Respiratory muscle training for obstructive sleep apnea: Systematic review and meta-analysis.

Obstructive sleep apnea is the most common sleep disorder. This review aims to evaluate the effectiveness and safety of respiratory muscle training in the treatment of patients with obstructive sleep apnea. The study protocol was registered in Prospero Platform (CRD42018096980). We performed searches in the main databases: Medical Literature Analysis and Retrieval System Online (MEDLINE) via Pubmed; Excerpta Medica dataBASE (Embase) via Elsevier; Cochrane Central Register of Controlled Trials (CENTRAL) via Cochrane Library; Latin American and Caribbean Literature on Health Sciences (LILACS) through the Portal of the Virtual Health Library and Physiotherapy Evidence Database (PEDro) for all randomised-controlled trials published before July 2022. The randomised-controlled trials were assessed for risk of bias and certainty of evidence. Thirteen randomised-controlled trials were included. All studies had an overall high risk of bias. Inspiratory muscle training probably improves systolic blood pressure and sleepiness when compared with sham. However, inspiratory muscle training probably does not improve diastolic blood pressure and maximum expiratory pressure, and may not be superior to sham for apnea-hypopnea index, forced expiratory volume in 1 s, forced vital capacity, sleep quality and quality of life. In addition, it is uncertain whether there is any effect of inspiratory muscle training on maximum inspiratory pressure and physical capacity. Inspiratory muscle training may also improve maximum inspiratory pressure and maximum expiratory pressure compared with oropharyngeal exercises. However, it may not be superior for apnea-hypopnea index, sleep quality, sleepiness, quality of life and functional capacity. When associated with physical exercise, inspiratory muscle training may not be superior to physical exercise alone for maximum inspiratory pressure, maximum expiratory pressure, systolic and diastolic blood pressure, and functional capacity. At the same time, when associated with cardiac rehabilitation exercises, inspiratory muscle training may reduce apnea-hypopnea index, improve inspiratory muscle strength, sleepiness and sleep quality compared with cardiac rehabilitation alone. However, it may not be superior for improving quality of life. Regarding expiratory muscle training, it may improve expiratory muscle strength and sleep quality, but not sleepiness when compared with sham. The evidence on the effects of expiratory muscle training in apnea-hypopnea index is very uncertain.

Exposure to air pollution as an environmental determinant of how Sjögren's disease is expressed at diagnosis.

OBJECTIVES: To analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). METHODS: For the present study, the following variables were selected for harmonization and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD. RESULTS: The results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. CONCLUSIONS: For the first time, we suggest that pollution levels could influence how SjD appears at diagnosis in a large international cohort of patients. The most notable relationships were found between symptoms (dryness and general body symptoms) and NO/SO, CO, and PM2.5 levels.

Influence of exposure to climate-related hazards in the phenotypic expression of primary Sjögren's syndrome.

OBJECTIVES: To analyse how the key components at the time of diagnosis of the Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease) can be influenced by the potential exposure to climate-related natural hazards. METHODS: For the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Climate-related hazards per country were defined according to the OECD and included seven climate-related hazard types: extreme temperature, extreme precipitation, drought, wildfire, wind threats, river flooding, and coastal flooding. Climatic variables were defined as dichotomous variables according to whether each country is ranked among the ten countries with the most significant exposure. RESULTS: After applying data-cleaning techniques and excluding people from countries not included in the OECD climate rankings, the database study analysed 16,042 patients from 23 countries. The disease was diagnosed between 1 and 3 years earlier in people living in countries included among the top 10 worst exposed to extreme precipitation, wildfire, wind threats, river flooding, and coastal flooding. A lower frequency of dry eyes was observed in people living in countries exposed to wind threats, river flooding, and coastal flooding, with a level of statistical association being classified as strong (p<0.0001 for the three variables). The frequency of dry mouth was significantly lower in people living in countries exposed to river flooding (p<0.0001) and coastal flooding (p<0.0001). People living in countries included in the worse climate scenarios for extreme temperature (p<0.0001) and river flooding (p<0.0001) showed a higher mean ESSDAI score in comparison with people living in no-risk countries. In contrast, those living in countries exposed to worse climate scenarios for wind threats (p<0.0001) and coastal flooding (p<0.0001) showed a lower mean ESSDAI score in comparison with people living in no-risk countries. CONCLUSIONS: Local exposure to extreme climate-related hazards plays a role in modulating the presentation of Sjögren across countries concerning the age at which the disease is diagnosed, the frequency of dryness, and the degree of systemic activity.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

OBJECTIVE: To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. RESULTS: There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). CONCLUSION: In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

Safety and efficacy of SARS-CoV-2 vaccination in 1237 patients with primary Sjögren syndrome.

OBJECTIVES: To investigate the safety and efficacy of SARS-Cov-2 vaccination in patients with primary Sjögren syndrome (pSS) due to scarcity of data in this population. METHODS: By the first week of May 2021, all Big Data SS Consortium centres patients who had received at least one dose of any SARS-CoV-2 vaccine were included in the study. The in-charge physician asked patients about local and systemic reactogenicity to collect SARS-CoV-2 vaccination data. RESULTS: The vaccination data of 1237 patients were received. A total of 835 patients (67%) reported any adverse events (AEs), including local (53%) and systemic (50%) AEs. Subjective symptoms (63%) were the most common local AEs, followed by objective signs at the injection site (16%), and general symptoms were the most commonly reported systemic AEs (46%), followed by musculoskeletal (25%), gastrointestinal (9%), cardiopulmonary (3%), and neurological (2%). In addition, 141 (11%) patients reported a significant worsening/exacerbation of their pre-vaccination sicca symptoms and fifteen (1.2%) patients reported active involvement in the glandular (n=7), articular (n=7), cutaneous (n=6), pulmonary (n=2), and peripheral nervous system (n=1) domains due to post-vaccination SS flares. In terms of vaccination efficacy, breakthrough SARS-CoV-2 infection was confirmed after vaccination in three (0.24 %) patients, and positive anti-SARS-Cov-2 antibodies were detected in approximately 95% of vaccinated SS patients, according to data available. CONCLUSIONS: Our data suggest that patients with pSS develop adequate humoral response and no severe AEs after SARS-CoV-2 vaccination and therefore raise no concerns about the vaccine's efficacy or safety profile in this population.

Influence of the age at diagnosis in the disease expression of primary Sjögren syndrome. Analysis of 12,753 patients from the Sjögren Big Data Consortium.

OBJECTIVES: To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjögren's syndrome (pSS). METHODS: By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression. RESULTS: There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R2 0.87) and the frequency of abnormal oral tests (adjusted R2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.18%), and constitutional, cutaneous, and haematological involvements (the frequency decreased by 0.09% for each 1-year increase). In contrast, other domains showed an ascending pattern, especially pulmonary involvement (for each 1-year increase in the age at diagnosis, the frequency of activity increased by 0.22%), and peripheral nerve involvement (the frequency increased by 0.09% for each 1-year increase). CONCLUSIONS: The influence of the age at diagnosis on the key phenotypic features of pSS is strong, and should be considered critical not only for designing a personalised diagnostic approach, but also to be carefully considered when analysing the results of diagnostic tests and immunological parameters, and when internal organ involvement is suspected at diagnosis.

Autoimmune congenital heart block and primary Sjögren's syndrome: characterisation and outcomes of 49 cases.

OBJECTIVES: To characterise autoimmune congenital heart block (CHB) associated with a maternal diagnosis of primary Sjögren's syndrome (pSS) confirmed either before, concomitant or after the first pregnancy complicated with CHB. METHODS: The following inclusion criteria were applied: (i) Mothers with positive Ro/La autoantibodies detected previously or at the time of diagnosis of the first case of CHB; (ii) diagnosis of CHB confirmed by fetal echocardiography; (iii) AV block diagnosed in uterus, at birth or within the neonatal period (0-27 days after birth) (8); (iv) absence of anatomical cardiac abnormalities which might be causal of AV block; and (v) maternal fulfillment of the 2002 SS criteria before, during or after having a pregnancy complicated with CHB. RESULTS: We identified 49 cases of autoimmune CHB in children born from 44 mothers who had a mean age at the time of pregnancy of 30.3 years (range 18 to 41). At the time of diagnosis of autoimmune CHB, all mothers had positive anti-Ro antibodies and 28/44 (64%) were positive for anti-La antibodies. Only 10 (22%) mothers with affected pregnancies had a diagnosis of primary SS at the time of diagnosis of the first pregnancy complicated by CHB (a mean of 4 years before, ranging from 1 to 10 years). In 6 (14%) mothers, primary SS was diagnosed during pregnancy or less than 12 months after the delivery/termination. In the remaining 28 (64%) mothers, pSS was confirmed 1-5 years after CHB diagnosis (n=19, 68%), 6-10 years after (n=2, 7%), or more than 10 years after the first case of CHB was diagnosed (n=7, 25%). CHB was diagnosed in uterus in all cases but two. AV block was initially incomplete in 11 fetuses and complete in 36 (no available data in 2 cases). Among the 35 (71%) surviving children with CHB, 5 (14%) developed other features of neonatal lupus. After the index pregnancy, 12 women had 20 subsequent pregnancies: five were complicated by a CHB (recurrence rate of CHB of 25%). The 4 women who had recurrent CHB were double-positive for anti-Ro and anti-La antibodies, and all had a confirmed pSS before having the first index case of CHB. CONCLUSIONS: In pSS, autoimmune CHB could be one of the first "indirect" signs of the disease in women of childbearing-age, in whom the diagnosis is confirmed several years later. Some maternal characteristics could be related with recurrent CHB, such as having an already-confirmed diagnosis of pSS and carrying the two Ro/La autoantibodies.

Systemic phenotype related to primary Sjögren's syndrome in 279 patients carrying isolated anti-La/SSB antibodies.

OBJECTIVES: To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjögren's syndrome (pSS) fulfilling the 2002 classification criteria. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immunological phenotypes: double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/SSB, and immunonegative. RESULTS: The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score ≥1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in comparison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group. CONCLUSIONS: Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients.

Systemic manifestations of primary Sjögren's syndrome out of the ESSDAI classification: prevalence and clinical relevance in a large international, multi-ethnic cohort of patients.

OBJECTIVES: To analyse the frequency and characterise the systemic presentation of primary Sjögren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded. RESULTS: Information about non-ESSDAI features was available in 6331 patients [5,917 female, mean age at diagnosis 52 years, mainly White (86.3%)]. A total of 1641 (26%) patients had at least one of the ESSDAI systemic features. Cardiovascular manifestations were the most frequent organ-specific group of non-ESSDAI features reported in our patients (17% of the total cohort), with Raynaud's phenomenon being reported in 15%. Patients with systemic disease due to non-ESSDAI features had a lower frequency of dry mouth (90.7% vs. 94.1%, p<0.001) and positive minor salivary gland biopsy (86.7% vs. 89%, p=0.033), a higher frequency of anti-Ro/SSA (74.7% vs. 68.7%, p<0.001), anti-La/SSB antibodies (44.5% vs. 40.4%, p=0.004), ANA (82.7% vs. 79.5%, p=0.006), low C3 levels (17.4% vs. 9.7%, p<0.001), low C4 levels (14.4% vs. 9.6%, p<0.001), and positive serum cryoglobulins (8.6% vs. 5.5%, p=0.001). Systemic activity measured by the ESSDAI, clinESSDAI and DAS was higher in patients with systemic disease out of the ESSDAI in comparison with those without these features (p<0.001 for all comparisons). CONCLUSIONS: More than a quarter of patients with primary SS may have systemic manifestations not currently included in the ESSDAI classification, with a wide variety of cardiovascular, digestive, pulmonary, neurological, ocular, ENT (ear, nose, and throat), cutaneous and urological features that increase the scope of the systemic phenotype of the disease. However, the individual frequency of each of these non-ESSDAI features was very low, except for Raynaud's phenomenon.

Diacerein for osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases. There is currently no consensus on what is the best treatment to improve OA symptoms and slow disease progression. Diacerein is an anthraquinone synthesised in 1980 that interferes with interleukin-1, an inflammatory mediator. It has been proposed that diacerein acts as a slow-acting, symptom-modifying and perhaps disease-structure-modifying drug for OA. This is an update of a Cochrane review first published in 2006. OBJECTIVES: To assess the benefits and harms of diacerein for the treatment of adults with OA when compared with placebo and other pharmacologically active interventions (nonsteroidal anti-inflammatory drugs (NSAIDs) and other symptom-modifying, slow-acting drugs) for OA. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) - The Cochrane Library, Issue 10, 2013, MEDLINE (1966 to 2013), EMBASE (1980 to 2013), LILACS (1982 to 2013), and ACP Journal Club, and we handsearched reference lists of published articles. We also searched the World Health Organization International Clinical Trials Platform ( http://www.who.int/trialsearch/Default.aspx) to identify ongoing trials and screened reference lists of retrieved review articles and trials to identify potentially relevant studies. All searches were up to date as of March 2013. Pharmaceutical companies and authors of published articles were contacted. We searched the websites of the regulatory agencies using the keyword 'diacerein' in November 2013. No language restrictions were applied. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomised controlled trials that compared diacerein with placebo or another active pharmacological intervention in participants with OA. DATA COLLECTION AND ANALYSIS: Data abstraction and quality assessment were performed by two independent investigators, and their results were compared. The Cochrane risk of bias tool was used. The quality of evidence obtained was assessed using the GRADE approach. MAIN RESULTS: We identified three new trials (141 participants), and this updated review now includes 10 trials, totalling 2,210 participants. The most frequent risk of bias was incomplete outcome data, identified in approximately 80% of the studies. Allocation concealment and random sequence generation were unclear in 90% and 40% of the studies, respectively, because of poor reporting.Low-quality evidence from six trials (1,283 participants) indicates that diacerein has a small beneficial effect on overall pain (measured on a 100 mm visual analogue scale) at three to 36 months (mean difference (MD) -8.65, 95% confidence interval (CI) -15.62 to -1.68), which is equivalent to a 9% pain reduction in the diacerein group (95% CI -16% to -2%) compared with the placebo group. This benefit may not be clinically significant.No statistically significant differences in physical function (4 studies, 1006 participants) were noted between the diacerein and placebo groups (Lequesne impairment index, 0 to 24 points) (MD -0.29, 95% CI -0.87 to 0.28).Low-quality evidence from two trials (616 participants) on slowing of joint space narrowing (a decrease greater than 0.50 mm) in the knee or hip favoured diacerein over placebo (risk ratio (RR) 0.85, 95% CI 0.72 to 0.99), with an absolute risk difference of -6% (95% CI -15% to 2%) and a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 8 to 203). Analysis of the knee joint alone (1 study, 170 participants) did not reach statistical significance (RR 0.94, 95% CI 0.51 to 1.74).None of the trials of diacerein versus placebo measured quality of life. According to one trial (161 participants), which compared diacerein versus non-steroidal anti-inflammatory drugs (NSAIDs), the quality of life of participants in the two groups (as assessed by the Short Form (SF)-36 health survey questionnaire (0 to 800 sum score)) did not differ significantly (MD -40.70, 95% CI -85.20 to 3.80).Low-quality evidence from seven trials showed significantly more adverse events in the diacerein group compared with the placebo group after two to 36 months, mainly diarrhoea (RR 3.52, 95% CI 2.42 to 5.11), with an absolute risk increase of 24% (95% CI 12% to 35%), and a number needed to treat for an additional harmful outcome (NNTH) of 4 (95% CI 3 to 7).No statistically significant differences in participant withdrawal due to adverse events were seen at two to 36 months for diacerein compared with placebo (RR 1.29, 95% CI 0.83 to 2.01).A search of regulatory websites found a recommendation from the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) that the marketing authorization of diacerein should be suspended across Europe because of harms (particularly the risk of severe diarrhoea and potentially harmful effects on the liver) outweighing benefits. However, this guidance is not final as the PRAC recommendation will be re-examined. AUTHORS' CONCLUSIONS: In this update, the strength of evidence for effectiveness outcomes was low to moderate. We confirmed that symptomatic benefit provided by diacerein in terms of pain reduction is minimal. The small benefit derived in terms of joint space narrowing is of questionable clinical relevance and was observed only for OA of the hip. With respect to adverse effects of diacerein, diarrhoea was most frequent. Given the recent guidance issued by the EMA recommending suspension of diacerein in Europe, the EMA website should be consulted for further recommendations regarding the use of diacerein.

Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus.

BACKGROUND: Neuropsychiatric involvement in systemic lupus erythematosus (SLE) is complex and it is an important cause of morbidity and mortality. Management of nervous system manifestations of SLE remains unsatisfactory. This is an update of a Cochrane review first published in 2000 and previously updated in 2006. OBJECTIVES: To assess the benefits and harms of cyclophosphamide and methylprednisolone in the treatment of neuropsychiatric manifestations of SLE. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, SCOPUS and WHO up to and including June 2012. We sought additional articles through handsearching in relevant journals as well as contact with experts. There were no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials that compared cyclophosphamide to methylprednisolone in patients with SLE of any age and gender and presenting with any kind of neuropsychiatric manifestations. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted, assessed and cross-checked data. We produced a 'Summary of findings' table. We presented dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). MAIN RESULTS: We did not include any new trials in this update. One randomised controlled trial of 32 patients is included. Concerning risk of bias, generation of the allocation sequence was at low risk; however, allocation concealment, blinding and selective reporting were at high risk. Treatment response, defined as 20% improvement from basal conditions by clinical, serological and specific neurological measures, was found in 94.7% (18/19) of patients using cyclophosphamide compared with 46.2% (6/13) in the methylprednisolone group at 24 months (RR 2.05, 95% CI 1.13 to 3.73). This was statistically significant and the number needed to treat for an additional beneficial outcome (NNTB) of treatment response is three. We found no statistically significant differences between the groups in damage index measurements (Systemic Lupus International Collaborating Clinics (SLICC)). The median SLE Disease Activity Index (SLEDAI) rating favoured the cyclophosphamide group. Cyclophosphamide use was associated with a reduction in prednisone requirements. All the patients in the cyclophosphamide group had electroencephalographic improvement but there was no statistically significant difference in decrease between groups in the number of monthly seizures. No statistically significant differences in adverse effects, including mortality, were reported between the groups. AUTHORS' CONCLUSIONS: This systematic review found one randomised controlled trial with a small number of patients in the different clinical subgroups of neurological manifestation. There is very low-quality evidence that cyclophosphamide is more effective in reducing symptoms of neuropsychiatric involvement in SLE compared with methylprednisolone. However, properly designed randomised controlled trials that involve large numbers of individuals, with explicit clinical and laboratory diagnostic criteria, sufficient duration of follow-up and description of all relevant outcome measures, are necessary to guide practice. As we did not find any new trials to include in this review at update, the conclusions of the review did not change.

Interventions for treating traumatised permanent front teeth: luxated (dislodged) teeth.

BACKGROUND: Dental trauma is common especially in children and young adults. One group of dento-alveolar injuries is classified as luxation. This group includes a subgroup of severe injuries where the tooth is displaced from its original position. These injuries are classified further by the direction in which the tooth has been displaced, namely: intrusion, extrusion and lateral luxation. OBJECTIVES: To evaluate the effects of a range of interventions for treating displaced luxated permanent front teeth. SEARCH METHODS: Search strategies were developed for MEDLINE via OVID and revised appropriately for the following databases: Cochrane Oral Health Group's Trials Register (to 20 August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 8), MEDLINE via OVID (1966 to August 2012), EMBASE via Elsevier (1974 to August 2012), and LILACS via BIREME (1982 to August 2012). Dissertations, Theses and Abstracts were searched as were reference lists from articles. There were no language restrictions. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of treatment interventions for displaced luxated permanent front teeth. Included trials had to have a minimum follow-up period of 12 months. DATA COLLECTION AND ANALYSIS: Two review authors independently and in duplicate assessed the eligibility of all reports identified in the searches. Authors were contacted for additional information where required. MAIN RESULTS: No randomised or quasi-randomised controlled trials were found. AUTHORS' CONCLUSIONS: We found no randomised or quasi-randomised trials of interventions to treat displaced luxated permanent front teeth. Current clinical guidelines are based on available information from case series studies and expert opinions. Randomised controlled trials in this area of dental trauma are required to robustly identify the benefits of different treatment strategies.

Immune checkpoint inhibitor-associated sarcoidosis: A usually benign disease that does not require immunotherapy discontinuation.

OBJECTIVE: To analyse the clinical patterns of sarcoidosis triggered by immune checkpoint inhibitors (ICIs) in patients with cancer. PATIENTS AND METHODS: The ImmunoCancer International Registry is a big data-sharing multidisciplinary network from 18 countries dedicated to evaluating the clinical research of immune-related adverse events related to cancer immunotherapies. RESULTS: We identified 32 patients with biopsy-proven sarcoidosis. Underlying cancer included mainly melanoma (n = 24). Cancer immunotherapy consisted of monotherapy in 19 cases (anti-PD-1 in 18 and ipilimumab in 1) or combined ipilimumab + nivolumab in 13. The time median interval between initiation of ICI and sarcoidosis diagnosis was 3 months (range, 2-29 months). The use of combined ICI was associated with a shorter delay in developing sarcoidosis symptoms. The disease was symptomatic in 19 (59%) cases with mostly cutaneous, respiratory and general symptoms. The organs involved included mainly the mediastinal lymph nodes (n = 32), the lungs (n = 11), the skin (n = 10) and the eyes (n = 5). Pulmonary computed tomography studies showed bilateral hilar lymphadenopathy in all cases. There was no severe manifestation. Specific systemic therapy was required in only 12 patients (37%): oral glucocorticoids in 9, and hydroxychloroquine in 3. ICIs were held in 25 patients (78%) and definitively discontinued in 18 (56%) patients. Seven patients continued ICI treatment with a second flare in one case. In six additional patients, an ICI was reintroduced with no harm, and sarcoidosis relapsed in one of them. CONCLUSION: Our study shows that ICI-related sarcoidosis seems to have a specific profile, possibly more benign than that of idiopathic sarcoidosis, and does not necessarily imply ICI discontinuation.

Balance training (proprioceptive training) for patients with rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis may have an increased risk of falls due to impairments in lower-extremity joints, which may result in either mobility, or postural stability problems. There is evidence in the literature suggesting that balance, agility and coordination training techniques can induce changes in lower-extremity muscle activity patterns that result in improvement in dynamic joint stability.The mechanoreceptors present in and around the joints are responsible for maintaining postural control and joint position sense. These receptors are integrated to compose the somatosensorial system. In combination with visual and auditory inputs, which improve our spatial perception even further, the systems are able to maintain a stable body posture.However, there is a lack of information on the efficacy of balance training alone in patients with rheumatoid arthritis. OBJECTIVES: To assess the effectiveness and safety of balance training (proprioceptive training) to improve functional capacity in patients with rheumatoid arthritis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 4), MEDLINE via PubMed (January 1966 to December 2008), EMBASE (January 1980 to December 2008), LILACS (January 1982 to December 2008), CINAHL (January 1982 to December 2008), PEDro and Scirus (inception to 2008). We also handsearched conference abstracts. SELECTION CRITERIA: All eligible randomised controlled trials (RCT) or controlled clinical trials (CCT) comparing balance training (proprioceptive training) with any other intervention or with no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed titles or abstracts, or both, for inclusion criteria. MAIN RESULTS: The electronic search identified 864 studies. From this search, 17 studies described general exercises in rheumatoid arthritis patients as the main topic. After analysing them, we observed that the main interventions were exercises to improve muscle strength, endurance, and dynamic exercises (swimming, walking, etc). As we did not find any studies investigating the effects of balance training alone or in combination with other therapies in patients with rheumatoid arthritis, it was not possible to include any data regarding the chosen topic in this systematic review. AUTHORS' CONCLUSIONS: There is no research available examining the efficacy of balance training alone in patients with rheumatoid arthritis. The effectiveness and safety of balance training to improve functional capacity of these patients remains unclear. We suggest that future research should give more importance to balance training by either increasing the number and duration of sessions or investigating its efficacy alone.

Effects of neuromuscular electrical stimulation combined with exercises versus an exercise program on the pain and the function in patients with knee osteoarthritis: a randomized controlled trial.

OBJECTIVES: To investigate the effect of 8 weeks of NMES + Ex (neuromuscular electrical stimulation combined with exercises) on pain and functional improvement in patients with knee osteoarthritis (OA) compared to exercise (Ex) alone. DESIGN: Randomized controlled trial. SETTING: A specialty outpatient clinic. PARTICIPANTS: Patients (N = 100; women = 86, men = 14; age range, 50-75 years) with knee OA. INTERVENTIONS: Participants were randomly assigned to NMES + Ex or Ex group. OUTCOME MEASURES: Numerical Rating Scale 0 to 10 (NRS) and the Timed Up and Go (TUG) test were the primary outcomes. The secondary outcomes used were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). RESULTS: Following the interventions, a statistically significant improvement in both groups was observed in all outcomes assessed. For the comparison between the groups, no statistically significant difference was found between the NMES + Ex and the Ex groups in NRS (P = 0.52), TUG test (P = 0.12), and aspects of WOMAC: pain (P = 0.26), function (P = 0.23), and stiffness (P = 0.63). CONCLUSION: THE addition of NMES to exercise did not improve the outcomes assessed in knee OA patients. This study was registered at the Australian Clinical Trials Registry (ACTRN012607000357459).