Estimating the prevalence and predictors of musculoskeletal disorders in Tanzania: a cross-sectional pilot study.

Introduction: musculoskeletal (MSK) disorders account for approximately 20% of all years lived with disability worldwide however studies of MSK disorders in Africa are scarce. This pilot study aimed to estimate the community-based prevalence of MSK disorders, identify predictors, and assess the associated disability in a Tanzanian population. Methods: a cross-sectional study was conducted in one village in the Kilimanjaro region from March to June 2019. The Gait, Arms, Legs, Spine (GALS) or paediatric GALS (pGALS) examinations were used during household and school visits. Individuals positive in GALS/pGALS screening were assessed by the regional examination of the musculoskeletal system (REMS) and Modified Health Assessment Questionnaire (MHAQ). Results: among the 1,172 individuals enrolled in households, 95 (8.1%, 95% CI: 6.6 - 9.8) showed signs of MSK disorders using the GALS/pGALS examination and 37 (3.2%, 95% CI: 2.2 - 4.3) using the REMS. Among 682 schools enrolled children, seven showed signs of MSK disorders using the GALS/pGALS examination (1.0%, 95% CI: 0.4 - 2.1) and three using the REMS (0.4%, 95% CI: 0.0 - 1.3). In the household-enrolled adult population, female gender and increasing age were associated with GALS and REMS-positive findings. Among GALS-positive adults, increasing age was associated with REMS-positive status and increasing MHAQ score. Conclusion: this Tanzanian study demonstrates a prevalence of MSK disorders and identifies predictors of MSK disorders comparable to those seen globally. These findings can inform the development of rheumatology services and interventions in Tanzania and the design of future investigations of the determinants of MSK disorders, and their impacts on health, livelihoods, and well-being.

Four-factor risk score for the prediction of interstitial lung disease in rheumatoid arthritis.

OBJECTIVE: Interstitial lung disease (ILD) is one of the commonest systemic complications in patients with rheumatoid arthritis (RA) and carries a significant morbidity and mortality burden. We aimed to identify key variables to risk-stratify RA patients in order to identify those at increased risk of developing ILD. We propose a probability score based on the identification of these variables. METHODS: A retrospective, multicentre study using clinical data collected between 2010 and 2020, across 20 centres. RESULTS: A total of 430 RA (210 with ILD confirmed on high-resolution computed tomography (HRCT)) patients were evaluated. We explored several independent variables for the risk of developing ILD in RA and found that the key significant variables were smoking (past or present), older age and positive rheumatoid factor/anti-cyclic citrullinated peptide. Multivariate logistic regression models were used to form a scoring system for categorising patients into high and low risk on a scale of 0-9 points and a cut-off score of 5, based on the area under the receiver operating characteristic curve of 0.76 (CI 95% 0.71-0.82). This yielded a sensitivity of 86% and a specificity of 58%. High-risk patients should be considered for investigation with HRCT and monitored closely. CONCLUSION: We have proposed a new model for identifying RA patients at risk of developing ILD. This approach identified four simple clinical variables: age, anti-cyclic citrullinated peptide antibodies, Rheumatoid factor and smoking, which allowed development of a predictive scoring system for the presence of ILD in patients with RA.

How to differentiate between Eosinophilic Granulomatous Polyangiitis and Henoch-Schönlein Purpura.

We present a 29-year-old gentleman admitted with eight years of recurrent, bilateral, erythematous, macular rash involving the legs, occurring every summer. Other symptoms included intermittent joint aches with dysaesthesia. He was investigated previously with a renal biopsy, a skin biopsy and endoscopy and had been diagnosed as Henoch-Schönlein Purpura (HSP). However, his past medical history included progressive asthma and sinusitis. Investigations revealed peripheral eosinophilia, positive rheumatoid factor and elevated IgE levels with mild renal impairment. During admission, he became hypoxic. A CT pulmonary angiogram (CTPA) showed changes consistent with early pulmonary manifestations of EGPA, which improved on a repeat scan after commencing the patient on high dose prednisolone. Revising the diagnosis, his condition fulfilled criteria for ANCA negative EGPA rather than HSP.

The spectrum and burden of in-patient paediatric musculoskeletal diseases in Northern Tanzania.

BACKGROUND: Musculoskeletal diseases (MSD) are a major contributor to the global burden of disease and disability, and disproportionally affect low- and middle-income countries; however, there is a dearth of epidemiological data. Affected children often face increased morbidity, social isolation and economic hardship. AIM: To assess the spectrum and burden of paediatric MSD in children aged 5-18 years admitted to a major referral hospital in Tanzania. METHODS: This was a retrospective cohort study of children aged 5-18 years admitted to Kilimanjaro Christian Medical Centre (KCMC) whose initial diagnosis was recognised as a musculoskeletal condition by the International Classification of Diseases-10 between 1 January and 31 December 2017. RESULTS: During 2017, 163 cases of confirmed paediatric MSD were admitted to KCMC, representing 21.2% of all admissions of children aged 5-18 years (n = 769). Bone disease was the most common diagnosis. They comprised 106 (65.0%) traumatic fractures, 31 (19.0%) osteo-articular infections, 9 (5.5%) malunions and 3 (1.8%) pathological fractures. Congenital defects and rheumatic disease were relatively uncommon, accounting for only 6 (3.7%) and 4 (2.5%) MSD admissions, respectively. CONCLUSION: The majority of cases of MSD were related to fractures, followed by osteo-articular infections, while recognised cases of rheumatic disease were rare. The study, although small, identified the sizeable burden and spectrum of paediatric MSD admitted to a hospital in Tanzania over a 12-month period and highlights the need for larger studies to inform the optimal allocation of health resources. ABBREVIATION: CI: confidence interval; HIC: high-income countries; HIV: human immunodeficiency virus; ICD-10: International Classification of Diseases 10; IQR: interquartile range; JIA: juvenile idiopathic arthritis; KCMC: Kilimanjaro Christian Medical Centre; LMIC: low- and middle-income countries; MSD: musculoskeletal diseases: NAI: non-accidental injury; NIHR: National Institute for Health Research; PAFLAR: Paediatric Society of the African League Against Rheumatism; RTA: road traffic accidents; SCD: sickle cell disease; SLE: systemic lupus erythematosus; SSA: sub-Saharan Africa.

Nintedanib in Patients With Autoimmune Disease-Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the INBUILD Trial.

OBJECTIVE: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype. METHODS: The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs. RESULTS: Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively. CONCLUSION: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients.

Prior COVID-19 infection is associated with increased Adverse Events (AEs) after the first, but not the second, dose of the BNT162b2/Pfizer vaccine.

The BNT162b2/Pfizer SARS-CoV-2 vaccine has been widely used in the UK, particularly amongst healthcare workers (HCWs). To establish whether previous COVID-19 influenced vaccine-associated Adverse Events (AEs), we conducted a survey-based study of HCWs in Northeast England. Out of 1238 HCWs, 32% self-reported prior positive PCR and/or antibody test for SARS-CoV-2. Post-dose AEs were worse in those with prior COVID-19 after the first, but not the second dose of vaccine. Second dose AEs were greater in frequency/severity, regardless of COVID-19 history, and they were more systemic in nature. Women and younger HCW were more likely to report AEs after both doses, while dosing interval had no effect on AEs. Ongoing Symptomatic COVID-19 was associated with greater frequency/severity of AEs after dose 2, but not dose one. Overall, AEs were self-limiting and short-lived (i.e.,<48 h) in nature. These findings have implications for vaccine hesitancy and informing guidelines for recommended dosing protocols.

There are similarities between rheumatic disease with lung involvement and COVID-19 pneumonia.

INTRODUCTION: There is considerable overlap between the clinical manifestations of covid-19 pneumonia and the acute interstitial lung disease seen in certain rheumatic disorders. In addition, pulmonary fibrosis is increasingly recognised as a potentially serious consequence of both. METHODS: This review explores this overlap of clinical features, risk factors and causation, offering insights into the immune mechanisms that contribute to both sets of disorders. RESULTS: The therapeutic role of immunosuppression and biologic agents in the treatment of covid-19 is explained in the light of this. DISCUSSION: We propose how lessons learned from the insights recently gained into each disorder can improve our insight into immunological mechanisms and application of therapeutic interventions in the other.

Symptoms and predictors of depression among university students in the Kilimanjaro region of Tanzania: a cross-sectional study.

BACKGROUND: Depression is the second leading cause of death among young people worldwide, and severity and suicidality are useful predictors of an adverse outcome. AIM: This study aimed at examining factors associated with depression among university students in Tanzania. METHODS: A cross-sectional study was conducted between March 2018 and July 2019 of undergraduate students across four universities. They completed a self-reported questionnaire collecting socio-demographic, together with a Patient Health Questionnaire (PHQ-9) to screen for depression. A multivariate logistic regression model was used to determine independent predictors of depression. RESULTS: A total of 1047 students completed the study. Their mean (±SD) age was 24.2 (±7) years. 219 students (21.3%) screened positive for probable depression (survey-1 34% vs survey-2 13%). A total of 228 (21.9%) students reported having thoughts of serious self-harm. Factors independently influencing depression included year of study, substance abuse, unhappy interpersonal relationships and chronic mental or physical illness. The presence of an eating disorder was a predictor of depression and was recorded in 7.4% of all students. CONCLUSION: Significant probable depression is present in one fifth of undergraduate students in this study. These results demonstrate a worrying degree of self- reported features of depression among North Tanzanian university students.

Rheumatoid arthritis related interstitial lung disease - improving outcomes over 25 years: a large multicentre UK study.

OBJECTIVE: This study explores whether the prognosis of interstitial lung disease in rheumatoid arthritis (RA-ILD) has improved over time and assesses the potential influence of drug therapy in a large multicentre UK network. METHODS: We analysed data from 18 UK centres on patients meeting criteria for both RA and ILD diagnosed over a 25-year period. Data included age, disease duration, outcome and cause of death. We compared all cause and respiratory mortality between RA controls and RA-ILD patients, assessing the influence of specific drugs on mortality in four quartiles based on year of diagnosis. RESULTS: A total of 290 RA-ILD patients were identified. All cause (respiratory) mortality was increased at 30% (18%) compared with controls 21% (7%) (P =0.02). Overall, prognosis improved over quartiles with median age at death rising from 63 years to 78 years (P =0.01). No effect on mortality was detected as a result of DMARD use in RA-ILD. Relative risk (RR) of death from any cause was increased among patients who had received anti-TNF therapy [2.09 (1.1-4.0)] P =0.03, while RR was lower in those treated with rituximab [0.52(0.1-2.1)] or mycophenolate [0.65 (0.2-2.0)]. Patients receiving rituximab as their first biologic had longer three (92%), five (82%) and seven year (80%) survival than those whose first biologic was an anti-TNF agent (82%, 76% and 64%, respectively) (P =0.037). DISCUSSION: This large retrospective multicentre study demonstrates survival of patients with RA-ILD has improved. This may relate to the increasing use of specific immunosuppressive and biologic agents.

Effect of rituximab or tumour necrosis factor inhibitors on lung infection and survival in rheumatoid arthritis-associated bronchiectasis.

OBJECTIVE: To evaluate rituximab (RTX) in patients with RA-associated bronchiectasis (RA-BR) and compare 5-year respiratory survival between those treated with RTX and TNF inhibitors (TNFi). METHODS: A retrospective observational cohort study of RA-BR in RTX or TNFi-treated RA patients from two UK centres over 10 years. BR was assessed using number of infective exacerbation/year. Respiratory survival was measured from therapy initiation to discontinuation either due to lung exacerbation or lung-related deaths. RESULTS: Of 800 RTX-treated RA patients, 68 had RA-BR (prevalence 8.5%). Post-RTX, new BR was diagnosed in 3/735 patients (incidence 0.4%). At 12 months post-Cycle 1 RTX, 21/68 (31%) patients had fewer exacerbations than the year pre-RTX, 36/68 (53%) remained stable and 11/68 (16%) had increased exacerbations. The rates of exacerbation improved after Cycle 2 and stabilized up to 5 cycles. Of patients who received ≥2 RTX cycles (n = 60), increased exacerbations occurred in 7/60 (12%) and were associated with low IgG, aspergillosis and concurrent alpha-1-antitrypsin deficiency. Overall, 8/68 (11.8%) patients discontinued RTX while 15/46 (32.6%) discontinued TNFi due to respiratory causes. The adjusted 5-year respiratory survival was better in RTX-treated compared with TNFi-treated RA-BR patients; HR 0.40 (95% CI 0.17, 0.96); P =0.041. CONCLUSION: The majority of RTX-treated RA-BR patients had stable/improved pulmonary symptoms in this long-term follow-up. In isolated cases, worsening of exacerbation had definable causes. Rates of discontinuation due to adverse lung outcomes were better for RTX than a matched TNFi cohort. RTX is an acceptable therapeutic choice for RA-BR if a biologic is needed.

Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes.

The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.

Patient-reported involvement of the eighth cranial nerve in giant cell arteritis.

INTRODUCTION: The frequency of eighth nerve lesions in patients with giant cell arteritis (GCA) has rarely been examined. However, sudden onset deafness has been recorded as a presenting feature of GCA on several occasions. This study sought to establish how common this and other symptoms of eighth nerve involvement are in a large retrospective survey. METHODS: We contacted 170 patients with GCA and 250 matched PMR patients, inviting them to participate in a questionnaire survey of symptoms of eighth nerve dysfunction. We compared the presence of deafness, tinnitus, loss of balance and vertigo in both groups and examined the relationship between the onset of these symptoms and other features of GCA. RESULTS: A total of 317 patients were recruited. The percentage of patients with symptoms of possible vestibulocochlear disease prior to commencement of steroid therapy was significantly greater among GCA patients than PMR patients for all domains. Hearing loss which was twice as common in GCA as in PMR (53% vs 26%) [p = 0.001]. Deafness was concurrent in 35% of GCA patients with other symptoms and 45% reported colocation with headache. Recovery with steroids occurred in 56% of these. CONCLUSION: Symptoms of eighth nerve dysfunction are present in over half of patients with GCA. Recovery with steroids was predicted by concurrence with headache in terms of both timing and location. It appears that eighth nerve involvement, especially acute hearing loss, is a not infrequent feature of GCA and often responds well to steroid therapy. Clinicians should enquire about these symptoms when evaluating a patient for possible GCA.Key Points• Deafness is a frequent presenting feature of giant cell arteritis.• Vertigo, tinnitus and loss of balance are also often reported by GCA sufferers.• Steroid therapy is more likely to relieve these symptoms if they are ipsilateral and concurrent with headache.

Mortality in patients with interstitial lung disease treated with rituximab or TNFi as a first biologic.

OBJECTIVES: Guidelines cautioned prescribing of tumour necrosis factor inhibitors (TNFi) to patients with rheumatoid arthritis and interstitial lung disease (RA-ILD) after reports of new or worsening of ILD. Less is known about outcomes among patients with RA-ILD who receive rituximab (RTX). This study compares mortality in patients with RA-ILD who received RTX or TNFi as their first biologic. METHODS: Participants with RA-ILD recruited to the British Society for Rheumatology Biologics Register for RA were included. Death rates were calculated and risk comparisons were made using Cox regression. Causes of death, including the frequency in which ILD was recorded on death certificates were examined. RESULTS: 43 patients on RTX and 309 on TNFi were included. RTX recipients had shorter disease duration and less disability. Death rates were 94.8 (95%CI: 74.4 to 118.7) and 53.0 (22.9 to 104.6) per 1000 person years, respectively. The adjusted mortality risk was halved in the RTX cohort, but the difference was not statistically significant (HR 0.53, 95% CI: 0.26 to 1.10). ILD was the underlying cause of death in 1 of 7 RTX deaths (14%) and 12 of 76 TNFi deaths (16%). CONCLUSIONS: Patients with RA-ILD who received RTX had lower mortality rates compared to TNFi. The absence of information on ILD severity or subtype prevents conclusions of which drug represents the best choice in patients with RA-ILD and active arthritis.

Heightened autoantibody immune response to citrullinated calreticulin in bronchiectasis: Implications for rheumatoid arthritis.

Calreticulin (CRT) and citrullinated (citCRT) are implicated in rheumatoid arthritis (RA) pathology. citCRT binds to RA shared epitopes (SE) on HLA-DR molecules with high affinity and triggers pro-inflammatory events in adjacent cells. The aim of the study was to detect the presence of citCRT prior to developing RA and evaluate if citCT is a target for autoantibodies in RA cohorts with and without lung disease. Antibodies were assessed by ELISA against native CRT, citCRT and general protein citrullination, in sera from 50 RA patients without lung disease, 122 bronchiectasis (BR) patients, 52 bronchiectasis patients with RA (BRRA), 87 asthma patients and 77 healthy controls (HC). Serum citCRT was detected by immunoblotting and mass spectrometry. Genomic DNA was genotyped for HLA-DRB1 alleles. Patients were assessed for DAS28, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies. Extracellular citCRT was detected in BR patients sera prior to them developing RA. A citCRT SE binding peptide GEWKPR261citQIDNPDYK was identified. Anti-CRT antibodies were observed in 18% of BR patients with or without RA. Anti-citCRT antibodies were observed in ∼35% of BR or RA patients, increasing to 58% in BRRA patients. In the RA alone patients 7/20 (35%) who were negative for RF and anti-CCP were anti-CRT antibody positive and had higher DAS28 scores than triple negative RA alone patients. Three of the four BR patients who developed RA over 18 months were anti-citCRT+ve SE+ve. The detection of citCRT in BR and development of anti-citCRT in BR patients suggests citCRT antigens are early targets of antigenicity in these patients, especially in SE+ve patients prior to the onset of RA.