Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection.

UNLABELLED: European and Asian studies report conflicting data on the risk of hepatitis B virus (HBV) reactivation in rheumatologic patients with a previously resolved HBV (prHBV) infection undergoing long-term biologic therapies. In this patient category, the safety of different immunosuppressive biologic therapies, including rituximab, was assessed. A total of 1218 Caucasian rheumatologic patients, admitted consecutively as outpatients between 2001 and 2012 and taking biologic therapies, underwent evaluation of anti-HCV and HBV markers as well as liver amino transferases every 3 months. Starting from January 2009, HBV DNA monitoring was performed in patients with a prHBV infection who had started immunosuppressive biologic therapy both before and after 2009. Patients were considered to have elevated aminotransferase levels if values were >1× upper normal limit at least once during follow-up. We found 179 patients with a prHBV infection (14 treated with rituximab, 146 with anti-tumor necrosis factor-alpha, and 19 with other biologic therapies) and 959 patients without a prHBV infection or other liver disease (controls). The mean age in the former group was significantly higher than the controls. Patients with a prHBV infection never showed detectable HBV DNA serum levels or antibody to hepatitis B surface antigen/hepatitis B surface antigen seroreversion. However, when the prevalence of elevated amino transferases in patients with prHBV infection was compared to controls, it was significantly higher in the former group only for aminotransferase levels >1× upper normal limit but not when aminotransferase levels >2× upper normal limit were considered. CONCLUSION: Among patients with a prHBV infection and rheumatologic indications for long-term biologic therapies, HBV reactivation was not seen; this suggests that universal prophylaxis is not justified and is not cost-effective in this clinical setting.

Treating rheumatoid arthritis to target: an Italian rheumatologists' survey on the acceptance of the treat-to-target recommendations.

OBJECTIVES: An educational programme was conducted in Italy in order to favour the diffusion of the rheumatoid arthritis (RA) treat-to-target (T2T) recommendations among Italian rheumatologists. Our objective was to measure the level of acceptance and applicability of the 10 recommendations to treat RA to a target of remission/low disease activity in the Italian rheumatology community, before and after the educational programme. METHODS: One hundred rheumatologists working throughout Italy were invited to participate in this two-stage web-based survey (S1-2). Three questions concerning agreement with, applicability of and possible barriers to the applicability of each of the ten T2T recommendations were administered before (S1) and after (S2) an educational event on the T2T strategy in RA. The agreement with each of the 10 recommendations was measured by a 10-point Likert scale. The applicability of each recommendation was assessed by a 5-point Likert scale (never, almost never, sometimes, almost always, always). Finally, three possible barriers to each recommendation applicability were identified. RESULTS: Seventy-one rheumatologists participated in S1 and 61 in S2. Level of agreement was high (mean score: 8.9 in S1, 9.1 in S2), with each recommendation receiving a score ≥7.9. The highest agreement score was achieved by recommendation 7 in both surveys. Recommendation 8 received the lowest overall agreement in both surveys. Concerning applicability, the majority of responses was 'almost always'. Following the educational programme, the mean degree of agreement with the recommendations increased significantly for recommendations 3, 4, 6, and 10. CONCLUSIONS: The level of knowledge of and agreement with the T2T recommendations for RA among Italian rheumatologists is high and increased significantly for some recommendations following a specific educational event, indicating that a deeper knowledge of the T2T strategy may increase agreement and acceptance.

Lipid profile of rheumatoid arthritis patients treated with anti-tumor necrosis factor-alpha drugs changes according to disease activity and predicts clinical response.

Patients with active rheumatoid arthritis (RA) frequently show an atherogenic lipid profile, which has been linked with the inflammatory reaction. Inflammatory cytokines, and particularly tumor necrosis factor-alpha (TNF-α), are implicated in the pathogenesis of both atherosclerosis and RA, and also involved in the development of the impaired lipid profile detected in active RA. Although anti-TNF-α agents have been proven effective in controlling joint damage and systemic inflammation, controversy remains about the effect of these drugs on the lipid profile; therefore, the aim of our study was to investigate the effect of anti-TNF-α treatment, in combination with disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroid therapy, on the lipid profile of patients with active RA. Our data suggest that the combination anti-TNF-α/DMARDs/steroids do not significantly interfere with the lipid profile of RA patients. However, analysis of clinical response data showed that patients achieving low disease activity or remission seem to have a protective lipid profile, suggesting that better control of inflammation and disease activity can affect lipid metabolism. The available evidence indicates that high inflammation interferes with lipid metabolism, whereas good control of the chronic inflammatory state may positively influence the lipid profile and cardiovascular risk. Low cholesterol levels at baseline could predict a favorable outcome with anti-TNF-α treatment, but these data need to be confirmed by large prospective studies with long-term follow-up.

Comprehensive clinical and histological evaluation of bovine hydroxyapatite bone graft with polypropylene membrane versus leukocyte- and platelet-rich fibrin for alveolar preservation after tooth extraction.

BACKGROUND: Osseointegrated implant placement in the ideal prosthetic position necessitates a sufficient residual alveolar ridge. Tooth extraction and the subsequent healing process often lead to bony deformities, characterized by a reduction in alveolar ridge height and width, resulting in unfavorable ridge architecture for dental implant placement. Several materials, including allografts, alloplastics, xenografts, and autogenous bone, are commonly used to address these concerns. In this context, leucocyte- and platelet-rich fibrin (L-PRF) emerges as a promising solution. METHODS: This case report aims to compare the clinical and histological efficacy of bovine hydroxyapatite bone graft covered with polypropylene membrane (BHAG-PM) and leucocyte- and platelet-rich fibrin (L-PRF) in preserving dental alveoli following tooth extraction. Extraction, graft placement in the alveoli, and the anterior border between extracted elements were performed for both treatment groups. RESULTS: Up to 24 months of follow-up revealed satisfactory and comparable clinical and histological outcomes. These results suggest that both BHAG-PM and L-PRF effectively promote alveolar preservation, paving the way for ideal implant placement. CONCLUSIONS: In general, bone-substitute materials are effective in reducing alveolar changes after tooth extraction. Xenograft materials should be considered as among the best of the available grafting materials for alveolar preservation after tooth extraction. Both techniques effectively preserve the alveolar bone and facilitate the placement of osseointegrated implants in ideal positions, paving the way for successful oral rehabilitation.

Minor salivary gland biopsy and Sjögren's syndrome: comparative analysis of biopsies among different Italian rheumatologic centers.

OBJECTIVES: The minor salivary gland biopsy (MSGB) is widely considered an important component of the diagnostic algorithm of primary Sjögren's syndrome (pSS) and is mentioned in all the classification criteria sets for the disease. The aim of this study, coordinated by the Italian Society of Rheumatology, was to verify the inter-observer agreement on the evaluation of MSGB among different experienced Italian rheumatologic centres, in order to better standardise the diagnostic methodology. METHODS: Seven centres participated in the study, providing a total of 50 MSGB samples. Each center blindly classified all the samples according to the Chisholm and Mason (CM) grading. The results were collected and analysed. RESULTS: The inter-observer agreement was satisfactory when the samples were stratified as consistent and non-consistent with the final diagnosis of pSS (median κ =0.75; mean κ =0.70). Nonetheless, significant discrepancies in the histopathologic evaluation of MSGB emerged when the agreement was assessed on the single scores. Considering the modal CM grading for each sample as the correct grading, upon re-examination, a potential bias in the final clinical diagnosis was detected in 7 out of 50 samples. CONCLUSIONS: This study has shown significant discrepancies in the evaluation of MSGB among different rheumatologic centres in the same country. Greater standardisation of the procedure is clearly necessary, both to improve the diagnostic performance and scientific communication.

From Bench to Bedside in Precision Medicine: Diabetes Mellitus and Peri-Implantitis Clinical Indices with a Short-Term Follow-Up: A Systematic Review and Meta-Analysis.

Background and objective: Diabetes mellitus (DM) refers to a group of metabolic disorders characterized by hyperglycemia resulting from impaired secretion or action of insulin. The high levels of glucose in the blood can negatively affect the healing processes through alterations in vascularization, bone remodeling, and with increased susceptibility to infections. Diabetes mellitus is therefore a risk factor not only for many systemic diseases, but also for localized problems such as peri-implantitis. The objective of this systematic review was to identify a clear relationship between peri-implant inflammation indices and glycemic levels, through the investigation of prospective studies that report data on a short-term follow-up period. Our hypothesis was that peri-implant inflammatory indices may already present themselves in a statistically significant way as altered in patients with DM compared to patients without DM. Materials and methods: This review was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). Results: More than 992 records were identified in the PubMed, Scopus, and Cochrane Central Register of Controlled Trial electronic databases and only seven studies were included in the meta-analysis. The results of the meta-analysis report worse outcomes in patients with DM, even in the short period of six months, for peri-implatitis inflammation indices, such as Marginal bone loss (standardized (Std). mean difference (MD) 12\6 months 0.81 [0.45, 1.17]\1.82 [0.53, 3.10]), Bleeding on probing (Std. MD 12\6 months 2.84 [1.34, 4.34]\3.44 [1.41, 5.50]), Probing depth (Std. MD 12\6 months 1.14 [0.60, 1.68]\2.24 [0.66, 3.83]), and the plaque index (Std. MD 12 months 2.83 [0.09, 5.57]). Conclusion: The literature linking glycaemic control to peri-implant disease is highly heterogeneous due to lack of consistency of the definition of peri-implantitis and its clinical indicators among studies. Therefore, interpretation of finding and relevance to clinical practice should be considered on individual bases. In the era of personalized medicine, the clinician should utilize individualized information from translational researches and analyze all risk factors to provide the patient with evidence-based treatment options.

An Ancient Science to Improve Today's Clinical Practice: Oral Surgery Meets Human Anatomy.

Human body dissection was a ubiquitous practice in the past, to better understand anatomy and to develop medicine. Today, its role could still be important to answer everyday clinical queries and help surgeons. The example of the possible lack of anesthesia during symphysis surgeries can emphasize the usefulness of dissection. The mandibular symphysis usually receives innervation from inferior alveolar nerve terminations, but, in some rare cases, a particular anastomosis involves the lingual nerve and the nerve to the mylohyoid. The anatomical knowledge resulting from body dissections could help oral surgeons to understand the reason why the patient could feel pain during the surgery, and ensure performance of the right lingual nerve block to obtain complete anesthesia. This clinical situation shows the educational role of an ancient, yet still valid, practice, human dissection, and the importance of anatomical studies to improve surgical skills, to provide better treatment for the patient.

Digital laser doppler flowmetry may discriminate "limited" from "diffuse" systemic sclerosis.

OBJECTIVES: To investigate skin blood flux and microvascular functional changes by laser Doppler flowmetry (LD) in patients with systemic sclerosis (SSc) at baseline and following dynamic stimulations. METHODS: Skin blood flux of the dorsal hands was recorded by LD at baseline and after the cold test and the post-occlusive hyperemia test in 59 SSc patients (49 limited cutaneous, 10 diffuse cutaneous). Twenty-five patients with primary Raynaud's phenomenon (PRP), and 31 healthy donors (HD) were studied as controls. RESULTS: After the cold test, SSc patients had a significantly higher reduction of the blood flux (-38.4%+/-28) than PRP (-21.1%+/-37) and HD (-22.1%+/-23) subjects (p<0.05). Within the SSc group, the cold test flux was significantly reduced in limited-SSc (-399%+/-28, p<0.05), but not in diffuse-SSc (-31.2%+/-29), whereas, the time needed to recover the basal flux after the occlusive/ischemic test was significantly longer in diffuse-SSc (18.8s+/-21)than in limited-SSc (4.5s+/-4, p<0.01) or HD (2.2s+/-2, p<0.01) or PRP (0.4s+/-0.7, p<0.01). CONCLUSIONS: These data clearly indicate an impairment of vascular tone regulatory mechanisms in SSc and suggest that a peculiar pathogenic mechanism may be involved in different SSc subset. Nevertheless, it has clear that PRP and SSc-associated RP have a distinct pattern at LD evaluation, and monitoring patients with PRP could be helpful to understand whether a change in the LD pattern might predict the development of SSc.

Gastrointestinal symptoms and motility disorders in patients with systemic scleroderma.

BACKGROUND: Studies on gastrointestinal symptoms, dysfunctions, and neurological disorders in systemic scleroderma are lacking so far. METHODS: Thirty-eight scleroderma patients (34 limited, 4 diffuse), 60 healthy controls and 68 dyspeptic controls were scored for upper and lower gastrointestinal symptoms (dyspepsia, bowel habits), gastric and gallbladder emptying to liquid meal (functional ultrasonography) and small bowel transit (H2-breath test). Autonomic nerve function was assessed by cardiovascular tests. RESULTS: The score for dyspepsia (mainly gastric fullness) was greater in scleroderma patients than healthy controls, but lower than dyspeptic controls who had multiple symptoms, instead. Scleroderma patients with dyspepsia had a longer disease duration. Fasting antral area and postprandial antral dilatation were smaller in scleroderma patients than dyspeptic and healthy controls. Gastric emptying was delayed in both scleroderma patients (particularly in those with abnormal dyspeptic score) and dyspeptic controls, who also showed a larger residual area. Despite gallbladder fasting and postprandial volumes were comparable across the three groups, gallbladder refilling appeared delayed in dyspeptic controls and mainly dependent on delayed gastric emptying in scleroderma. Small intestinal transit was also delayed in 74% of scleroderma and 66% of dyspeptic controls. Bowel habits were similar among the three groups. Autonomic neuropathy was not associated with dyspepsia, gastric and gallbladder motility and small intestinal transit. CONCLUSION: In scleroderma patients dyspepsia (mainly gastric fullness), restricted distension of the gastric antrum and diffuse gastrointestinal dysmotility are frequent features. These defects are independent from the occurrence of autonomic neuropathy.

Cutaneous lesions as presenting symptoms of primary biliary cirrhosis: an undifferentiated connective tissue disease-like onset.

We describe two patients with primary biliary cirrhosis (PBC) who presented with specific symptoms mimicking an undifferentiated connective tissue disease (arthromyalgia, fatigue, cutaneous lesions either morbillous-like or urticarial, the latter with an eosinophil infiltrate of upper dermis). Subsequent detection firstly of eosinophilia in the blood and secondarily of antimitochondrial antibodies with results of liver biopsy allowed a diagnosis of asymptomatic PBC. In our cases, a peculiar sign of early stage of PBC was represented also by the eosinophilia in the liver.

Low Risk of Hepatitis B Virus Reactivation in HBsAg-negative/Anti-HBc-positive Carriers Receiving Rituximab for Rheumatoid Arthritis: A Retrospective Multicenter Italian Study.

OBJECTIVE: Patients with resolved hepatitis B virus (HBV) infection, i.e., hepatitis B surface antigen (HBsAg)-negative/antihepatitis B core antigen (anti-HBc)-positive, undergoing rituximab (RTX)-based chemotherapy for hematological malignancies without anti-HBV prophylaxis are at risk of HBV reactivation, but the risk in such patients receiving RTX for rheumatological disorders is not clear. We evaluated this risk in HBsAg-negative/anti-HBc-positive patients with rheumatoid arthritis (RA) undergoing RTX without prophylaxis. METHODS: Thirty-three HBsAg-negative/anti-HBc-positive outpatients with RA with undetectable HBV DNA by sensitive PCR assay [73% women, median age 60 years, 85% with HBsAg antibodies (anti-HBs), 37% with antihepatitis B envelope antigen] received a median of 3 cycles of RTX (range 1-8) over 34 months (range 0-80) combined with disease-modifying antirheumatic drugs (DMARD) without prophylaxis. All underwent clinical and laboratory monitoring during and after RTX administration, including serum HBsAg and HBV DNA measurements every 6 months or whenever clinically indicated. RESULTS: None of the patients seroreverted to HBsAg during RTX treatment, but 6/28 (21%) showed a > 50% decrease in protective anti-HBs levels, including 2 who became anti-HBs-negative. One patient (3%) who became HBV DNA-positive (44 IU/ml) after 6 months of RTX treatment was effectively rescued with lamivudine before any hepatitis flare occurred. Among the 14 patients monitored for 18 months (range 0-70) after RTX discontinuation, no HBV reactivation was observed. CONCLUSION: The administration of RTX + DMARD in patients with RA with resolved HBV infection leads to a negligible risk of HBV reactivation, thus suggesting that serum HBsAg and/or HBV DNA monitoring but not universal anti-HBV prophylaxis is justified.

Refractory knee giant cell tumor of the synovial membrane treated with intra-articular injection of Infliximab: a case series and review of the literature.

Giant cell tumor (GCT) of the synovial membrane, also known as pigmented villonodular synovitis, causes a progressive, relapsing and destructive arthropathy affecting one or more synovial joints. Systemic therapy can be combined to intra-articular treatments, including surgical synoviectomy, especially when monoarticular. Despite that, the synovial membrane commonly grows again with clinical relapse. Here, we report three case of patients diagnosed with GCT of the knee who had an early relapse of the disease even after surgical synoviectomy. All of them underwent intra-articular therapy with infliximab and subsequent synoviectomy to eradicate residual tissue. A complete remission of CGT was achieved without relapse occurring during the follow-up. These preliminary data need to be confirmed by further clinical trials; however, intra-articular therapy with infliximab might be deemed a potential option to treat CGT of a single joint.

Sjögren's Syndrome Disease Damage Index and disease activity index: scoring systems for the assessment of disease damage and disease activity in Sjögren's syndrome, derived from an analysis of a cohort of Italian patients.

OBJECTIVE: To develop valid instruments for the assessment of disease-related damage and disease activity in Sjögren's syndrome (SS). METHODS: Data on 206 patients with primary SS were collected in 12 Italian centers. Each patient was scored by 1 investigator, on the basis of a global assessment of the degree of disease damage and disease activity. Patients judged to have active disease at the time of enrollment underwent a second evaluation after 3 months. Univariate and multivariate analyses were performed to select the clinical and serologic variables that were the best predictors of damage and of disease activity, and these variables were used to construct the Sjögren's Syndrome Disease Damage Index (SSDDI) and the Sjögren's Syndrome Disease Activity Index (SSDAI). The weight of each variable in the index was determined by the beta coefficients in multivariate regression models. Scores obtained using the SSDDI and the SSDAI were compared with scores initially given by the investigators. Finally, a receiver operating characteristic (ROC) curve was used to determine the cutoff value in the SSDAI with the highest level of accuracy in identifying patients with a significant level of disease activity. RESULTS: A multivariate model with 9 variables was the best predictor of investigator scores of damage. The scores obtained using the SSDDI were closely correlated with investigator ratings (R = 0.760, P < 0.0001). A model composed of 11 variables was the best predictor of investigator scores of disease activity. The scores obtained using the SSDAI were strongly correlated with the investigator ratings both at the time of enrollment and 3 months after enrollment (R = 0.872, P < 0.0001, and R = 0.817, P < 0.0001, respectively). The differences between scores given by investigators at study enrollment and after 3 months, a measure of variation of disease activity over time, were also closely correlated with the differences calculated using the SSDAI (R = 0.683, P < 0.0001). The ROC curve analysis showed that patients with the highest level of disease activity could be identified on the basis of an SSDAI score of >or=5. CONCLUSION: Our findings indicate that the SSDDI is an adequate instrument to objectively measure damage in patients with SS, and that the SSDAI is a valid tool to measure disease activity when used either as a single-state index or as a transition index.

Use of etanercept in the treatment of dermatomyositis: a case series.

OBJECTIVE: To evaluate the efficacy of etanercept, a recombinant human soluble fusion protein of tumor necrosis factor-alpha (TNF-alpha) type II receptor and IgG1, in patients with adult dermatomyositis (DM). METHODS: Five patients with active DM were studied. All patients reported muscle weakness and had elevated muscle enzymes creatine kinase and lactate dehydrogenase. Because of lack of response to steroid and cytotoxic therapy, etanercept was given at a dose of 25 mg subcutaneously twice a week for at least 3 months. RESULTS: All patients experienced an exacerbation of disease, with increase of muscle weakness, elevation of muscle enzyme levels, and unchanged rash. Treatment with etanercept was stopped. After receiving a combination of methotrexate (MTX) and azathioprine, disease manifestations improved in all patients. CONCLUSIONS: In our case series, TNF-alpha inhibition by etanercept was not effective, suggesting that a broad immunosuppressive therapy is needed to treat DM.

Microscopic polyangiitis associated with primary biliary cirrhosis.

We describe a patient with microscopic polyangiitis and primary biliary cirrhosis (PBC) who presented with a non-erosive polyarthritis followed by pulmonary and renal involvement and signs of liver disorder. Detection of pANCA and antimitochondrial antibodies with results of renal and liver biopsies allowed a diagnosis of microscopic polyangiitis and PBC. To our knowledge, this is the first report of an association between the 2 diseases.