks of treatment when compared to placebo (p < 0.00001). Moreover, it was demonstrated that tofacitinib was significantly superior to adalimumab in achieving the ACR50 response criteria at week 12 (p = 0.003). For the safety analysis, there were no statistically significant differences between tofacitinib-, adalimumab-, and placebo-treated patients in respect to the risk of serious adverse events or treatment discontinuation due to adverse reactions (p > 0.05). The findings of this systematic review with meta-analysis indicate that tofacitinib monotherapy or with background methotrexate provides early statistically significant and clinically important improvement in rheumatoid arthritis symptoms and has an acceptable safety profile comparable to that of placebo. The results of the present meta-analysis show that the frequency of serious adverse events was not increased after tofacitinib treatment. In addition, tofacitinib might provide an effective treatment option compared to intravenous or subcutaneous biological DMARDs, as suggested by the result of the comparison made regarding tofacitinib vs. adalimumab ACR50 response rate.
PMCID: PMC3778229  PMID: 23877486
Meta-analysis; Rheumatoid arthritis; Systematic review; Tofacitinib
22.  Prevalence of pulmonary arterial hypertension in patients with connective tissue diseases: a systematic review of the literature 
Clinical Rheumatology  2013;32(10):1519-1531.
Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Understanding of PAH prevalence remains limited, but PAH has been reported as a frequent complication in connective tissue diseases. This study estimated prevalence of PAH in patients with connective tissue diseases and prevalence of idiopathic PAH using a systematic review of the literature. We searched PubMed through May 19, 2012 for all studies on prevalence of PAH in patients with connective tissue diseases or prevalence of idiopathic PAH. To be included, studies had to be in English, have humans as subjects, and determine prevalence within a time interval of up to 2 years. Studies only investigating pediatric patients were excluded. Pooled prevalence estimates were calculated. Twenty studies were identified in the review. Seventeen of the 20 studies reported prevalence of PAH in connective tissue diseases and three reported prevalence of idiopathic PAH. The pooled prevalence estimate of idiopathic PAH was 12 cases per million population (95 % CI 5 cases per million to 22 cases per million) with estimates ranging from 5.9 cases per million population to 25 cases per million population. The pooled prevalence estimate of PAH in patients with connective tissue diseases was 13 % (95 % CI, 9.18 % to 18.16 %) with reported estimates ranging from 2.8 % to 32 %. Prevalence of PAH in patients with connective tissue diseases was substantially higher than that of idiopathic PAH based on pooled prevalence estimates. Comparisons of PAH prevalence in persons with connective tissue disease and idiopathic PAH using a large observational study would be helpful in better assessing relative prevalence.
PMCID: PMC3778216  PMID: 23780636
Connective tissue diseases; Prevalence; Pulmonary hypertension; Review
24.  Prevalence and impact of chronic widespread pain in the Bangladeshi and White populations of Tower Hamlets, East London 
Clinical Rheumatology  2013;32(9):1375-1382.
The prevalence and impact of chronic pain differ between ethnic groups. We report a study of the comparative prevalence and impact of chronic pain in Bangladeshi, British Bangladeshi and White British/Irish people. We posted a short questionnaire to a random sample of 4,480 patients registered with 16 general practices in the London Borough of Tower Hamlets and conducted a longer questionnaire with patients in the waiting areas at those practices. We distinguished between Bangladeshi participants who were born in the UK or had arrived in the UK at the age of 14 or under (British Bangladeshi) and those who arrived in UK at the age of over 14 (Bangladeshi). We obtained 1,223/4,480 (27 %) responses to the short survey and 600/637 (94 %) to the long survey. From the former, the prevalence of chronic pain in the White, British Bangladeshi and Bangladeshi groups was 55, 54 and 72 %, respectively. The corresponding figures from the long survey were 49, 45 and 70 %. Chronic widespread pain was commoner in the Bangladeshi (16 %) than in the White (10 %) or British Bangladeshi (9 %) groups. People with chronic pain experienced poorer quality of life (odds ratio for scoring best possible health vs. good health (or good vs. poor health) 5.6 (95 % confidence interval 3.4 to 9.8)), but we found no evidence of differences between ethnic groups in the impact of chronic pain on the quality of life. Chronic pain is commoner and, of greater severity, in Bangladeshis than in Whites. On most measures in this study, British Bangladeshis resembled the Whites more than the Bangladeshis.
Electronic supplementary material
The online version of this article (doi:10.1007/s10067-013-2286-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3751214  PMID: 23719834
Chronic pain; Comparative prevalence; Ethnicity; Quality of life
25.  Comparison of indirect immunofluorescence and multiplex antinuclear antibody screening in systemic sclerosis 
Clinical rheumatology  2011;30(10):1363-1368.
Indirect immunofluorescence antinuclear antibodies (IIF-ANA) are detected in approximately 90% of scleroderma patients, and the staining pattern correlates with scleroderma-specific antibody subsets. Solid-phase ANA assays that are dependent on multiplex bead technology (MULTIPLEX-ANA) are replacing immunofluorescence in many commercial labs; however, performance of these assays has not been compared to IIF-ANA in scleroderma. The purpose of this study was to evaluate whether a proportion of scleroderma patients have negative testing on MULTIPLEX-ANA assays and demonstrate whether negative MULTIPLEX-ANA is associated with particular scleroderma-specific autoantibodies. A retrospective chart review was completed on all 238 scleroderma patients evaluated in the Georgetown scleroderma clinic between June 1, 2008 and May 31, 2009. Autoantibody results, demographics, and scleroderma features were collected. Data were analyzed using unpaired t test and Mann–Whitney U test for continuous variables, and Fisher’s exact test for dichotomous variables. Simple kappa coefficient was used to measure the level of agreement between MULTIPLEX-ANA and IIF-ANA results. Two-tailed p values <0.05 were considered significant. MULTIPLEX-ANA testing was available in 57 patients and only 29 (51%) tested positive. In contrast, IIF-ANA was positive in 91% of these patients. Using simple kappa coefficient, there was a good agreement between the MULTIPLEX-ANA, and presence of Scl70, RNP, and centromere antibodies (0.76; 95% CI 0.59, 0.92), but there was no agreement between MULTIPLEX-ANA and presence of other IIF-ANA patterns including nucleolar ANA (−0.40; 95% CI −0.64, −0.16). Because RNA polymerase III and nucleolar antibodies are seen in 43% of the entire scleroderma population, we are concerned that these false-negative tests could result in delays in referral and diagnosis. Until the MULTIPLEX-ANA assays can be modified to include the antigens for RNA polymerase III and the nucleolar ANA subsets, IIF-ANA remains the recommended screening test for ANA in suspected scleroderma.
PMCID: PMC3664239  PMID: 21614475
Antinuclear antibody; Autoantibody; IF-ANA; Immunofluorescence; Multiplex; Scleroderma

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