ATRPred: A machine learning based tool for clinical decision making of anti-TNF treatment in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic autoimmune condition, characterised by joint pain, damage and disability, which can be addressed in a high proportion of patients by timely use of targeted biologic treatments. However, the patients, non-responsive to the treatments often suffer from refractoriness of the disease, leading to poor quality of life. Additionally, the biologic treatments are expensive. We obtained plasma samples from N = 144 participants with RA, who were about to commence anti-tumour necrosis factor (anti-TNF) therapy. These samples were sent to Olink Proteomics, Uppsala, Sweden, where proximity extension assays of 4 panels, containing 92 proteins each, were performed. A total of n = 89 samples of patients passed the quality control of anti-TNF treatment response data. The preliminary analysis of plasma protein expression values suggested that the RA population could be divided into two distinct molecular sub-groups (endotypes). However, these broad groups did not predict response to anti-TNF treatment, but were significantly different in terms of gender and their disease activity. We then labelled these patients as responders (n = 60) and non-responders (n = 29) based on the change in disease activity score (DAS) after 6 months of anti-TNF treatment and applied machine learning (ML) with a rigorous 5-fold nested cross-validation scheme to filter 17 proteins that were significantly associated with the treatment response. We have developed a ML based classifier ATRPred (anti-TNF treatment response predictor), which can predict anti-TNF treatment response in RA patients with 81% accuracy, 75% sensitivity and 86% specificity. ATRPred may aid clinicians to direct anti-TNF therapy to patients most likely to receive benefit, thus save cost as well as prevent non-responsive patients from refractory consequences. ATRPred is implemented in R.

Anti-tumour necrosis factor-alpha response associated with combined CD226 and HLA-DRB1[*]0404 haplotype in rheumatoid arthritis.

OBJECTIVES: Predicting response to anti-tumour necrosis factor alpha (anti-TNFα) drugs at baseline remains an elusive goal in rheumatoid arthritis (RA) management. The purpose of this study was to determine if baseline genetic variants of PTPRC, AFF3, myD228, CHUK, MTHFR1, MTHFR2, CD226 and a number of KIR and HLA alleles could predict response to anti-TNF-α in rheumatoid arthritis patients. METHODS: Peripheral blood samples were collected from 238 RA patients treated with anti-TNFα drugs. Genotyping was performed using biochip array technology by Randox Laboratories Ltd. and sequence specific polymerase chain reaction. Linear regression analysis was performed to investigate the role of these genotypes in predicting response to treatment, as defined by European League Against Rheumatism (EULAR) response classification and absolute change in disease activity score (DAS28). RESULTS: Of 238 RA patients analysed, 50.4% received adalimumab, 29.7% received etanercept, 14.8% received infliximab, 3.4% certoluzimab and 1.7% golimumab. The MTHFR1 variant rs1801133 was significantly associated with the EULAR response, p=0.044. Patients with the HLA-DRB1*0404 allele displayed a significantly larger reduction in DAS28 compared to non-carriers (mean -2.22, -1.67 respectively, p=0.033). CD226 rs763361 was the only SNP variant significantly associated with ΔDAS28 (p=0.029). CONCLUSIONS: This study has investigated individual allele associations with reductions in DAS28 across a range of anti-TNFα treatments. A combined predictive model indicates that patients with the HLA-DRB1*0404 allele and without the CD226 rs763361 polymorphism exhibit the largest reduction in DAS28 after anti-TNF-α treatment.

Senescence Biomarkers CKAP4 and PTX3 Stratify Severe Kidney Disease Patients.

INTRODUCTION: Cellular senescence is the irreversible growth arrest subsequent to oncogenic mutations, DNA damage, or metabolic insult. Senescence is associated with ageing and chronic age associated diseases such as cardiovascular disease and diabetes. The involvement of cellular senescence in acute kidney injury (AKI) and chronic kidney disease (CKD) is not fully understood. However, recent studies suggest that such patients have a higher-than-normal level of cellular senescence and accelerated ageing. METHODS: This study aimed to discover key biomarkers of senescence in AKI and CKD patients compared to other chronic ageing diseases in controls using OLINK proteomics. RESULTS: We show that senescence proteins CKAP4 (p-value < 0.0001) and PTX3 (p-value < 0.0001) are upregulated in AKI and CKD patients compared with controls with chronic diseases, suggesting the proteins may play a role in overall kidney disease development. CONCLUSIONS: CKAP4 was found to be differentially expressed in both AKI and CKD when compared to UHCs; hence, this biomarker could be a prognostic senescence biomarker of both AKI and CKD.

Effects of TNF-α inhibition versus secukinumab on active ultrasound-confirmed enthesitis in psoriatic arthritis.

Introduction: Enthesitis is a hallmark of psoriatic disease, but its clinical assessment is problematic in terms of diagnostic sensitivity and overlap with other comorbid conditions. Ultrasound is a useful tool that can give a more detailed assessment of enthesitis. Research demonstrates that those with persistent ultrasound entheseal disease are at risk of progressive articular damage. With limited data to guide choice between biologic therapy for psoriatic arthritis (PsA) patients, we wanted to assess the response of ultrasound-confirmed enthesitis to different forms of biologic therapies and study its utility in making more informed decisions. Methods: This was an open label observational study including patients aged ⩾18 years, who fulfil the classification criteria for PSA (CASPAR) and were due to commence on their first biologic therapy. The primary outcome was the change in MAdrid Sonographic Enthesitis Index (MASEI) score at 16 weeks of treatment. The MASEI score was also modified to assess the active elementary lesions (ActiveMASEI). Results: In all, 80 PsA patients were enrolled with 75 patients completing the study [secukinumab n = 23 and tumour necrosis factor inhibitor (TNFi) n = 52]. The mean reduction in MASEI score after 16 weeks of treatment was 3.42 with TNFi versus 1.74 with secukinumab (p = 0.097). There was a significant difference in the change in the MASEIActive score for TNFi versus secukinumab (4.37 versus 2.26; p = 0.030) and this difference was more pronounced when only power Doppler signal within 2 mm of the enthesis insertion was included (4.37 versus 2.00; p = 0.007). Clinical outcomes were similar for both classes of biologic apart from a significant reduction in regards to the Dermatology Life Quality Index and Psoriasis Area and Severity Index score with secukinumab versus TNFi. Conclusions: We have for the first time compared the effect of ultrasound-confirmed enthesitis between different forms of biologic therapies for PsA. We have seen an overall improvement in entheseal scores for both classes of medications and demonstrated a larger reduction in active entheseal disease for TNFi versus secukinumab that merits further exploration.

Introduction: An enthesis is the point at which ligament and tendon insert into the bone and enthesitis is the inflammation at these sites causing pain and reduced function.Enthesitis is particularly common in patients with psoriatic arthritis and it has been shown to be important in the development, diagnosis and prognosis of the condition. Clinical examination has limitations and imaging techniques like ultrasound have been proven to give a more detailed assessment of enthesitis potentially revealing clues to the condition itself. In psoriatic arthritis, we do not have a good way of choosing between biologic therapies that can treat inflammation. With a better understanding of enthesitis and its response to various therapies, we may be able to make better decisions. We wanted to examine the extent of enthesitis within a group of psoriatic arthritis patients who were to commence on their first biologic therapy by examining them both with ultrasound and then with clinical examination. Methods: We recruited 80 patients in which their consultant rheumatologist had decided to commence them on therapy. We carried out an ultrasound assessment of six entheseal sites as per an established assessment tool called the MAdrid Sonographic Enthesitis Index (MASEI). We then proceeded to take a history from the patients and examine all aspects of their joint disease just before they began their therapy. We repeated the ultrasound and clinical examination after 16 weeks of treatment without knowing what treatment they were on. Results: In all, 75 patients completed the study and 23 of these were treated with secukinumab, a drug that targets interleukin-17a (IL-17i), an important protein in psoriatic disease and 52 patients were treated with medications that target tumour necrosis factor inhibitor (TNFi), another important inflammatory protein. Overall, we demonstrated a reduction in ultrasound scores for entheseal disease in those treated with both classes of medication. For the TNFi group, there was a larger improvement in scores compared with the IL-17i which was not significant for the primary focus of the study, the overall MASEI score. We have also demonstrated that there may be a larger improvement in TNFi response versus IL-17i when only counting the inflammatory disease component of the MASEI score. In terms of clinical results, the findings were broadly similar except that secukinumab was better at improving skin psoriasis. Conclusion: Our work is the first with ultrasound to compare outcomes for enthesitis between classes of biologic therapy and should form the basis of future studies attempting to confirm these findings to make better decisions for those living with psoriatic arthritis.

The relationship between the nail and systemic enthesitis in psoriatic arthritis.

OBJECTIVE: Psoriatic nail disease is more common in PsA than in isolated skin psoriasis (PsO). The nail is closely integrated to the DIP joint entheses. US data have shown that those patients with nail disease in PsO are more likely to have systemic enthesitis. We examined whether there was a relationship between nail disease, DIP enthesitis and systemic enthesitis in established PsA. METHODS: Forty-six PsA participants with nail disease underwent US scanning of the nail unit and the DIP entheses along with peripheral entheseal sites according to the Madrid sonographic enthesitis index (MASEI). RESULTS: At the finger level, there was a mild to moderate correlation between nail US changes and both clinical nail disease and DIP enthesis changes (DIP US) [Spearman correlation (r S) = 0.30, P < 0.001 and r S = 0.16, P < 0.001, respectively]. At the patient level, there was a moderate correlation between the nail US score and nail psoriasis severity index score and DIP US (r S = 0.33, P = 0.024 and r S = 0.43, P = 0.003, respectively). At the patient level, there was also a positive correlation between a higher nail US score and the active peripheral enthesitis score (MASEI-active) (r S = 0.35, P = 0.018). When power Doppler was part of nail US score, similar results were demonstrated at both the finger and patient levels. CONCLUSION: This study has demonstrated the utility of nail US imaging and the close relationship, on scanning, between the DIP entheses and the nail unit. In PsA, we have seen a correlation between active US changes at the nail and peripheral enthesitis, which requires further analysis. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03955861.

Evidence-based clinical guidelines: a new system to better determine true strength of recommendation.

RATIONALE, AIMS AND OBJECTIVES: Clinical practice guidelines often grade the 'strength' of their recommendations according to the robustness of the supporting research evidence. The existing methodology does not allow the strength of recommendation (SOR) to be upgraded for recommendations for which randomized controlled trials are impractical or unethical. The purpose of this study was to develop a new method of determining SOR, incorporating both research evidence and expert opinion. METHODS: A Delphi technique was employed to produce 10 recommendations for the role of exercise therapy in the management of osteoarthritis of the hip or knee. The SOR for each recommendation was determined by the traditional method, closely linked to the category of research evidence found on a systematic literature search, and on a visual analogue scale (VAS). Recommendations were grouped A-D according to the traditional SOR allocated and the mean VAS calculated. Difference across the groups was assessed by one-way ANOVA variance analysis. RESULTS: Mean VAS scores for the traditional SOR groups A-D and one proposition which was 'not recommended' showed significant linearity on one-way ANOVA. However, certain recommendations which, for practical reasons, could not assessed in randomized controlled trials and therefore could not be recommended strongly by the traditional methodology, were allocated a strong recommendation by VAS. CONCLUSIONS: This new system of grading strength of SOR is less constrained than the traditional methodology and offers the advantage of allowing SOR for procedures which cannot be assessed in RCTs for practical or ethical reasons to be upgraded according to expert opinion.

Cardiac involvement as the main presenting feature in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis is usually characterised by asthma, allergic rhinitis and peripheral eosinophilia. Presentations can vary greatly especially when there is cardiac involvement as demonstrated in these two case reports. Patient A initially presented to casualty with severe sinus pain and was diagnosed with severe sinonasal polyposis. After routine nasal polypectomy he had a cardiac arrest and was transferred to intensive care. Patient B presented to his general practitioner with a 4-week history of breathlessness, joint pain and a rash resulting in admission to hospital. Both patients had significant eosinophilia on routine bloods. High-sensitivity troponin T levels were raised in both; however, patient B's was significantly higher. Patient A had a large pericardial effusion on echo, the aspirate of which revealed numerous eosinophils. Patient B's echo was normal. Patient A's cardiac MRI was normal while Patient B's revealed myocarditis. Both were successfully treated with intravenous methylprednisolone and cyclophosphamide.

A case report on parvovirus b19 associated myositis.

Introduction. Whilst there are reports of viral myopathies affecting children and the immunocompromised, infective myositis is a relatively rare inflammatory myopathy in adults. The clinical spectrum can range from benign myalgias to more serious complications in certain risk groups. Case Presentation. We present two cases of myositis as a result of parvovirus B19 infection. Conclusion. Viral myositis and parvovirus B19 associated myositis should be considered in adults presenting with significant myalgia.

The effectiveness of physiotherapy exercises in subacromial impingement syndrome: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of exercise in the treatment of people with subacromial impingement syndrome (SAIS). METHODS: A systematic review and meta-analysis were conducted. Ten electronic databases were searched from the dates of their inception until August 2010. Included studies were randomized controlled trials investigating exercise in the management of SAIS. Outcomes were pain, strength, function, and quality of life. Data were summarized qualitatively using a best evidence synthesis. Treatment effect size and variance of individual studies were used to give an overall summary effect and data were converted to standardized mean difference with 95% confidence intervals (standardized mean difference (SMD) (CI)). RESULTS: Sixteen studies were included (n = 1162). There was strong evidence that exercise decreases pain and improves function at short-term follow-up. There was also moderate evidence that exercise results in short-term improvement in mental well-being and a long-term improvement in function for those with SAIS. The most common risk of bias across the studies was inadequately concealed treatment allocation. Six studies in the review were suitable for meta-analysis. Exercise had a small positive effect on strength of the rotator cuff in the short term (SMD -0.46 (-0.76, 0.16); P = 0.003) and a small positive effect on long-term function (SMD -0.31 (-0.57, 0.04); P = 0.02). CONCLUSIONS: Physiotherapy exercises are effective in the management of SAIS. However, heterogeneity of the exercise interventions, coupled with poor reporting of exercise protocols, prevented conclusions being drawn about which specific components of the exercise protocols (ie, type, intensity, frequency and duration) are associated with best outcomes.

Autosomal dominant early childhood seizures associated with chondrocalcinosis and a mutation in the ANKH Gene.

We describe the pattern of early childhood seizures within a family with autosomal dominant chondrocalcinosis (CCAL, which causes adult-onset arthritis). All affected family members with CCAL experienced seizures in early childhood, usually, but not always, associated with fever. Similarities exist to the syndrome of generalized epilepsy with febrile seizures plus (GEFS+). A mutation within the ANKH gene on chromosome 5p has been found previously in this family; other patients with familial CCAL (but without seizures) have mutations in the same gene. ANKH codes for a transmembrane protein involved in the regulation of extracellular pyrophosphate ion levels, although its precise mechanism of action remains unclear. It is highly expressed in the brain, and its expression may be influenced by seizure activity. The mutation within this family creates a premature initiation codon, adding four amino acids to the N-terminus of the protein. We postulate that this may lead to a gain of function, causing seizure susceptibility as well as chondrocalcinosis. Mutations within this gene may underlie other forms of genetic epilepsy and febrile seizures.

Mutations in the amino terminus of ANKH in two US families with calcium pyrophosphate dihydrate crystal deposition disease.

OBJECTIVE: To analyze ANKH in families with calcium pyrophosphate dihydrate crystal deposition disease (CPPD) for disease-causing mutations. METHODS: Two US families (one of British ancestry and the other of German/Swiss ancestry) with autosomal-dominant CPPD, whose disease phenotypes were found to be linked to chromosome 5p15.1 (locus symbol CCAL2), were screened by direct sequencing for mutations in ANKH, a gene in the CCAL2 candidate interval that has been shown to harbor mutations in other families with CPPD. Observed sequence variants were confirmed by antisense sequencing, and expression of the mutant allele was verified by reverse transcriptase-polymerase chain reaction amplification of messenger RNA followed by direct sequencing. RESULTS: The two US families displayed the same mutation at position 5 of the ANKH gene product (P5T). All affected members were heterozygous for the P-to-T variant, and the mutation was not seen in 204 control alleles. The two families displayed distinct disease haplotypes, suggesting that they were unrelated to each other. CONCLUSION: These observations represent the fourth and fifth families with heritable CPPD whose disease phenotypes are linked to the CCAL2 locus and who have missense mutations in the amino terminus of ANKH. This same position (P5) was the site of a missense mutation in an Argentine family of northern Italian ancestry; however, the sequence variant in that family generated a P5L mutation. The distinct disease haplotypes among the 3 families with P5 mutations suggest that the mutations arose independently and that the evolutionarily conserved P5 position of ANKH may represent a hot spot for mutation in families with autosomal-dominant CPPD.

Mutations in ANKH cause chondrocalcinosis.

Chondrocalcinosis (CC) is a common cause of joint pain and arthritis that is caused by the deposition of calcium-containing crystals within articular cartilage. Although most cases are sporadic, rare familial forms have been linked to human chromosomes 8 (CCAL1) or 5p (CCAL2) (Baldwin et al. 1995; Hughes et al. 1995; Andrew et al. 1999). Here, we show that two previously described families with CCAL2 have mutations in the human homolog of the mouse progressive ankylosis gene (ANKH). One of the human mutations results in the substitution of a highly conserved amino acid residue within a predicted transmembrane segment. The other creates a new ATG start site that adds four additional residues to the ANKH protein. Both mutations segregate completely with disease status and are not found in control subjects. In addition, 1 of 95 U.K. patients with sporadic CC showed a deletion of a single codon in the ANKH gene. The same change was found in a sister who had bilateral knee replacement for osteoarthritis. Each of the three human mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro. All three of the human mutations showed significantly more activity than a previously described nonsense mutation that causes severe hydroxyapatite mineral deposition and widespread joint ankylosis in mice. These results suggest that small sequence changes in ANKH are one cause of CC and joint disease in humans. Increased ANK activity may explain the different types of crystals commonly deposited in human CCAL2 families and mutant mice and may provide a useful pharmacological target for treating some forms of human CC.