Hipercalcemia en pacientes con artritis reumatoide: un estudio retrospectivo / Hypercalcemia in patients with rheumatoid arthritis: a retrospective study

Objetive: To investigate the prevalence of hypercalcemia in patients with rheumatoid arthritis (RA) and analyze the clinical features and causes of hypercalcemia. Material and methods: Retrospective case-based review study that included 500 patients with RA. Patients with increased calcium levels on at least two occasions were identified. Results: Hypercalcemia was present in 24 of the 500 RA patients (4.8%). The age ranged between 50 and 80 years, with a mean of 68±10 years. The mean duration of the disease was 10±7 years. Of the patients with hypercalcemia, 22 were postmenopausal women (92%) and only two were men (8%). Hyperparathyroidism was found in 9 patients in the series; only one patient had malignant hypercalcemia due to multiple myeloma, and one case was a consequence of vitamin D intoxication. In one patient, hypercalcemia appeared to be related to calcium-alkali syndrome. In the remaining patients, hypercalcemia was idiopathic (8/24) or the study was incomplete (4/24). No obvious relationship was found between disease activity and the appearance of hypercalcemia. Conclusion: As in the general population, primary hyperparathyroidism is the most common cause of hypercalcemia in patients with RA. In some patients, no other disorders causing hypercalcemia were identified, raising the possibility of a causal relationship between RA and hypercalcemia. (AU)

Objetivo: Investigar la prevalencia de hipercalcemia en pacientes con artritis reumatoide (AR) y analizar las características clínicas y las causas de la hipercalcemia. Material y métodos: Estudio retrospectivo de revisión basado en casos que incluyó 500 pacientes con AR. Se identificaron los pacientes con niveles de calcio aumentados en al menos dos ocasiones. Resultados: La hipercalcemia estuvo presente en 24 de los 500 pacientes con AR (4,8%). La edad osciló entre 50 y 80 años, con una media de 68±10 años. La duración media de la enfermedad fue de 10±7 años. De los pacientes con hipercalcemia, 22 eran mujeres postmenopáusicas (92%) y solo dos eran hombres (8%). El hiperparatiroidismo se encontró en 9 pacientes de la serie; solo un paciente tenía una hipercalcemia maligna debido a un mieloma múltiple, y un caso fue consecuencia de una intoxicación por vitamina D. En un paciente la hipercalcemia parecía relacionada con el síndrome calcio-alcalino. En el resto de pacientes, la hipercalcemia fue idiopática (8/24) o el estudio fue incompleto (4/24). No se encontró una relación evidente entre la actividad de la enfermedad y la aparición de hipercalcemia. Conclusión: Al igual que sucede en la población general, el hiperparatiroidismo primario es la causa más común de hipercalcemia en pacientes con AR. En algunos pacientes no se identificaron otros trastornos causantes de hipercalcemia, lo que plantea la posibilidad de una relación causal entre la AR y la hipercalcemia. (AU)

Differences in clinical manifestations and increased severity of systemic lupus erythematosus between two groups of Hispanics: European Caucasians versus Latin American mestizos (data from the RELESSER registry).

BACKGROUND: Systemic lupus erythematosus (SLE) is regarded as a prototype autoimmune disease because it can serve as a means for studying differences between ethnic minorities and sex. Traditionally, all Hispanics have been bracketed within the same ethnic group, but there are differences between Hispanics from Spain and those from Latin America, not to mention other Spanish-speaking populations. OBJECTIVES: This study aimed to determine the demographic and clinical characteristics, severity, activity, damage, mortality and co-morbidity of SLE in Hispanics belonging to the two ethnic groups resident in Spain, and to identify any differences. METHODS: This was an observational, multi-centre, retrospective study. The demographic and clinical variables of patients with SLE from 45 rheumatology units were collected. The study was conducted in accordance with Good Clinical Practice guidelines. Hispanic patients from the registry were divided into two groups: Spaniards or European Caucasians (EC) and Latin American mestizos (LAM). Comparative univariate and multivariate statistical analyses were carried out. RESULTS: A total of 3490 SLE patients were included, 90% of whom were female; 3305 (92%) EC and 185 (5%) LAM. LAM patients experienced their first lupus symptoms four years earlier than EC patients and were diagnosed and included in the registry younger, and their SLE was of a shorter duration. The time in months from the first SLE symptoms to diagnosis was longer in EC patients, as were the follow-up periods. LAM patients exhibited higher prevalence rates of myositis, haemolytic anaemia and nephritis, but there were no differences in histological type or serositis. Anti-Sm, anti-Ro and anti-RNP antibodies were more frequently found in LAM patients. LAM patients also had higher levels of disease activity, severity and hospital admissions. However, there were no differences in damage index, mortality or co-morbidity index. In the multivariate analysis, after adjusting for confounders, in several models the odds ratio (95% confidence interval) for a Katz severity index >3 in LAM patients was 1.45 (1.038-2.026; p = 0.02). This difference did not extend to activity levels (i.e. SLEDAI >3; 0.98 (0.30-1.66)). CONCLUSION: SLE in Hispanic EC patients showed clinical differences compared to Hispanic LAM patients. The latter more frequently suffered nephritis and higher severity indices. This study shows that where lupus is concerned, not all Hispanics are equal.

2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative

Therapy for polymyalgia rheumatica (PMR) varies widely in clinical practice as international recommendations for PMR treatment are not currently available. In this paper, we report the 2015 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations for the management of PMR. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology as a framework for the project. Accordingly, the direction and strength of the recommendations are based on the quality of evidence, the balance between desirable and undesirable effects, patients' and clinicians' values and preferences, and resource use. Eight overarching principles and nine specific recommendations were developed covering several aspects of PMR, including basic and follow-up investigations of patients under treatment, risk factor assessment, medical access for patients and specialist referral, treatment strategies such as initial glucocorticoid (GC) doses and subsequent tapering regimens, use of intramuscular GCs and disease modifying anti-rheumatic drugs (DMARDs), as well as the roles of non-steroidal anti-rheumatic drugs and non-pharmacological interventions. These recommendations will inform primary, secondary and tertiary care physicians about an international consensus on the management of PMR. These recommendations should serve to inform clinicians about best practices in the care of patients with PMR.(AU)

Influence of the IL17A locus in giant cell arteritis susceptibility.

OBJECTIVE: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. METHODS: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. RESULTS: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E-03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10(-05)). CONCLUSIONS: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology.

Henoch-Schönlein purpura nephritis and IgA nephropathy: a comparative clinical study.

OBJECTIVES: Henoch-Schönlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) are related syndromes. In the present study we aimed to compare the clinical characteristics and outcome of a large and unselected series of patients diagnosed as having HSPN and IgAN. METHODS: Comparative study of a wide and unselected population of HSPN (142 patient) and IgAN (61 patients) from a teaching hospital of Northern Spain. RESULTS: All of the following comparisons were expressed between HSPN vs. IgAN, respectively. HSPN patients were younger (30.6±26.4 vs. 37.1±16.5 years, p<0.001). Precipitating events, usually an upper respiratory tract infection and/or drug intake, were more frequently observed in HSPN (38% vs. 23%, p=0.03). Extra-renal manifestations were also more common in HSPN than in IgAN; skin lesions (100% vs. 1.8%; p<0.001), gastrointestinal (62% vs. 7.4%; p<0.001), and joint involvement (61.3% vs. 3.6%; p<0.001). However, nephritis was less severe in HSPN, renal insufficiency (25% in HSPN vs. 63.4% in IgAN; p<0.001), nephrotic syndrome (12.5%, vs. 43.7%; p<0.001), and nephritic syndrome (6.8% vs. 10.7%; NS). Leukocytosis was more frequent in HSPN (22.5% vs. 8.2%; p=0.015) and anaemia in IgAN (12.7% in HSPN vs. 36% in IgAN, p<0.001). The frequency of corticosteroid (79.6% vs. 69%; NS) and cytotoxic drug (19% vs. 16.5%, NS) use was similar. The frequency of relapses was similar (38.6% in HSPN vs. 36.3% in IgAN). After a median follow-up of 120.8 (IQR; 110-132) months in HSPN and 138.6 (IQR; 117-156) in IgAN, requirement for dialysis (2.9% vs. 43.5%; p<0.001), renal transplant (0% vs. 36%, p<0.001) and residual chronic renal insufficiency (4.9% vs. 63.8%; p<0.001) was more frequently observed in patients with in IgAN. CONCLUSIONS: HSPN and IgAN represent different syndromes. IgAN has more severe renal involvement while HSPN is associated with more extra-renal manifestations.

Schnitzler's syndrome: diagnosis, treatment, and follow-up.

Schnitzler's syndrome is characterized by recurrent urticarial rash and monoclonal gammopathy, associated with clinical and biological signs of inflammation and a long-term risk of AA amyloidosis and overt lymphoproliferation. An extensive literature review was performed, and the following questions were addressed during an expert meeting: In whom should Schnitzler's syndrome be suspected? How should the diagnosis of Schnitzler's syndrome be established? How should a patient with Schnitzler's syndrome be treated? How should a patient with Schnitzler's syndrome be followed up?. A diagnosis of Schnitzler's syndrome is considered definite in any patient with two obligate criteria: a recurrent urticarial rash and a monoclonal IgM gammopathy, and two of the following minor criteria: recurrent fever, objective signs of abnormal bone remodeling, elevated CRP level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. It is considered probable, if only 1 minor criterion is present. In patients with monoclonal IgG gammopathies, diagnosis is definite if three minor criteria are present and possible if two are present. First-line treatment in patients with significant alteration of quality of life or persistent elevation of markers of inflammation should be anakinra. Follow-up should include clinical evaluation, CBC and CRP every 3 months and MGUS as usually recommended.

Multicenter longitudinal study of B-lymphocyte depletion in refractory systemic lupus erythematosus: the LESIMAB study.

OBJECTIVE: This study aimed to investigate the effectiveness and safety of single and repeated courses of rituximab in patients with refractory lupus. METHODS: LESIMAB is a multicenter, retrospective, longitudinal study of lupus patients who have not responded to standard therapy and have been treated with rituximab. Response rates at six months and at follow-up were defined as efficacy outcomes. Complete response was defined as a SELENA-SLEDAI score ≤ two and a SELENA-SLEDAI Flare Index of zero. Partial response was defined as a reduction in the SELENA-SLEDAI score of ≥four points with no new or worsening of symptoms. Adverse events were collected. RESULTS: Seventy-three (62.9%) of 116 patients achieved a response at six months (complete in 22 and partial in 51). Ninety-seven (77.6%) of 128 patients achieved a response after a mean follow-up of 20.0 ± 15.2 months (complete in 50 and partial in 47). High baseline SLEDAI score, previous treatment with ≥100 mg/day prednisone, and no history of severe hematologic flare were associated with response after the first treatment course. The median time to response was 6.5 months (95% CI, 5.0-8.0). Thirty-seven patients (38.1%) relapsed after the first infusion. The flare was severe in seven cases and mild to moderate in 29 cases. Serious infection rate was 12.6/100 patient-years. A schedule of four weekly doses was associated with more serious infections. Six patients died: two of infection and four of lupus complications. CONCLUSION: Rituximab can be an effective treatment option for patients who have refractory lupus with severe or life-threatening disease with an acceptable tolerance profile.

Circulating cytokines in active polymyalgia rheumatica.

OBJECTIVE: To characterise the circulating cytokine profile and the cellular source of circulating cytokines in polymyalgia rheumatica (PMR). METHODS: The study included 34 patients with active untreated PMR and 17 age-matched healthy controls (HC). Circulating cytokines were measured by cytometric bead array and ELISA. Intracellular cytokines were assessed in CD3+ and CD14+ cells by flow cytometry. Cytokines in cell culture supernatants were also determined after polyclonal stimulation of patients' peripheral blood mononuclear cells. RESULTS: Circulating levels of interleukin-6 (IL6) were significantly higher in subjects with active PMR than in HC. Corticosteroid (CS) treatment was followed by a decrease in the level of IL6. Intracellular cytokine staining showed that circulating monocytes did not produce higher amounts of proinflammatory cytokines in patients with PMR than in HC. There was a discordance between serum levels and cytokine-producing monocyte and T cells, and it was not possible to demonstrate a Th1 bias in the peripheral compartment. CONCLUSIONS: Active PMR is characterised by increased serum levels of IL6, but not of other proinflammatory cytokines, that are rapidly suppressed by CS treatment. As circulating monocytes do not show increased production of proinflammatory cytokines, IL6 may be mainly produced in the inflamed tissue. A study of the circulating cytokine profile and its cellular source may provide a clue to new therapeutic options.

Interleukin-12 gene polymorphisim in patients with giant cell arteritis, polymyalgia rheumatica and elderly-onset rheumatoid arthritis.

OBJECTIVE: The cytokine profile suggests that giant cell arteritis (GCA) is a Th1-driven disease, in which local IFN-gamma plays a critical role in the development of a systemic arteritis. IL-12 is a potent inducer of IFN-gamma and is critically involved in biasing an immune response towards a Th1 pathway. The purpose of this study was to investigate whether there was an association between an IL-12 gene polymorphism (-1188 A/C 3UTR) and disease susceptibility for GCA and two other age-related inflammatory conditions, such as polymyalgia rheumatica (PMR) and elderly-onset rheumatoid arthritis (EORA). Furthermore, we attempted to correlate such polymorphism with in vitro IL-12 production. MATERIALS AND METHODS: We analyzed genotypes at -1188 in the 3UTR of the IL-12 promoter by PCR-RFLP in 68 GCA, 138 PMR, and 72 EORA patients as well as in 465 healthy controls (HC). IL-12p70 levels in culture supernatants after stimulation with PMA+Ionomycin was assessed by ELISA. RESULTS: All groups were in Hardy-Weinberg equilibrium. Allelic and gen-omic distribution was not significantly different among the study groups. None of the genetic variants was associated with disease severity. Although the differences were not statistically significant, HC genotypes were associated with distinct IL-12 p70 production. CONCLUSIONS: The IL-12 (-1188 A/C 3UTR) gene polymorphism is not associated with disease susceptibility or severity in three age-related chronic inflammatory syndromes. The production of IL-12 p70 is dependent on the genetic background in HC, although in patients such association may be biased by other unknown factors.

A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects.

OBJECTIVE: Open label studies have suggested that tumour necrosis factor (TNF) antagonists led to sustained improvement and corticosteroid sparing effect in patients with giant cell arteritis (GCA). To confirm these observations, we conducted a randomised, double-blind, placebo controlled trial with etanercept in patients with biopsy-proven GCA with side effects secondary to corticosteroids. METHODS: We randomly assigned patients with GCA to receive etanercept (n = 8) or placebo (n = 9) over 1 year together with corticosteroids that were reduced according to a predefined schedule. The primary outcome was the ability to withdraw the corticosteroid therapy and control the disease activity at 12 months. RESULTS: Baseline characteristics were similar in the two groups, although patients in the etanercept group showed higher levels of basal glycaemia (p = 0.02) and a higher erythrocyte sedimentation rate (ESR) (p = 0.01). After 12 months, 50% of the patients in the etanercept group and 22.2% in the placebo group were able to control the disease without corticosteroid therapy (p value not significant). Patients in the etanercept group had a significant lower dose of accumulated prednisone during the first year of treatment (p = 0.03). There were no differences in the number and type of adverse events. CONCLUSION: The limited number of patients included in this study does not allow us to draw definitive conclusions. Etanercept therapy was well tolerated in this aged population. The therapeutic role of etanercept in patients with GCA should be evaluated in studies with a larger number of patients.

Innate immune response gene expression profiles characterize primary antiphospholipid syndrome.

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disorder characterized by thromboembolic episodes and pregnant morbidity with an increasing clinical importance. To gain insight into the pathogenesis of PAPS, we have investigated the gene expression profiles that characterize peripheral blood mononuclear cells derived from PAPS patients. We show that the transcriptional activity of genes involved in innate immune responses, such as toll-like receptor 8 and CD14, as well as downstream genes of this pathway, such as STAT1, OAS2, TNFSF13 and PLSCR1 are significantly increased in PAPS patients. In addition, the expression of monocyte-specific cytokines is also elevated in PAPS mononuclear cells stimulated in vitro with lipopolysaccharide. Taken together, these results reveal a 'response to pathogen' signature in PAPS, which could reflect an altered monocyte activity. Finally, microarray analyses also revealed a reduced expression of genes coding for proteins involved in transcriptional control. Interestingly, a significant proportion of them exhibit E2F-binding sites in their promoter, suggesting that a deregulated RB/E2F activity could play a role in the pathogenesis of antiphospholipid syndrome.

Serum levels of antibodies to Chlamydia pneumoniae and human HSP60 in giant cell arteritis patients.

OBJECTIVE: To measure the serum levels of IgG anti-Chlamydia pneumoniae (C. pneumoniae) and human heat shock protein (hHSP) 60 antibodies in patients with active giant cell arteritis (GCA) and to determine whether such levels decrease with corticosteroid therapy and remission of symptoms. METHODS: IgG anti-C. pneumoniae and anti-hHSP60 antibodies were quantified by commercial and in-house ELISA tests, respectively, in serum samples from 17 GCA patients, 39 polymyalgia rheumatica (PMR) patients and 23 age-matched healthy subjects. RESULTS: Serum IgG anti-hHSP60, but not anti-C. pneumoniae, antibodies were significantly increased in GCA patients in comparison with PMR patients or healthy controls. After steroid therapy, both anti-hHSP60 and -C. pneumoniae antibodies decreased significantly in both groups of patients. CONCLUSIONS: Although some infectious agents have been suggested to participate in GCA pathogenesis, our data do not suggest that C. pneumoniae might be one of them. The production of anti-hHSP60 antibodies is shared in GCA with other systemic diseases and may be triggered by unknown infectious agents and/or other inflammatory factors.

Recall injection-site reactions associated with etanercept therapy: report of two new cases with immunohistochemical analysis.

Injection site reactions (ISRs) are the most common adverse effect reported with etanercept therapy. It has been observed that some patients treated with etanercept develop ''recall ISRs'', that are reactions at sites where etanercept was previously injected after the last injection. Etanercept-associated recall ISRs have been scarcely published. We report two patients with rheumatoid arthritis who developed recall ISRs during etanercept therapy. Biopsy specimens from ISRs demonstrated a superficial perivascular lymphocytic infiltrated with a few eosinophils. Immunohistochemical study in both cases revealed that T cells bearing a CD4+ phenotype mostly composed the inflammatory infiltrate. Our observations suggest that ISRs may be mediated by classic cellular-hypersensitivity reactions directed by CD4+ T lymphocytes.

Plasma adrenomedullin levels in patients with polymyalgia rheumatica and giant cell arteritis.

OBJECTIVE: Plasma adrenomedullin (AM) levels are elevated in several inflammatory rheumatic diseases. The aims of the present study were: a) to assess whether plasma AM levels are abnormal in patients with polymyalgia rheumatica and giant cell arteritis (PMR and GCA) and b) to investigate if this parameter is related to clinical and biochemical indicators of disease activity in these patients. MATERIALS AND METHODS: AM plasma levels were analyzed in 17 patients with PMR and GCA and in 14 healthy subjects. Twelve patients (9 PMR and 3 GCA) were studied when they had active disease before any steroid therapy and the remaining 5 patients (2 PMR and 3 GCA) were in complete clinical remission and no longer receiving steroid treatment. AM was measured by a specific radioimmunoassay. RESULTS: Plasma AM concentration was significantly higher in patients with active GCA compared to the control group (p < 0.05) and with patients with isolated PMR (p < 0.05). However, there were no significant differences between patients with active PMR and the control group. Within the PMR/GCA group with active disease, AM plasma levels were positively correlated with ESR (r = 0.6, p = 0.02), and negatively with hematocrit (r = -0.57, p = 0.03) and hemoglobin (r = -0.55, p = 0.04). No correlations were found between AM and CRP. CONCLUSION: Plasma levels of AM are elevated in patients with active GCA and correlate with parameters that reflect the acute phase response. The differences in the secretion of AM between patients with PMR and GCA might reflect the severity of the vascular endothelial cell damage in these conditions. The role of AM in the pathogenesis of PMR and GCA needs to be assessed in a larger series of patients.

Clinical disease activity and titers of anti-dsDNA antibodies measured by an automated immunofluorescence assay in patients with systemic lupus erythematosus.

Autoantibodies specific for double stranded DNA (anti-dsDNA Abs) are a serological biomarker of systemic lupus erythematosus (SLE) and constitute useful tools for monitoring many SLE patients. A new automated immunofluorescence and quantitative assay (EliA dsDNA) has recently become available. Its performance has been demonstrated to be equivalent to the Farr and Crithidia luciliae fluorescence (CLIFT) tests. The aim of the present work was to assess the utility of this new assay to monitor clinical activity in a large cohort of SLE patients. To this end, 1020 sera from 181 SLE patients were evaluated by the two methods. Results showed a higher frequency of positive results of anti-dsDNA Abs during lupus flares measured by EliA dsDNA than by CLIFT. Likewise, titers of those Abs were significantly increased in active SLE in comparison with inactive SLE when measured by EliA dsDNA but not by CLIFT. Serum titers of anti-dsDNA Abs by both assays showed a significant negative association with concentrations of C3 and C4. In summary, this retrospective study on a large cohort of patients demonstrated that EliA dsDNA was at least as useful as CLIFT as monitoring tool in the follow-up of SLE patients, but with the advantages of being automated, quick and quantitative.

Lack of effect of rapamycin in anti-CCP antibody production in a rheumatoid arthritis kidney allograft recipient.

Autoimmune diseases may lead to end-stage renal disease and, as a consequence, kidney transplantation. Classical immunosuppressive drugs, such as cyclosporine or corticosteroids, are well-established therapies for both transplantation and autoimmune diseases. Rapamycin is a new immunosuppressant useful for allograft transplantation and with a promising future for autoimmune diseases, although it has not been extensively studied in humans. Here the case of a patient diagnosed with rheumatoid arthritis (RA) who received a renal allograft is reported. She was started on prednisolone, azathioprine and cyclosporine immunosuppression and changed to rapamycin instead of cyclosporine 4 years after transplantation, because of chronic allograft nephropathy. At present, the patient has a functioning graft. However, the arthritis symptoms reappeared after the change in immunosuppressant. Titers of RA-specific anti-cyclic citrullinated peptides antibodies increased whereas rheumatoid factor titers decreased. This case report suggests that rapamycin used for kidney transplantation might have a different influence on the spectrum of RA autoantibodies.