Can the Dose of Belimumab be Reduced in Patients with Systemic Lupus Erythematosus?

OBJECTIVES: The aims of this study were to investigate the prevalence of dose reduction in patients with SLE treated with belimumab (BEL) in Spain, analyze treatment modalities, and determine impact on control of disease activity. METHODS: Retrospective longitudinal and multicentre study of SLE patients treated with BEL. Data on disease activity, treatments and outcomes were recorded before and after reduction (6-12 months), and they were compared. RESULTS: A total of 324 patients were included. The dose was reduced in 29 patients (8.9%). The dosing interval was increased in 9 patients receiving subcutaneous BEL and in 6 patients receiving intravenous BEL. The dose per administration was reduced in 16 patients.Pre-reduction status was remission (2021 DORIS) in 15/26 patients (57.7%) and LLDAS in 23/26 patients (88.5%). After reduction, 2/24 patients (8.3%) and 3/22 patients (13.6%) lost remission at 6 months and 12 months, respectively (not statistically significant [NS]). As for LLDAS, 2/23 patients (8.7%) and 2/21 patients (9.5%) lost their status at 6 and 12 months, respectively (NS). Significantly fewer patients were taking glucocorticoids (GCs) at their 12-month visit, although the median dose of GCs was higher at the 12-month visit (5 [0.62-8.75] vs 2.5 [0-5] at baseline). CONCLUSION: Doses of BEL can be reduced with no relevant changes in disease activity-at least in the short term-in a significant percentage of patients, and most maintain the reduced dose. However, increased clinical or serologic activity may be observed in some patients. Consequently, tighter post-reduction follow-up is advisable.

Urinary neutrophil gelatinase-associated lipocalin and monocyte chemoattractant protein 1 as biomarkers for lupus nephritis in Colombian SLE patients.

Background Information regarding urinary biomarkers in Mestizo and Afro-Latin-American patients is very limited. We investigated whether levels of urinary neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemoattractant protein 1 (MCP-1) are good biomarkers to differentiate patients with lupus nephritis among Latin-American systemic lupus erythematosus (SLE) patients. Methods SLE patients meeting the revised American College of Rheumatology classification criteria for SLE were recruited. Urinary levels of NGAL and MCP-1 were measured using a commercial ELISA kit. Serum anti-C1q antibodies were measured by ELISA. SLE activity was measured with the systemic lupus erythematosus disease activity index (SLEDAI). Mann-Whitney tests were used to compare data and Spearman's rank correlations were used to examine associations between continuous variables. In addition, receiver operating characteristic curves were performed. Results One hundred and twenty SLE patients were recruited (87% women) with a median age of 32.8 ± 12.1 years and median disease duration of 7.3 ± 6.9 years. Afro-Latin-Americans had a significantly higher prevalence of lupus nephritis and higher SLEDAI scores than Mestizos. The three biomarkers were significantly higher in patients with lupus nephritis than in patients without lupus nephritis. In addition, urinary NGAL and MCP-1 were significantly higher in patients with active lupus nephritis than in inactive lupus nephritis. Urinary NGAL levels were significantly higher in Afro-Latin-American patients. A receiver operating characteristic curve for urinary biomarkers for lupus nephritis in all SLE patients showed a good level of sensitivity and specificity. Conclusion In our cohort of SLE patients, we found that urinary NGAL and MCP-1 in addition to anti-C1q antibodies were useful biomarkers for the identification of renal involvement and discrimination of active lupus nephritis among patients with renal disease.

Organ Damage and Quality of Life in Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) affects young patients in the most productive years of their life, and the consequences of organic or tissue damage involve a decrease in health-related quality of life (HRQoL). While acute disease manifestations of APS are well known, information on the long-term prognosis and damage in affected patients is still very limited. Systemic lupus erythematosus (SLE) patients would be expected to experience long-term complications and even die as a consequence of APS. Organ damage in APS has been evaluated using different methods and definitions, including the SLICC/ACR Damage Index (SDI), which tend to underestimate aPL-related damage. A new damage index in APS has been proposed (DIAPS), and it seems to be more accurate than SDI. Given the implications for morbidity and mortality, it is imperative to assess accurately aPL-related damage and HRQoL in patients with APS.

Clinical and structural damage outcomes in axial spondyloarthritis patients receiving NSAIDs or advanced therapies: a description of a real-life cohort.

Introduction: This study aims to describe the clinical characteristics, disease activity, and structural damage in patients with axial spondyloarthritis (axSpA) who receive chronic treatment with nonsteroideal anti-inflammatory drugs (NSAIDs) or advanced therapies in a clinical setting. Methods: Cross-sectional study on axSpA patients consecutively recruited from the outpatient clinic of a tertiary hospital. We collected data on clinical and demographic characteristics, as well as treatment patterns involving NSAIDs and advanced therapies. Structural damage was assessed using mSASSS. Results: Overall, data from 193 axSpA patients (83% ankylosing spondylitis) were gathered, with a mean disease duration of 21.4 years. Of these, 85 patients (44%) were exclusively taking NSAIDs, while 108 (56%) were receiving advanced therapies, with TNF inhibitors being the predominant choice (93 out of 108, 86.1%). Among patients using NSAIDs, 64.7% followed an on-demand dosing regimen, while only 17.6% used full doses. Disease activity was low, with a mean BASDAI of 3.1 and a mean ASDAS-CRP of 1.8. In comparison to patients under chronic NSAID treatment, those taking advanced therapies were primarily male (69.4% versus 51.8%, p = 0.025) and significantly younger (mean age of 49 versus 53.9 years, p = 0.033). Additionally, patients on advanced therapies exhibited lower ASDAS-CRP (p = 0.046), although CRP serum levels and BASDAI scores did not differ between the two groups. In the multivariable analysis, therapy (NSAID versus biological treatment) was not independently associated with ASDAS-CRP, BASDAI or mSASSS. Conclusion: This cross-sectional analysis of a real-world cohort of axSpA patients shows positive clinical and radiological outcomes for both NSAIDs and advanced therapies.

Disability measured by the modified health assessment questionnaire in early rheumatoid arthritis: prognostic factors after two years of follow-up.

OBJECTIVE: To analyze the rate and baseline prognostic factors of disability measured by the modified HAQ (MHAQ), in a series of patients with early rheumatoid arthritis (RA) after two years of therapy with a structured algorithm using disease-modifying anti-rheumatic drugs (DMARDs). METHODS: One hundred and five patients (81% female) with early RA (disease duration <2 years) treated with the same therapeutic protocol using gold salts and methotrexate in a step-up strategy, together with methylprednisolone (4 mg/day), were followed up for two years. The outcome was the absence of disability (MHAQ=0) after two years of DMARD therapy. Clinical, biological, immunogenetic and radiographic data (Larsen score) were analyzed at study entry and at 12 and 24 months of follow-up. RESULTS: The MHAQ decreased significantly at 6 months after initiation of DMARD therapy and the reduction was maintained at 24 months (mean+/-SD: 0.97+/-0.56 at baseline, 0.51+/- 0.57 at month 6 and 0.45+/-0.5 at month 24). No disability (MHAQ=0) was observed in 26.6% of patients after two years of follow-up. Age, MHAQ>0.5, DAS28>5.1, VAS pain, positive rheumatoid factor and ESR at baseline were associated with disability in the univariate analysis. In the logistic regression analysis, only age (OR: 1.058, 95%CI 1.017; 1.101 p<0.006), rheumatoid factor status (OR: 3.772 95%CI 1.204; 11.813, p<0.02) and MHAQ>0.5 (OR:4.023, 95%CI 1.373; 11.783, p<0.02) were associated with disability (MHAQ>0) at two years. CONCLUSION: In a series of early RA patients treated with a structured algorithm using DMARDs and very low doses of glucocorticoids, no disability was observed in a quarter of patients after two years. Age, rheumatoid factor positivity and MHAQ>0.5 were independent predictors of disability at two years.

Prognostic factors of radiographic progression in early rheumatoid arthritis: a two year prospective study after a structured therapeutic strategy using DMARDs and very low doses of glucocorticoids.

The objective of the study was to analyze the prognostic factors of radiographic progression in a series of patients with early rheumatoid arthritis (RA) after 2 years of therapy with a structured algorithm using disease-modifying antirheumatic drugs (DMARDs) and very low doses of oral glucocorticoids. One hundred and five patients (81% female) with early RA (disease duration <2 years) treated with the same therapeutic protocol using gold salts and methotrexate in a step-up strategy, together with methylprednisolone (4 mg/day), were followed up for 2 years. The outcome variable was radiographic progression after 2 years of DMARD therapy using the modified Larsen method. Clinical, biological, immunogenetic, and radiographic data were analyzed at study entry and after 1 and 2 years of follow-up. Radiographic progression (increase of four or more units in the Larsen score) was observed in 32% of patients after 2 years of follow-up. The percentage of erosive disease increased from 18.3% at baseline to 28.9% at 12 months and 44.6% at 24 months, in spite of a significant improvement in disease activity. New erosions appeared in 33% of patients after 2 years. Several baseline parameters were associated with radiographic progression in the univariate analysis: shared epitope (SE) homozygozity, HLA-DRB*04 alleles, female gender, hemoglobin, erythrocyte sedimentation rate, and anticyclic citrullinated peptide antibodies (anti-CCP). In the multivariate analysis, female gender [odds ratio (OR) 5.5, 95% confidence interval (CI): 1.1-28.2, p = 0.04], DRB1*04 alleles (OR 3.1, 95% CI 1.1-9, p = 0.03) and, marginally, anti-CCP antibodies (OR 3.6, 95% CI 0.9-14.5, p = 0.06), were associated with progression. Female patients with both DRB1*04 alleles and anti-CCP antibodies showed the highest scores in radiographic progression. The presence, but not the titer, of anti-CCP antibodies predicted progression. The positive predictive value of the multivariate model for progression was only 53.9% whereas the negative predictive value was 80.3%. In a series of early RA patients treated with a structured algorithm using DMARDs and very low doses of glucocorticoids, radiographic progression was observed in one third of patients after 2 years. Female gender, DRB1*04 alleles (rather than the SE), and the presence of anti-CCP antibodies at baseline (independently of the titer) were the most important predictors of progression. The utility of these parameters in clinical practice is limited by their relatively low positive predictive value.

Antiphospholipid syndrome in Latin American patients: clinical and immunologic characteristics and comparison with European patients.

The objective of this study was to analyse the prevalence and characteristics of the main clinical and immunological manifestations at the onset and during the evolution of the disease in a cohort of patients from Latin America (mainly of mestizo origin) and to compare the Latin American with the European patients. Clinical and serological characteristics of 100 APS patients from Mexico and Ecuador were collected in a protocol form that was identical to that used to study the ;Euro-Phospholipid' cohort. The cohort consisted of 93 female patients (93.0%) and seven (7.0%) male patients. There were 91 mestizos (91.0%), seven whites (7.0%) and two Amerindians (2.0%). The most common manifestations were livedo reticularis (40.0%), migraine (35.0%), inferior extremity deep vein thrombosis (32.0%), thrombocytopenia (28.0%) and hemolytic anemia (20.0%). Several clinical manifestations were more prevalent in Latin American than in European patients and they included mainly neurological (migraine, transient global amnesia, acute ischemic encephalopathy, amaurosis fugax) and cutaneous (livedo reticularis, skin ulcerations, superficial cutaneous necrosis, multiple subungual splinter hemorrhages) manifestations as well as hemolytic anemia. The APS has a wide variety of clinical and immunological manifestations at the onset and during the evolution of the disease and the ethnic origin in addition to environmental and socioeconomic factors can modify the disease expression.

Anti-chromatin (anti-nucleosome) antibodies.

Chromatin is the native complex of histones and DNA found in the cell nucleus of eukaryotes. The fundamental subunit of chromatin is the nucleosome, which is composed of a core particle in which 146 bp of helical DNA are wrapped around an octamer made up of two H2A-H2B dimers that surround an H3-H4 tetramer. The prevalence of anti-chromatin (nucleosome) antibodies in systemic lupus erythematosus (SLE) varies from 50% to 90%, being similar to that of the classical positive LE cell. The presence of these antibodies can be used, in conjunction with clinical findings and other laboratory tests, to help in the diagnosis of SLE and drug induced lupus. The presence of anti-chromatin antibodies has also been linked to glomerulonephritis in SLE patients.

The acute respiratory distress syndrome in catastrophic antiphospholipid syndrome: analysis of a series of 47 patients.

BACKGROUND: The acute respiratory distress syndrome (ARDS) is a non-cardiogenic form of pulmonary oedema characterised by severe hypoxaemia refractory to oxygen therapy, with diffuse pulmonary infiltrates on chest radiographs. It can be precipitated by various serious medical and surgical conditions, including systemic autoimmune diseases. The "catastrophic" variant of the antiphospholipid syndrome (APS) is an accelerated form of this systemic autoimmune condition which results in multiorgan failure because of multiple small vessel occlusions. OBJECTIVE: To analyse the clinical and laboratory characteristics of patients with catastrophic APS who develop ARDS. METHODS: Cases with ARDS were selected from the web site based international registry of patients with catastrophic APS (CAPS registry) (http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM) and their characteristics examined. RESULTS: Pulmonary involvement was reported in 150 of 220 patients with catastrophic APS (68%) and 47 patients (21%) were diagnosed as having ARDS. Nineteen (40%) of these patients died. Pathological studies were undertaken in 10 patients and thrombotic microangiopathy was present in seven. There were no differences in age, sex, precipitating factors, clinical manifestations, or mortality between catastrophic APS patients with and without ARDS. CONCLUSIONS: ARDS is the dominant pulmonary manifestation of catastrophic APS. Thus the existence of ARDS in the context of an APS makes it necessary to rule out the presence of the catastrophic variant of this syndrome.

Prevalence of the antiphospholipid syndrome in primary systemic vasculitis.

BACKGROUND: The antiphospholipid (APS or Hughes') syndrome, anticardiolipin antibodies (aCL), and the lupus anticoagulant (LA) are associated with systemic lupus erythematosus, malignancy, infection, and drugs. It has been described in patients with primary systemic vasculitis (PSV). OBJECTIVE: To determine the prevalence of APS in patients with PSV attending a vasculitis clinic and the prevalence of patients with positive aCL and/or the LA who do not fulfil the classification criteria for APS. METHODS: All case notes of patients attending the vasculitis clinic over a 12 month period were reviewed. Outpatients and inpatients were both included and were assessed for features of the APS and presence of aPL. Patients with positive aCL or LA tests were classified according to the significance of these results. RESULTS: Of 144 patients with PSV, 25 had positive aCL or LA on at least one occasion, representing a point prevalence of 17%. Of these, nine had definite APS (classified by the Sapporo criteria) and a further four patients had clinical and serological features of APS, although insufficient to satisfy the Sapporo criteria. Twelve had only positive aPL. CONCLUSION: The antiphospholipid syndrome, aCL, and the LA may occur in association with PSV.

Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome.

OBJECTIVE: To describe the characteristics of patients with catastrophic antiphospholipid syndrome (APS) included in the International Registry of patients with this condition (CAPS registry) and to analyse the value of the recently proposed preliminary criteria for the classification of catastrophic APS. METHODS: A review of the first 220 patients included in the website based CAPS registry was undertaken and the preliminary criteria for their classification were tested; 175 unselected patients with systemic lupus erythematosus or APS, or both, acted as controls. RESULTS: The mean age of the patients was 38 (14) years (range 7 to 74), with a female preponderance (F/M, 153/67). The main clinical manifestations included renal involvement in 154 (70%), pulmonary in 146 (66%), cerebral in 133 (60%), cardiac in 115 (52%), and cutaneous in 104 (47%); 114 patients (52%) recovered after the catastrophic APS event (mortality 48%). Patients who received the combination of anticoagulation plus steroids plus plasma exchange or intravenous immunoglobulins had the best survival rate (63%, p = 0.09). Sufficient data could be analysed for application of the classification criteria in 176 patients. According to the preliminary criteria, 89 patients (51%) could be classified as having "definite" and 70 (40%) as having "probable" catastrophic APS, thus given a sensitivity of 90.3% with a specificity of 99.4%. Positive and negative predictive values were 99.4% and 91.1%, respectively. CONCLUSIONS: The preliminary criteria for the classification of catastrophic APS and the CAPS registry are useful tools for epidemiological studies.

Dementia associated with the antiphospholipid syndrome: clinical and radiological characteristics of 30 patients.

OBJECTIVE: To analyse the clinical and radiological characteristics of patients with dementia associated with the antiphospholipid syndrome (APS). METHODS: Twenty-five patients were identified by a computer-assisted (MEDLINE, National Library of Medicine, Bethesda, MD) search of the literature to locate all cases of dementia associated with APS published in English, Spanish and French from 1983 to 2003. Additionally, we included five patients from our clinics. RESULTS: There were 21 (70%) females and 9 (30%) males. The mean age of patients was 49+/-15 yr (range 16-79 yr). Fourteen (47%) of the patients suffered from primary APS, 9 (30%) had systemic lupus erythematosus and 7 (23%) had 'lupus-like' syndrome. Ten (33%) patients had Sneddon's syndrome and 2 (7%) had cerebral lesions described as Binswanger's disease. Other APS-related manifestations included thrombocytopenia in 12 (40%) patients, cerebrovascular accidents in 11 (37%), heart valve lesions in 8 (27%), deep vein thrombosis in 7 (28%), migraine in 7 (23%), seizures in 4 (13%); five of the 21 (24%) female patients had nine spontaneous abortions. Lupus anticoagulant was present in 21/29 (72%) patients and anticardiolipin antibodies were present in 24/29 (83%) patients. Cortical infarcts were found in 19 (63%) patients, subcortical infarcts in 9 (30%), basal ganglia infarcts in 7 (23%) and signs of cerebral atrophy in 11 (37%). Anticoagulation was used in 14/25 (56%) patients, steroids in 12/25 (48%), aspirin in 6/25 (24%) and dypiridamole in 5/25 (20%). CONCLUSIONS: Dementia is an unusual manifestation of APS but one which has a high disability impact in a patient's daily life. In order to prevent these consequences, an echocardiographic and cerebral CT or MRI evaluation are recommended in all patients with APS. Furthermore, ruling out APS should be recommended in the clinical approach to dementia, especially in young patients.

Disseminated intravascular coagulation in catastrophic antiphospholipid syndrome: clinical and haematological characteristics of 23 patients.

BACKGROUND: Disseminated intravascular coagulation (DIC) is an acquired syndrome characterised by formation of microthrombi and fibrin deposition in the microvasculature. The catastrophic antiphospholipid syndrome (APS) is characterised by multiorgan thrombosis, mainly involving small vessels. A broad spectrum of disorders may develop DIC features; however, the catastrophic APS has not previously been recognised as a cause of DIC. OBJECTIVE: To analyse the clinical and laboratory characteristics of catastrophic APS patients with DIC features. METHODS: The web site based international registry of patients with catastrophic APS (CAPS registry) (http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM) was analysed and the cases with DIC features selected. RESULTS: In 173 patients with catastrophic APS, 23 (13%) were found with DIC features. The clinical and immunological characteristics were similar in catastrophic APS patients with and without DIC features; a significant difference was found only in the prevalence of thrombocytopenia (100% in patients with DIC features v 59% in those without DIC features). CONCLUSIONS: DIC features are not rare in catastrophic APS, supporting the need for systematic screening of antiphospholipid antibodies in all patients with DIC features without precipitating factors. The presence of DIC features in the context of an APS makes it imperative to rule out the catastrophic variant of this syndrome.

Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics of 100 patients.

OBJECTIVE: To describe and analyse the clinical characteristics of 100 patients with antiphospholipid syndrome (APS) associated with infections. METHODS: Patients were identified by a computer assisted search (Medline) of published reports to locate all cases of APS published in English, Spanish, and French from 1983 to 2003. The bilateral Fisher exact test was used for statistics. RESULTS: 59 female and 41 male patients were identified (mean (SD) age, 32 (18) years (range 1 to 78)): 68 had primary APS, 27 had systemic lupus erythematosus, two had "lupus-like" syndrome, two had inflammatory bowel disease, and one had rheumatoid arthritis. APS presented as a catastrophic syndrome in 40% of cases. The main clinical manifestations of APS included: pulmonary involvement (39%), skin involvement (36%), and renal involvement (35%; nine with renal thrombotic microangiopathy, RTMA). The main associated infections and agents included skin infection (18%), HIV (17%), pneumonia (14%), hepatitis C (13%), and urinary tract infection (10%). Anticoagulation was used in 74%, steroids in 53%, intravenous immunoglobulins in 20%, cyclophosphamide in 12%, plasma exchange in 12%, and dialysis in 9.6%. Twenty three patients died following infections and thrombotic episodes (16 with catastrophic APS). Patients given steroids had a better prognosis (p = 0.024). The presence of RTMA and requirement for dialysis carried a worse prognosis (p = 0.001 and p = 0.035, respectively). CONCLUSIONS: Various different infections can be associated with thrombotic events in patients with APS, including the potentially lethal subset termed catastrophic APS. Aggressive treatment with anticoagulation, steroids, and appropriate antibiotic cover is necessary to improve the prognosis.