Ioannis Antonopoulos

Treatment of Systemic Sclerosis-Associated Calcinosis: A Case Report of Rituximab-Induced Regression of CREST-Related Calcinosis and Review of the Literature

OBJECTIVES Calcinosis is frequently encountered in patients with systemic sclerosis (SSc) and may be associated with significant morbidity. No treatment has shown so far an unequivocal beneficial effect. METHODS We performed an extensive internet search (MEDLINE) using the keywords calcinosis, calcification, scleroderma, systemic sclerosis, and treatment. RESULTS Our patient had extensive Calcinosis, Raynaud, Esophagitis, Sclerodactyly, telangiectasia (CREST)-related calcinosis, frequently ulcerating and painful. Following 2 rituximab courses (consisting of 4 weekly infusions, 375 mg/m(2) each), calcinosis significantly improved and pain disappeared. Pharmacologic agents used in the treatment of SSc-associated calcinosis include diltiazem, minocycline, warfarin, biphosphonates, and intravenous immunoglobulin. Other therapeutic approaches include surgical excision, laser vaporization, and extracorporeal shock wave lithotripsy. CONCLUSIONS Evidence for all existing therapies is weak and therefore larger scale controlled studies are needed. Rituximab appears as a promising treatment especially in view of recent evidence that this therapy may be also effective in the underlying disease.

Cardiovascular risk factors and not disease activity, severity or therapy associate with renal dysfunction in patients with rheumatoid arthritis

Objectives The present study aimed to evaluate the prevalence and associations of renal dysfunction in patients with rheumatoid arthritis (RA). It specifically addressed the hypotheses that renal dysfunction in these patients may associate with the presence of insulin resistance, dyslipidaemia, uric acid levels and/or current levels of systemic inflammation. Methods Renal function was assessed by estimated glomerular filtration rate (GFR) using the modification of diet in renal disease equation in 400 consecutive RA patients for this cross-sectional, single-centre study. Risk factors for renal dysfunction were recorded/measured in all participants. Correlations between GFR and other variables were analysed by Pearson or Spearman test as appropriate. Linear regression was used to test the independence of the associations between GFR and other variables. Results In this RA patient cohort, 67.75% of patients had a reduced GFR of less than 90 ml/minute per 1.73 m2 and 12.75% had a GFR of less than 60 ml/minute per 1.73 m2. Multivariable analysis revealed significant associations between GFR and age (β = −0.370, p<0.001), female sex (β = −0.181, p=0.002), total cholesterol (β = −0.112, p=0.022), serum uric acid (SUA) (β = −0.425, p<0.001) and the presence of extra-articular disease, apart from sicca and/or nodules (β = −0.084, p=0.040). Conclusions Renal dysfunction in RA is quite common and associates with classic cardiovascular risk factors such as advanced age and dyslipidaemia, levels of SUA and the presence of extra-articular disease. Renal dysfunction was not related to other RA-related factors including disease activity and duration, disability and past or present use of nephrotoxic medications.

A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease

OBJECTIVES Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment. METHODS A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1-7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10). RESULTS Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups. CONCLUSIONS Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed.

Uric acid is a strong independent predictor of renal dysfunction in patients with rheumatoid arthritis

IntroductionRecent evidence suggests that uric acid (UA), regardless of crystal deposition, may play a direct pathogenic role in renal disease. We have shown that UA is an independent predictor of hypertension and cardiovascular disease (CVD), and that CVD risk factors associate with renal dysfunction, in patients with rheumatoid arthritis (RA). In this study we investigated whether UA associates with renal dysfunction in patients with RA and whether such an association is independent or mediated through other comorbidities or risk factors for renal impairment.MethodsRenal function was assessed in 350 consecutive RA patients by estimated glomerular filtration rate (GFR) using the six-variable Modification of Diet in Renal Disease equation. Risk factors for renal dysfunction were recorded or measured in all participants. Linear regression was used to test the independence of the association between GFR and UA.ResultsUnivariable analysis revealed significant associations between GFR and age, systolic blood pressure, total cholesterol, triglycerides, RA duration and UA. UA had the most powerful association with renal dysfunction (r = -0.45, P < 0.001). A basic model was created, incorporating all of the above parameters along with body mass index and gender. UA ranked as the first correlate of GFR (P < 0.001) followed by age. Adjustments for the use of medications (diuretics, low-dose aspirin, cyclooxygenase II inhibitors and nonsteroidal anti-inflammatory drugs) and further adjustment for markers of inflammation and insulin resistance did not change the results.ConclusionsUA is a strong correlate of renal dysfunction in RA patients. Further studies are needed to address the exact causes and clinical implications of this new finding. RA patients with elevated UA may require screening for renal dysfunction and appropriate management.

ACTH as first line treatment for acute gout in 181 hospitalized patients

OBJECTIVE We aimed at assessing the efficacy and safety of adrenocorticotropic hormone (ACTH) for the treatment of acute gout in hospitalized patients. METHODS We retrospectively reviewed our inpatient consultation records and identified 181 cases of gout where ACTH was used as first line treatment. The hospital medical records of these patients were fully reviewed. A total of 181 patients were treated with 1mg of synthetic ACTH intramuscularly. RESULTS A response was seen in 77.90% of patients and was evident the day following ACTH injection. The majority of non-responders (87.50%) were treated once more with ACTH the day following the first injection; 82.85% of these patients responded. A relatively small percentage of responders suffered a second gouty attack (11.34%) at a median of four days from the initial attack. They were retreated with a single ACTH course and all responded. Blood pressure and potassium levels remained stable 24 and 48 hours following ACTH administration. Diabetic patients showed an increase in fasting glucose levels 24 hours following the injection compared to baseline but this increase was not evident at 48 hours. CONCLUSIONS Our data indicate that ACTH is effective and safe for the treatment of gout in hospitalized patients. ACTH is an attractive therapeutic option for hospitalized patients since the use of non-steroidal anti-inflammatory drugs, steroids or colchicine in this patient population may be problematic.

B-cell depletion therapy in patients with diffuse systemic sclerosis associates with a significant decrease in PDGFR expression and activation in spindle-like cells in the skin

IntroductionRecently, several studies assessing the clinical efficacy of rituximab (RTX) in systemic sclerosis (SSc) have reported encouraging results. We aimed at exploring whether RTX exerts its beneficial effects on fibrosis through attenuation of platelet-derived growth factor receptor (PDGFR) pathway activation.MethodsWe immunohistochemically assessed skin biopsies obtained from eight patients with SSc prior to and 6 months following RTX treatment, three control SSc patients (at the same time points) and three healthy subjects. We assessed the expression of platelet-derived growth factor, PDGFR and phosphorylated (activated) PDGFR.ResultsWe found a strong correlation of PDGFRα and PDGFRβ expression on spindle-like cells and collagen deposition in SSc biopsies (r = 0.97 and r = 0.96 for PDGFRα and PDGFRβ, respectively; P < 0.0001 for both), indicating a strong link between PDGFR expression and fibrosis. Expression of PDGFRα and PDGFRβ in the papillary dermis significantly decreased following RTX administration (mean ± standard error of the mean at baseline vs. 6 months, respectively: PDGFRα, 42.05 ± 5.03 vs. 26.85 ± 3.00, P = 0.004; and PDGFRβ, 37.14 ± 4.94 vs. 24.01 ± 3.27, P = 0.012). Similarly, expression of phosphorylated PDGFRα and PDGFRβ in the papillary dermis significantly decreased following RTX administration (P = 0.006 and P = 0.013 for phospho-PDGFRα and phospho-PDGFRβ, respectively). No changes in platelet-derived growth factor tissue expression or serum levels were found following RTX treatment.ConclusionRTX may favorably affect skin fibrosis through attenuation of PDGFR expression and activation, a finding that supports a disease-modifying role of RTX in SSc. Large-scale, multicenter studies are needed to further explore the efficacy of RTX in SSc.

Microalbuminuria in rheumatoid arthritis in the post penicillamine/gold era: association with hypertension, but not therapy or inflammation.

Rheumatoid arthritis (RA) associates with excess cardiovascular (CV) morbidity and mortality. New screening tools are needed to better identify patients at increased CV risk. Microalbuminuria (MA) has been shown to associate with inflammation and future cardiovascular disease (CVD). In the present study, we assessed the prevalence of MA in a secondary care cohort of RA patients, aimed to identify factors associated with its presence and addressed its relationship to CVD and the metabolic syndrome (MetS). A total of 342 RA patients were studied. MA was defined as an albumin-creatinine ratio ≥22 (males) or ≥31 (females) milligrams per gram creatinine. The independence of the associations of MA was evaluated using binary logistic regression analysis. Prevalence of MA was 11.9%. Subjects with MA had increased prevalence of hypertension (HT), insulin resistance and type 2 diabetes. In binary logistic regression, only HT (OR = 5.22, 95%CI: 1.51–18.07, p = 0.009) was significantly associated with MA. There was no association between prevalent CVD and MA, but patients with MA had twofold increased odds of having the MetS. MA is relatively common in RA patients and is independently associated with the presence of HT. Given the association of MA with MetS, future prospective studies are needed to establish the use of MA as a screening tool for RA patients at increased CVD risk.

ACTH as first line treatment for acute calcium pyrophosphate crystal arthritis in 14 hospitalized patients

Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 26 juin 2013

ACTH as a treatment for acute crystal-induced arthritis: update on clinical evidence and mechanisms of action.

BACKGROUND ACTH, a member of the melanocortin group of proteins, has long been used in the treatment of gout and is considered as an alternative therapeutic option, especially in difficult-to-treat patients. METHODS We performed a systematic electronic search (Medline and ScienceDirect) using the keywords gout, treatment, ACTH, adrenocorticotropic hormone, and pseudogout. We identified 5 studies assessing the efficacy of ACTH in acute crystal-induced arthritis. RESULTS In the studies for acute gout, a total of 266 patients have been treated with ACTH; treatment was highly efficacious with a response rate of 77.9-100%. Only few side effects, such as hyperglycemia, hypokalemia, and edema, were reported, all of which were mild. The available evidence for acute CPP crystal arthritis is limited. A total of 19 patients have been assessed in retrospective studies; the response rate was 90-100%, whereas no significant side effects were recorded. The mechanism of action of ACTH in acute crystal-induced arthritis is not entirely known but seems to extend beyond stimulation of steroid release from the adrenal glands; ACTH is able to stimulate melanocortin receptors on macrophages and downregulate gouty inflammation. CONCLUSIONS Data suggests that ACTH is effective in acute crystal-induced arthritis and may be a first-line therapy in patients with multiple medical problems. We propose that further evaluation of ACTH should be performed, with a large-scale, randomized controlled study focusing on safety issues in patients with multiple comorbidities.

SAT0222 B Cell Depletion Therapy in Systemic Sclerosis Associated Interstitial Lung Disease. A Multicenter, Open Label, Comparative Study with A Follow up of 94 Patient-Years

Background We have previously shown that rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). Objectives To assess long term efficacy and safety of RTX in SSc compared to standard treatment. Methods Fifty one patients with SSc associated interstitial lung disease were recruited and treated with RTX (n=33) or standard treatment (n=18). RTX cycles were repeated every 6 months throughout follow up apart from 6 patients where RTX was discontinued following 2 years of continuous treatment. Mean follow up was 2.9 years (range 1–7). Standard treatment consisted of azathioprine (n=2), methotrexate (n=6) and mycophenolate (n=10). Results Patients in the RTX group showed an increase in FVC during the first year of treatment (mean ± SEM of FVC: 80.60 ± 3.69 vs 83.02 ± 3.37 at baseline vs 1-year, respectively, p=0.13); this beneficial effect was further augmented at 2 years (86.90 ± 4.72, p=0.04 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow up. At 2 years, the RTX group was numerically better than the control group; however, differences tended but did not reach statistical significance (p=0.063). At the 7 year time point patients in the RTX group had higher FVC compared to baseline (mean ± SEM of FVC: 91.60 ± 6.62, p=0.15 compared to baseline) in contrast to patients in the control group where FVC deteriorated (p<0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group (p=0.013). DLCO also improved following 2 years of RTX treatment (mean ± SEM of DLCO: 59.22 ± 3.16 vs 61.51 ± 4.02 at baseline vs 2-years, respectively, p=0.05). In the standard treatment group DLCO constantly deteriorated throughout follow up. In 6 patients where RTX was stopped following 2 years of continuous treatment a decline in PFTs was evident. Improvement of skin thickening was found in both the RTX and the standard treatment group, however, direct comparison between groups strongly favored RTX at all time points (p=0.002, 0.015, 0.002, 0.053 0.029 for the 1, 2, 3, 4 and 5-year time point, respectively). In the RTX group, six cases of respiratory infection requiring hospitalization, one case of hepatitis B reactivation and one case of herpes zoster were recorded. Two patients were diagnosed with cancer (lung and prostate). Five deaths were recorded: end stage respiratory failure (n=2), lung cancer (n=1), sudden death (n=1), unknown (n=1). In the control group, five patients with respiratory and four patients with urinary infection were hospitalized. In four cases, infections were recurrent. Two deaths were reported due to respiratory infection. Conclusions Our data indicate that continuous treatment with RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Treatment was well-tolerated. Randomized controlled studies are highly needed. Disclosure of Interest None declared