Immunoglobulins in systemic sclerosis management. A large multicenter experience.

OBJECTIVE: To analyze the effectiveness and safety of intravenous immunoglobulin (IVIG) given in routine care to patients with systemic sclerosis (SSc). METHODS: A retrospective multicenter observational study was conducted in SSc patients treated with IVIG. We collected data on epidemiological parameters and clinical outcomes. Firstly, we assessed changes in organ manifestations during IVIG treatment. Secondly, we analyzed the frequency of adverse effects. The following parameters were collected from baseline to the last follow-up: the patient's weight, modified Rodnan Skin Score (mRSS), modified manual muscle strength scale (MRC), laboratory test(creatine kinase(CK), hemoglobin and protein levels), The University of California Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 (UCLA GIT 2.0) questionnaire, pulmonary function tests, and echocardiography. RESULTS: Data were collected on 78 patients (82% females; 59% with diffuse SSc). Inflammatory idiopathic myopathy was the most frequent concomitant overlap disease (41%). The time since Raynaud's phenomenon and SSc onset were 8.8 ± 18 and 6.2 ± 6.7 years respectively. The most frequent IVIG indication was myositis (38/78), followed by gastrointestinal (27/78) and cutaneous (17/78) involvement. The median number of cycles given were 5. 54, 53 and 9 patients have been treated previously with glucocorticoids, synthetic disease-modifying antirheumatic drugs and biologic therapies respectively. After IVIG use we found significant improvements in muscular involvement (MRC ≥ 3/5 92% IVIG, p = 0.001 and CK levels from 1149 ± 2026 UI to 217 ± 224 UI, p = 0.02), mRSS (15 ± 12.4 to 13 ± 12.5, p = 0.015) and improvement in total score of UCLA GIT 2.0 (p = 0.05). None Anti-RNA polymerase III patients showed an adequate response in gastrointestinal involvement (0/7) in comparison with other antibodies (0 vs. 25, p = 0,039). Cardiorespiratory involvement remained stable. A total of 12 adverse events were reported with only one withdrawn due to serious adverse effect. CONCLUSIONS: this study suggest that IVIG may improve myositis, gastrointestinal and skin involvement in SSc patients treated in routine care and seems to have a good safety profile.

Safe and successful treatment of refractory polyarteritis nodosa with tocilizumab in a patient with past hepatitis B virus infection: a case-based review.

Polyarteritis nodosa is a primary systemic necrotizing vasculitis whose evolution follows, in many cases, a chronic remitting-recurrent course with refractoriness to conventional immunosuppressants. We report here the clinical case of a 75-year-old patient with serologies suggestive of past hepatitis B virus infection who presented a flare of polyarteritis nodosa with great secondary functional impairment. She had not responded to several previous immunosuppressants and required high doses of glucocorticoids to control the flare. After the initiation of biological therapy with tocilizumab, the patient experienced a rapid and marked clinical and analytical improvement, going into clinical remission and being able to remarkably lower the corticosteroid dose and stop the rest of the immunosuppressants. There was no evidence of hepatitis B virus reactivation or changes in the titers of any of the parameters related to the aforementioned infection. This clinical case represents the first case reported in the literature about the successful and safe treatment of polyarteritis nodosa with tocilizumab in a patient with serologies suggestive of past hepatitis B virus infection.

No evidence of association between functional polymorphisms located within IL6R and IL6ST genes and systemic sclerosis.

Systemic sclerosis (SSc) is a complex autoimmune disease which genetic component has not been yet completely understood. IL6 encodes a cytokine with a crucial role in the development of autoimmunity and fibrosis and its actions mainly are controlled by IL-6 receptor (IL-6R). We aimed to investigate whether the functional genetic variants rs8192284 and rs2228044 previously associated with several autoimmune diseases, located within the IL-6 receptor (IL-6R) subunits IL6R and IL6ST genes, respectively, are involved in the susceptibility to SSc and/or its major clinical subphenotypes. A Spanish cohort including 1013 SSc patients and 1375 controls was genotyped using the TaqMan® allelic discrimination technology. SSc patients were subdivided according to the major clinical forms, autoantibody status and presence of fibrotic lung affection. Our data showed no influence of the selected variants in global SSc susceptibility (rs8192284: P=0.67, odds ratios (OR)=0.98; rs2228044: P=0.99, OR=1.00). Similarly, the clinical/autoantibody subphenotype analyses did not yielded significant results. Our data suggest that the analyzed polymorphisms may not play a significant role in the SSc susceptibility.

Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis.

OBJECTIVE: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes. METHODS: 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc. RESULTS: The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1). CONCLUSION: The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.

The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype.

The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.

The interleukin 23 receptor gene does not confer risk to systemic sclerosis and is not associated with systemic sclerosis disease phenotype.

OBJECTIVES: Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype. METHODS: An initial case-control study in 143 Dutch patients with SSc and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish patients with SSc and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay. RESULTS: Using a Dutch cohort of patients with SSc and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: p = 0.02 and p = 0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R-tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes. CONCLUSIONS: Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.

A large multicentre analysis of CTGF -945 promoter polymorphism does not confirm association with systemic sclerosis susceptibility or phenotype.

OBJECTIVE: To conduct a replication study to investigate whether the -945 CTGF genetic variant is associated with systemic sclerosis (SSc) susceptibility or specific SSc phenotype. METHODS: The study population comprised 1180 patients with SSc and 1784 healthy controls from seven independent case-control sets of European ancestry (Spanish, French, Dutch, German, British, Swedish and North American). The -945 CTGF genetic variant was genotyped using a Taqman 5' allelic discrimination assay. RESULTS: An independent association study showed in all the case-control cohorts no association of the CTGF -945 polymorphism with SSc susceptibility. These findings were confirmed by a meta-analysis giving a pooled OR = 1.12 (95% CI 0.99 to 1.25), p = 0.06. Investigation of the possible contribution of the -945 CTGF genetic variant to SSc phenotype showed that stratification according to SSc subtypes (limited or diffuse), selective autoantibodies (anti-topoisomerase I or anticentromere) or pulmonary involvement reached no statistically significant skewing. CONCLUSION: The results do not confirm previous findings and suggest that the CTGF -945 promoter polymorphism does not play a major role in SSc susceptibility or clinical phenotype.

Assessment of nailfold capillaroscopy by x 30 digital epiluminescence (dermoscopy) in patients with Raynaud phenomenon.

BACKGROUND: Dermoscopy is a useful tool for dermatologists to study melanocytic lesions. Its possible usefulness in the assessment of capillary nailfold morphological changes (capillaroscopy) has recently been advocated. OBJECTIVES: To assess the practical utility of digital epiluminescence microscopy as a capillaroscopic instrument in patients with Raynaud phenomenon (RP). To compare the sensitivity and specificity rates obtained by epiluminescence microscopy with those previously reported with conventional capillaroscopic devices. METHODS: Fifty-six consecutive patients with primary RP (PRP; n = 5) or secondary RP (SRP; n = 51) (11 men and 45 women in total) were included in the study. A control group of 10 healthy subjects was also evaluated. Twenty-six patients (46%) had systemic sclerosis (SS), 12 (21%) presystemic sclerosis (pre-SS), one (2%) dermatopolymyositis-SS, one (2%) mixed connective tissue disease, two (4%) Sjögren syndrome, two (4%) an overlap syndrome, one (2%) rheumatoid arthritis and six (11%) other connective tissue diseases. Capillary nailfold changes were studied using a nonportable digital epiluminescence device (magnification x 30). Following a systematized protocol, capillary nailfold morphology, density and distribution were evaluated. Several capillaroscopic patterns were identified (normal, sclerodermic, nonspecific, nondiagnostic) as previously defined. A possible relationship between capillary nailfold changes and the intensity of RP or the presence of associated autoimmune diseases was assessed. RESULTS: The sclerodermic pattern showed a sensitivity of 76.9% and a specificity of 90.9% in SS. A typical capillaroscopic SS pattern was observed in 73% of cases of limited SS and in 82% of cases of diffuse SS. Patients with Sjögren syndrome and dermatopolymyositis-SS showed a nonspecific capillaroscopic pattern. All patients with PRP presented a normal capillaroscopic pattern. A normal capillaroscopic pattern was also observed in 11 of 12 patients with pre-SS. In one of two patients presenting severe sclerodactyly and in all patients showing hand oedema (three of 56), capillaroscopic changes could not be evaluated. Avascular areas correlated significantly with severe RP (P < 0.002), bone resorption (P < 0.007) and diffuse SS (P < 0.008). CONCLUSIONS: Digital epiluminescence seems to be a useful and reliable technique in the evaluation of capillary nailfold morphological changes. This technical variation allows the identification of specific capillaroscopic patterns associated with connective tissue diseases. It also permits us to differentiate PRP from SRP. The results obtained with this technique are similar to those previously reported using standard capillaroscopy devices.

Calcificaciones subcutáneas y periostitis en extremidades inferiores en imágenes / Subcutaneus calcifications and periostitis in the lower extremities radiology

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Calcium as a treatment of osteoporosis.

The role of calcium in bone metabolism, optimal calcium intake, the use of calcium as monotherapy for osteoporosis or in combination with other drugs and the differences between various calcium salts are reviewed. Calcium is an essential element in bone mineralization and formation. There are sufficient data supporting the use of calcium in the prevention and treatment of osteoporosis and calcium in combination with vitamin D is widely used in the prevention and treatment of osteoporosis mainly in elderly patients, although its indication in postmenopausal osteoporosis is not yet clear. Numerous calcium preparations are available on the market and differ only in regard to their bioavailability. However, this difference has very little clinical significance except in patients with achlorhydria or elderly persons with low gastric secretion, in which cases pidolate and calcium citrate can be used since they are more efficiently absorbed.

[Analysis of experience in an integrated program of hospital rheumatological service and primary care]. / Análisis de la experiencia de un programa integrado de asistencia hospitalaria reumatológica en Atención Primaria.

BACKGROUND: In order to improve the health quality at the Primary care level, the Catalonian Health Authority (Servei Catala de la Salut) has begun a reform of the medical and surgical specialties. In this reform process the Hospital del Mar, Barcelona, Spain, has taken part in the incorporation of several medical and surgical hospital specialists to primary care within its influence area. In this study, we describe the results of the collaboration between Hospital health care and Primary care on rheumatic complaints during one year. METHODS: We carried out a descriptive study of some clinical and epidemiological variables of the population visited during one year (1995), at the Primary care level by the Rheumatologist. Our area has a population of 90,612 people, and its located in Barcelona City, Ciutat Vella Variables of study were collected during the period of time between January and December 1995. The following variables were recorded: age, gender, referral cause, rheumatologic diagnosis, intra-articular and peri-articular corticosteroid injections perform, techniques used for the diagnosis of rheumatic disease, follow-up level Data were statistically analyzed. RESULTS: Visits performed were 2,668 on 1,384 patients. Fifty-two percent were first visits, 48% were follow-up visits (Ratio first visits Nolfow-up visits: 0.57). Fifty-one percent of the patients were > 65 years old. Unspecific polyarthralgias, chronic low back pain, gonalgia and pathology of the shoulder were the most frequent complaints (> 50%). Osteoarthritis and soft-tissue diseases were the most frequent diagnosis with a percentage of 41% and 30.7%, respectively. Connective tissue diseases and spondyloarthropathies had account for 3.8% of global diagnosis. X-ray film has been the commonest technique used for the diagnosis of rheumatic diseases (80.5%). The waiting list for first visit initially has been 5 weeks, and at the end of study it has been 3 weeks. Ten percent of patients had been referred to the Hospital. CONCLUSIONS: Collaboration between Hospital care rheumatology and Primary care, improves the diagnostic quality, as well as it decreases the waiting list and allows the patients' control at the most appropriate care level.

[Favorable response to corticoid therapy in a patient with transverse myelitis in systemic lupus erythematosus]. / Respuesta favorable a la corticoterapia en una paciente afecta de mielitis transversa en el curso de lupus eritematoso sistémico.

Transverse myelitis is one of the most unusual neurologic complications of systemic lupus erythematosus. Its pathogenetic mechanisms are controversial. Several therapeutic regimens have been attempted with contradictory results. Corticotherapy appears to improve prognosis, although some authors question its beneficial effects. The case of a patient with systemic lupus erythematosus and transverse myelitis, who presented a favourable clinical course following early treatment with high-dose corticoids, is reported.

[Digestive manifestations and metabolic acidosis secondary to intravenous administration of cotrimoxazol]. / Manifestaciones digestivas y acidosis metabólica secundarias a la administración de cotrimoxazol intravenoso.

BACKGROUND: Digestive features and metabolic acidosis have been observed in patients with Pneumocystis carinii pneumonia treated with intravenous high dose co-trimoxazole. METHODS: To evaluate this phenomenon, a retrospective study of 22 patients (group A) and a prospective study of 12 patients (group B) were carried out. Group B patients were investigated following a protocol lasting for the 21 days of treatment. RESULTS: Metabolic acidosis developed in 23 (67%) of the overall number of study patients, and it was associated with digestive features such as nausea, vomiting and epigastralgia in 12. One patient had digestive features without metabolic acidosis. Metabolic acidosis developed early, between the days 4 and 7 of administration of the drug. The mean value of bicarbonate at the onset of therapy was 24,55 mEq; the mean value in the patients with metabolic acidosis was 16,43 mEq. The overall mean value of base excess at the onset of therapy was -2,39, and it was -8,46 in the patients who developed metabolic acidosis. CONCLUSIONS: As in all patients other causes of metabolic acidosis were ruled out, it became obvious that intravenous co-trimoxazole was directly related to the development of digestive features and metabolic acidosis, which disappeared with bicarbonate administration or with cessation of therapy.