Sickle cell disease chronic joint pain: Clinical assessment based on maladaptive central nervous system plasticity.

Chronic joint pain (CJP) is among the significant musculoskeletal comorbidities in sickle cell disease (SCD) individuals. However, many healthcare professionals have difficulties in understanding and evaluating it. In addition, most musculoskeletal evaluation procedures do not consider central nervous system (CNS) plasticity associated with CJP, which is frequently maladaptive. This review study highlights the potential mechanisms of CNS maladaptive plasticity related to CJP in SCD and proposes reliable instruments and methods for musculoskeletal assessment adapted to those patients. A review was carried out in the PubMed and SciELO databases, searching for information that could help in the understanding of the mechanisms of CNS maladaptive plasticity related to pain in SCD and that presented assessment instruments/methods that could be used in the clinical setting by healthcare professionals who manage chronic pain in SCD individuals. Some maladaptive CNS plasticity mechanisms seem important in CJP, including the impairment of pain endogenous control systems, central sensitization, motor cortex reorganization, motor control modification, and arthrogenic muscle inhibition. Understanding the link between maladaptive CNS plasticity and CJP mechanisms and its assessment through accurate instruments and methods may help healthcare professionals to increase the quality of treatment offered to SCD patients.

Maternal and perinatal outcomes in pregnant women with sickle cell disease: an update

ABSTRACT Introduction: The aim of this study was to describe maternal and perinatal outcomes in pregnant women with sickle cell disease (SCD) followed at Santa Casa de Sao Paulo over a 10-year period (between 2010 and 2019). Method: Fifty-five records of pregnancies were analyzed among 35 women with SCD. Results: Among 29 newborns, 19 (65.5%) were full-term and 10 pre-term; 24 (82.7%) caesareans and 5 (17.2%) natural births were observed. The mean gestational age at birth and mother's age were 36.6 weeks (30-40) and 26.7 years (17-39), respectively. No maternal death was observed. The main maternal obstetric and non-obstetric complications were: preeclampsia and gestational diabetes, and vaso-occlusive crisis, urinary tract infection and acute chest syndrome, respectively. Twenty-six (47.0%) fetal deaths were observed, 24 being intrauterine fetal (14 early abortions, 10 late abortions and 2 stillbirths). Regarding the red blood cell transfusion history, 40 (72.7%) out of 55 pregnancies received transfusion. Pregnant women who received 6 or more transfusions throughout pregnancy had a significantly lower number of abortions, i.e., no cases of early abortion and only 1 case of late abortion, versus 14 and 9 cases in pregnancies with 0-5 transfusions, respectively. Despite advances in the management of SCD, pregnant women with SCD (particularly those with HbSS) are at a high risk for maternal and fetal complications, even though they are followed in reference centers. Conclusion: The lower risk of intrauterine fetal death for those women who received more transfusions throughout pregnancy observed in the current study leads us once more to raise the need for prospective, multicenter, randomized trials to determine whether the potential benefits balance the risks of prophylactic transfusions.

Maternal and perinatal outcomes in pregnant women with sickle cell disease: an update.

INTRODUCTION: The aim of this study was to describe maternal and perinatal outcomes in pregnant women with sickle cell disease (SCD) followed at Santa Casa de Sao Paulo over a 10-year period (between 2010 and 2019). METHOD: Fifty-five records of pregnancies were analyzed among 35 women with SCD. RESULTS: Among 29 newborns, 19 (65.5%) were full-term and 10 pre-term; 24 (82.7%) caesareans and 5 (17.2%) natural births were observed. The mean gestational age at birth and mother`s age were 36.6 weeks (30-40) and 26.7 years (17-39), respectively. No maternal death was observed. The main maternal obstetric and non-obstetric complications were: pre-eclampsia and gestational diabetes, and vaso-occlusive crisis, urinary tract infection and acute chest syndrome, respectively. Twenty-six (47.0%) fetal deaths were observed, 24 being intrauterine fetal (14 early abortions, 10 late abortions and 2 stillbirths). Regarding the red blood cell transfusion history, 40 (72.7%) out of 55 pregnancies received transfusion. Pregnant women who received 6 or more transfusions throughout pregnancy had a significantly lower number of abortions, i.e., no cases of early abortion and only 1 case of late abortion, versus 14 and 9 cases in pregnancies with 0-5 transfusions, respectively. Despite advances in the management of SCD, pregnant women with SCD (particularly those with HbSS) are at a high risk for maternal and fetal complications, even though they are followed in reference centers. CONCLUSION: The lower risk of intrauterine fetal death for those women who received more transfusions throughout pregnancy observed in the current study leads us once more to raise the need for prospective, multicenter, randomized trials to determine whether the potential benefits balance the risks of prophylactic transfusions.

Predicting risk factors for thromboembolic complications in patients with sickle cell anaemia - lessons learned for prophylaxis.

OBJECTIVE: To assess the clinical and laboratory predictors of venous thromboembolism (VTE) in patients with sickle cell anaemia (SCA) and its relationship to morbidity and mortality. METHODS: This retrospective case-control study analysed data from patients with SCA that experienced VTE compared with matched control patients with SCA but no VTE (2:1 ratio). RESULTS: A total of 102 patients with SCA were enrolled (68 cases with VTE and 34 controls). Amongst the 68 cases (median age, 29.5 years), 26 (38.2%) presented with isolated pulmonary embolism (PE). A higher prevalence of splenectomy (73.5% versus 35.3%) was observed in the cases compared with the controls. A significantly higher prevalence of central venous catheter (CVC) insertion (42.6% versus 8.8%) was observed in the cases compared with the controls. High white blood cell counts, serum lactic dehydrogenase (LDH), bilirubin and C-reactive protein (CRP) and low haemoglobin (Hb) and HbF were significant risk factors for VTE. Forty-two cases (61.8%) developed acute chest syndrome, 10 (14.7%) had a stroke and seven (10.3%) died. CONCLUSIONS: VTE in patients with SCA has a high impact on morbidity and mortality. PE was the leading presentation of VTE, with CVC insertion, high LDH, bilirubin, CRP and white blood cell counts along with low Hb and HbF constituting other significant risk factors.

Time to rethink haemoglobin threshold guidelines in sickle cell disease.

Alleviating anaemia in patients with sickle cell disease (SCD) is crucial in managing acute complications, mitigating end-organ damage and preventing early mortality. Some disease-modifying and curative therapies have increased haemoglobin (Hb) levels to exceed 100 g/l, a threshold above which complications from red blood cell (RBC) transfusions have occurred, raising concern about whole-blood viscosity-related complications with these therapies. Here we discuss the rationale behind this limit, the effect of viscosity on blood flow and the applicability of this Hb threshold to therapies for SCD beyond RBC transfusions.

Opioids are not a major cause of death of patients with sickle cell disease.

According to the Center of Disease Control and Prevention (CDC) database, the total number of deaths due to opioid overdose from 1999 through 2018 was 840,629. Given the alarming nature of these statistics, patients who requested prescription for opioids became targets of suspicion and possible accusation of maladaptive behavior. Patients with sickle cell disease (SCD) were often not exempt from such accusations and became guilty by association. In order to clarify the effect of opioids on the mortality of patients with SCD, the mortality rates for children and adults with SCD were investigated using the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) Multiple Cause of Death database which is based on all the death certificates issued in the USA from 1999 to 2018. The data showed that 15,765 patients with SCD died from 1999 to 2018. Only 348 patients with SCD died due to opioids. The CDC database contains 27 categories of death based on ICD-10 codes in patients with SCD, and opioids were the 19th ranking cause of death. Surprisingly the most common causes of death of patients with SCD included circulatory, infection, respiratory, genitourinary, and vaso-occlusive crises/acute chest syndrome disorders in decreasing frequency. The mean age of death of females was 41.9 years and of males 39.3 years (p < 0.0001). Death due to SCD and death due to SCD and opioids were highest in the Southern Region of the USA.

Determinants of the Outcome of the Transition of Children with Sickle Cell Disease to Adult Programs.

Transition of adolescents with sickle cell disease to adult programs is associated with increased morbidity and mortality. The reasons for this poor outcome are not well known. This report describes the various factors that affect the outcome of the transition process. These include four inter-personal factors: country of residence, region within the country of residence, the health care system and intra-personal factors. Each factor is described in some detail. Understanding these factors and the establishment of guidelines or recommendations could improve the outcome of this critical transition in the life of patients with sickle cell disease.

Opioids and Sickle Cell Disease: From Opium to the Opioid Epidemic.

Sickle cell disease (SCD) is an inherited disorder of hemoglobin structure. The clinical effects of the sickle gene are pleiotropic in nature causing multiple phenotypic expressions associated with the various complications of the disease. The hallmark of the disease is pain that could be acute, chronic, nociceptive, or neuropathic that could occur singly or in various combinations. The acute vaso-occlusive painful crisis (VOC) is the most common cause of admissions to the Emergency Department and/or the hospital. Although progress has been made in understanding the pathophysiology of SCD as well as in developing preventive and curative therapies, effective pain management continues to lag behind and depend mostly on the use of opioids. This review describes the history of opioids from the ancient times of opium to the current use of the many controversial opioids. In addition, the major cause of death of patients with SCD is the complications of the disease itself and not the use of opioids. The use of opioids by patients with SCD has been stable over the years. Judicious use of opioids to treat sickle cell pain according to available guidelines could minimize the unnecessary suffering experienced by patients with SCD.

Case Series and Review of Hematological and Non-Hematological Malignancies in Aging Patients with Sickle Cell Disease in the Hydroxyurea Era.

Survival of adult patients with sickle cell disease has increased progressively since the 1970s. Aging patients with sickle cell disease are at risk of developing comorbidities that are not due to sickle cell disease itself, including malignancies. Many studies tried to assess the incidence of malignancy in patients with sickle cell disease. However, no studies have been done to evaluate cancer incidences in aging sickle cell patients, especially in the hydroxyurea (HU) era. In this review, we assessed the prevalence of malignancies in aging patients with sickle cell disease at our institution with or without HU therapy. Retrospective analysis of hospital records identified patients who had been diagnosed to carry sickle cell disease and malignancies before 2020 using the International Statistical Classification of Diseases and Related Health Problems (ICD-10) coding. Four hundred and eighty-three sickle cell disease patients were seen in our inpatients/outpatients offices. Among these, 12 sickle cell disease patients had a confirmed diagnosis of malignancy. The patients were classified into three categories based on age groups: four patients who were 60 years and older had multiple myeloma. Solid tumors were found in 5/6 patients, aged 40-60 who had the Hb S (HBB: c.20A>T) (ßS/ßS) genotype with signs of iron overload. Two patients, aged 25 and 35, had hematological malignancies. The number of patients on HU was too small to make any comment on relationship to malignancy or mortality. This study is only one institution's experience, further investigation on a larger scale is needed to look into cancer incidences in this population.

How I Treat Acute and Persistent Sickle Cell Pain.

Sickle pain is the hallmark of sickle cell disease (SCD). It could be acute, persistent/relapsing, chronic, or neuropathic. Although there is a general consensus that pain is a major manifestation of SCD, there is a controversy as to the types of pain and their interrelationship between acute, chronic, relapsing, persistent, etc. This report first reviews the general approach to the management of acute vaso-occlusive crisis (VOC) pain, including education, counseling, pharmacotherapy, non-pharmacotherapy, and fluid therapy. This is followed by the presentation of five patients that represent typical issues that are commonly encountered in the management of patients with SCD. These issues are: individualized treatment of pain, bilaterality of pain, use of illicit drugs, tolerance to opioids, opioid-induced hyperalgesia, and withdrawal syndrome. The clinical aspects and management of each of these issues are described. Moreover, such complications as tolerance and withdrawal may persist after discharge and may be mistaken as chronic pain rather than resolving, persistent or relapsing pain.

Risk factors associated with increased emergency department utilization in patients with sickle cell disease: a systematic literature review.

Sickle cell disease (SCD), a genetic disorder affecting up to 100,000 patients in the USA, impacts multiple organ systems. The emergency department (ED) is frequently utilized by patients with SCD who have severe pain from vaso-occlusive crises. The goal of this systematic literature review is to identify predictors for ED use among patients with SCD in the USA, as high ED reliance is not ideal because of the potential for discontinuity of care as well as higher costs. PubMed and Embase were searched for articles containing the keywords "sickle cell disease" AND ("emergency" OR "acute care") AND ("utilization" OR "health care") published between 2000 and 26 September 2019. A total of 26 publications were identified meeting the following inclusion criteria: report of ED or acute care clinic use; report of health care utilization for SCD; and report of ED visits independent of hospital admission, ED revisits, inpatient care visits, and SCD care unit visits. Articles unavailable in English or those focused on populations outside the USA were excluded. Of the 26 articles included, 4 were prospective and the remainder were retrospective. Qualitative analysis of the articles revealed a higher rate of ED utilization among adults than children, patients with public insurance than private insurance, and patients with more comorbidities, complications, or pain. Age and pain levels were both commonly cited as predictors of ED utilization. Additional prospective and interventional studies are needed to further define predictors of ED utilization and to uncover treatments that decrease ED visits.

The vaso-occlusive pain crisis in sickle cell disease: Definition, pathophysiology, and management.

Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) are critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. The development of agents for prevention and treatment of VOCs should be driven by our understanding of its pathophysiology.

Transcutaneous electrical nerve stimulation (TENS) for pain management in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD), one of the most common inherited disorders, is associated with vaso-occlusive pain episodes and haemolysis leading to recurrent morbidity, hospital admissions and work or school absenteeism. The crises are conventionally treated with opioids, non-opioids and other adjuvants with the risk of developing complications, addictions and drug-seeking behaviour. Different non-pharmacological treatments, such as transcutaneous electrical nerve stimulation (TENS) have been used for managing pain in other painful conditions. Hence, the efficacy of TENS for managing pain in SCD needs to be reviewed. OBJECTIVES: To assess the benefits and harms of TENS for managing pain in people with SCD who experience pain crises or chronic pain (or both). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries and the reference lists of relevant articles and reviews. Date of the last search: 26 Febraury 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs, where TENS was evaluated for managing pain in people with SCD. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of the trials identified by the literature searches according to the inclusion criteria. Two review authors then independently extracted data, assessed for risk of bias using the Cochrane standard tool and rated the quality of evidence using the GRADE guidelines. MAIN RESULTS: One double-blind cross-over RCT with 22 participants with SCD (aged 12 to 27 years) was eligible for inclusion. Following stratification into four pain crises severity grades, participants were then randomised to receive TENS or placebo (sham TENS). The trial was concluded after 60 treatment episodes (30 treatment episodes of each treatment group). There is a lack of clarity regarding the trial design and the analysis of the cross-over data. If a participant was allocated to TENS treatment for an episode of pain and subsequently returned with a further episode of a similar degree of pain, they would then receive the sham TENS treatment (cross-over design). For those experiencing a pain episode of a different severity, it is not clear whether they were re-randomised or given the alternate treatment. Reporting and analysis was based on the total number pain events and not on the number of participants. It is unclear how many participants were crossed over from the TENS group to the sham TENS group and vice versa. The trial had a high risk of bias regarding random sequence generation and allocation concealment; an unclear risk regarding the blinding of participants and personnel; and a low risk regarding the blinding of the outcome assessors and selective outcome reporting. The trial was small and of very low quality; furthermore, given the issue with trial design we were unable to quantitatively analyse the data. Therefore, we present only a narrative summary and caution is advised in interpreting the results. In relation to our pre-defined primary outcomes, the included trial did not report pain relief at two to four weeks post intervention. The trial authors reported that no difference was found in the changes in pain ratings (recorded at one hour and four hours post intervention) between the TENS and the placebo groups. In relation to our secondary outcomes, the analgesic usage during the trial also did not show any difference between groups. Given the quality of the evidence, we are uncertain whether TENS improves overall satisfaction as compared to sham TENS. The ability to cope with activities of daily living was not evaluated. Regarding adverse events, although one case of itching was reported in the TENS group, the site and nature of itching was not clearly stated; hence it cannot be clearly attributed to TENS. Also, two participants receiving 'sham' TENS reported a worsening of pain with the intervention. AUTHORS' CONCLUSIONS: Since we have only included one small and very low-quality trial, with a high risk of bias across several domains, we are unable to conclude whether TENS is harmful or beneficial for managing pain in people with SCD. There is a need for a well-designed, adequately-powered, RCT to evaluate the role of TENS in managing pain in people with SCD.

Review/overview of pain in sickle cell disease.

Sickle cell disease (SCD) is a highly complex inherited disorder of hemoglobin structure. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of the disease. Its manifestations could be acute, chronic, nociceptive, neuropathic that could occur singly or in various combinations. Pain continues to be the major factor of SCD phenotypic complications and the most common cause of admissions to the Emergency Department and/or the hospital. Although progress has been made in understanding the pathophysiology of SCD as well as in developing curative therapies such as hematopoietic stem cell transplantation and gene therapy, effective pain management continues to lag behind. Palliative therapies continue to be the major approach to the management of SCD and its complications. The advent of hydroxyurea made partial success in preventing the frequency of vaso-occlusive crises and l-glutamine awaits post-trial confirmation of benefits. The search for additional pharmacotherapeutic agents that could be used singly or in combination with hydroxyurea and/or l-glutamine awaits their dawn hopefully in the near future. The purpose of this review is to describe the various manifestations of SCD, their pathophysiology and their current management. Recent impressive advances in understanding the pathophysiology of pain promise the determination of agents that could replace or minimize the use of opioids.

Predictors of impending acute chest syndrome in patients with sickle cell anaemia.

Acute chest syndrome (ACS) is a major complication of sickle cell anaemia (SCA) and a leading cause for hospital admissions and death. We aimed to study the spectrum of clinical and laboratory features of ACS and to assess the predisposing factors and predictors of severity. A retrospective case-control cohort was studied by retrieving patient information from electronic medical records after ethical approval. One hundred adolescents and adults with SCA and hospital admissions for ACS were identified through the discharge summaries, along with 20 additional patients presenting with VOC, but without ACS (controls). Among the patients with ACS, fever (>38.5 °C), reduced oxygen saturation (<95) and asplenia significantly differed when compared to those of controls (p < 0.05, chi-squared test). The degree of severity was reflected in the use of non-invasive ventilation (NIV), simple and exchange transfusions, and the presence of bilateral pleural effusions and multi-lobar atelectasis/consolidation, which were significantly higher in the cases with ACS than in the controls. Lower haemoglobin (Hb) and high WBC counts were also significantly different between the two groups (p < 0.05, Student's t test). Using logistic regression, our study further demonstrated that asplenia, fever, and reduced O2 saturation, along with low Hb and leukocytosis, were important predictors for the development of ACS.

The Evolving Pharmacotherapeutic Landscape for the Treatment of Sickle Cell Disease.

Sickle cell disease (SCD) is an extremely heterogeneous disease that has been associated with global morbidity and early mortality. More effective and inexpensive therapies are needed. During the last five years, the landscape of the pharmacotherapy of SCD has changed dramatically. Currently, 54 drugs have been used or under consideration to use for the treatment of SCD. These fall into 3 categories: the first category includes the four drugs (Hydroxyurea, L-Glutamine, Crizanlizumab tmca and Voxelotor) that have been approved by the United States Food and Drug Administration (FDA) based on successful clinical trials. The second category includes 22 drugs that failed, discontinued or terminated for now and the third category includes 28 drugs that are actively being considered for the treatment of SCD. Crizanlizumab and Voxelotor are included in the first and third categories because they have been used in more than one trial. New therapies targeting multiple pathways in the complex pathophysiology of SCD have been achieved or are under continued investigation. The emerging trend seems to be the use of multimodal drugs (i.e. drugs that have different mechanisms of action) to treat SCD similar to the use of multiple chemotherapeutic agents to treat cancer.

Randomized clinical trial of computerized PAINRelieveIt® for patients with sickle cell disease: PAINReportIt® and PAINUCope®.

OBJECTIVE: To compare effects of a tailored multimedia education program versus usual-care on barriers to pain management of adult patients with SCD. METHODS: Pretest/posttest randomized controlled trial (RCT) of 228 outpatients with SCD randomized to the tablet-based PAINUCope intervention focused on barriers to pain management, pain, and analgesic adherence or selection of games (control). Outcomes were barriers to pain management, pain, and analgesic adherence. RESULTS: The barriers to pain management and pain scores did not change significantly from pretest to posttest for either condition. Changes in analgesic adherence rates from pretest to posttest were statistically significant for the intervention group (p = .046) but not for the usual care group (p = .419). The group difference was not statistically significant. CONCLUSIONS: This first RCT of a tailored multimedia education intervention with adult patients with SCD did not significantly reduce the outcomes of interest compared to the control group. Findings provide insights for improving intervention delivery and reinforcement of patient behaviors. PRACTICE IMPLICATIONS: Study redesign is warranted with modifications that include theoretical and methodological approaches and patient-centered delivery of the intervention that take advantage of recent technology developments.