MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C).

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. INTERPRETATION: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with the COVID-19 Pandemic (MIP-C).

Background: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 senses single-stranded RNA and is a key pattern recognition receptor for the SARS-CoV-2 virus. Methods: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018-December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak. Results: Sixty new anti-MDA5+, but not other MSAs surged between 2020-2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. Few (8/60) had a prior history of COVID-19, whereas 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. Conclusions: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.

The Relationship Between Physical Examination and Ultrasonography of Large Entheses of the Achilles Tendon and Patellar Tendon Origin.

OBJECTIVE: To investigate the relationship between physical examination (PE) and sonographic features of enthesitis, based on anatomical sites. METHODS: The analysis was done using merged raw data of 3 studies on 2298 entheses. RESULTS: Patients with clinical Achilles enthesitis had more abnormalities on ultrasound (US): hypoechogenicity, p < 0.001; thickening, p = 0.001; Doppler signals, p = 0.002; and erosions, p = 0.02. The patellar tendon origin also correlated with PE but distal patellar tendon insertion and plantar aponeurosis were uncoupled from the US. CONCLUSION: The relationship between clinical and sonographic findings for large entheses is dependent on the anatomical site. For the patellar tendon origin and Achilles entheses, PE is significantly linked to US findings.

Potential use of optical coherence tomography and high-frequency ultrasound for the assessment of nail disease in psoriasis and psoriatic arthritis.

BACKGROUND/OBJECTIVE: Psoriatic nail disease is increasingly recognised to be of major clinical and research relevance. Clinical assessment remains the current gold standard for its evaluation. OBJECTIVE: We compared optical coherence tomography (OCT) and ultrasound (US) for nail disease assessment in psoriatic disease. METHODS: 18 patients with at least one involved nail and 12 healthy controls were scanned using OCT; psoriatic patients also had an US scan (using a linear probe at 9-14 MHz). Nail and contour abnormalities were documented. Clinical onychopathy was scored independently using the modified Nail Psoriasis Severity Index. RESULTS: Among 180 nails, 67.8% had clinical findings whereas 33.9% were abnormal by US and 44.4% had abnormalities on OCT. A positive OCT had a sensitivity and specificity of 44.4 and 95.8%, respectively, with a positive likelihood ratio of 10.7 for nail disease. OCT demonstrated 76.3% absolute agreement compared with clinical assessment and 65% with US. OCT detected subtle abnormalities in 12 clinically normal nails and in 41 nails with normal US findings. CONCLUSION: These findings show that OCT has a potential for the systematic characterisation of psoriatic nail changes and could be useful in diagnosis and more objective assessment of treatment response.

Methotrexate for pain relief in knee osteoarthritis: an open-label study.

OBJECTIVE: Synovitis is very common in knee OA and associated with pain. This open-label study evaluated an anti-synovitis therapy, MTX, for pain relief in knee OA. METHODS: Inclusion criteria included pain visual analogue scale (VAS) >40/100 mm, ACR clinical criteria for knee OA and intolerance/inefficacy of NSAID and opioids. US at baseline and 24 weeks assessed effusion and synovial thickness. Patients received MTX up to 20 mg/week for 24 weeks. RESULTS: Thirty participants were recruited; mean age 64.5 years, median pain VAS 68 mm. At 24 weeks, 13/30 (43%) achieved ≥30% reduction in pain VAS, 7 (23%) achieved ≥50% reduction and 4 (13%) had worsened. Thirteen achieved Osteoarthritis Research Society International (OARSI) responder criteria. All had effusion/synovitis at baseline. There was no correlation between change in imaging and change in pain scores at 24 weeks. CONCLUSION: This open-label trial suggests analgesic efficacy for MTX in OA knee and suggests that a randomized controlled trial is warranted. Trial Registration. Current controlled trials, http://www.controlled-trials.com/, ISRCTN66676866.

The link between enthesitis and arthritis in psoriatic arthritis: a switch to a vascular phenotype at insertions may play a role in arthritis development.

OBJECTIVE: Subclinical enthesopathy is recognised in both psoriasis and psoriatic arthritis (PsA). This study used ultrasonography with power Doppler (PD) to test the hypothesis that subclinical enthesopathy in PsA was associated with an 'inflammatory' or vascular phenotype compared to that seen in psoriasis. METHODS: 100 patients with a mean age of 46.3 years (SD 15) (42 with psoriasis and 58 with PsA) and 23 matched healthy controls (HC) from two centres were included. 1230 lower limb entheses were scanned by ultrasonographers blinded to clinical details. Both inflammatory and chronic features of enthesopathy were scored. RESULTS: Psoriasis patients (with or without arthritis) were more likely to express a vascular phenotype, with higher inflammation-related enthesopathy scores than HC (for inflammation p<0.0001, for chronicity p=0.02, for total ultrasound scores p<0.0001). The PsA patients had higher ultrasound enthesopathy scores than psoriasis patients (inflammation p=0.04, chronicity p=0.02) and HC (inflammation p<0.0001, chronicity p=0.003). When symptomatic entheses were excluded, PsA patients still had higher PD scores than psoriasis patients (p=0.003). Doppler positivity in at least one entheseal site was observed more frequently in PsA (21/58, 36.2%) versus psoriasis (4/42, 9.5%; p=0.002). CONCLUSIONS: This study shows that the ultrasound appearances of subclinical enthesitis in psoriasis differ from the subclinical enthesitis in PsA, with PsA patients having more PD. This is suggestive of a more inflammatory or vascular process in PsA, and offers potentially novel insights into the progression from skin to joint disease in psoriasis.

Ultrasonographic assessment of nail in psoriatic disease shows a link between onychopathy and distal interphalangeal joint extensor tendon enthesopathy.

OBJECTIVE: We compared ultrasonography (US) with the modified nail psoriasis severity index (mNAPSI) to investigate the nail plate, nail matrix and adjacent tendons in subjects with psoriatic nail disease and to test the hypothesis that nail involvement was specifically linked to extensor tendon enthesopathy. METHODS: 86 psoriatic patients (169 nails) and 20 healthy controls (HC) (40 nails) were assessed with both the mNAPSI and US. The thickness of the nail plate, nail matrix region and adjacent extensor tendon were assessed and compared with physical examination findings. RESULTS: A good agreement between clinical and sonographic nail findings was noted (kappa value = 0.52, p < 0.0001). Entheseal thickening of the extensor tendon on US was more frequent in patients with clinical nail disease compared to patients without clinical nail disease in both psoriasis and psoriatic arthritis (38 vs. 16%, p = 0.03, and 47 vs. 19%, p = 0.008, respectively). Nail thickness, nail matrix and adjacent skin thickness were higher in psoriatic patients compared to HC. CONCLUSION: US and clinical findings show good correlation for the assessment of the nail in psoriatic disease. The demonstration of extensor tendon enthesopathy in both psoriasis and psoriatic arthritis supports the importance of enthesopathy in nail disease pathogenesis whether or not clinical arthritis is present.

GRAPPA Trainees Symposium 2011: a report from the GRAPPA 2011 annual meeting.

The 2011 annual meeting in Naples, Italy, of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) began with a Trainees Symposium, which has become an important aspect of the meeting. In 2011, 25 trainees currently involved in research in psoriasis or psoriatic arthritis were invited to deliver an oral abstract or poster presentation. We present a brief overview of the oral and poster presentations, which show the diversity and focus of current research performed by members and trainees of GRAPPA.

The role of tocilizumab in the management of rheumatoid arthritis.

INTRODUCTION: The introduction of biological treatments has improved the outlook for patients diagnosed with rheumatoid arthritis. There are now a range of different agents, targeting various pathways involved in the inflammatory process. Tocilizumab , a fully humanised anti-interleukin-6 receptor monoclonal antibody is licensed for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis. AREAS COVERED: This article reviews and appraises the available evidence regarding the efficacy and safety of tocilizumab in rheumatoid arthritis, as identified in PubMed and Embase searches. EXPERT OPINION: Clinical trial data suggest that tocilizumab has similar efficacy both clinically and in reducing structural progression to that seen with the TNF inhibitors. Patients who might be particularly suitable for tocilizumab are those who have failed multiple TNF inhibitors, those with a high inflammatory response as part of their disease and those unable to tolerate methotrexate, given the good responses seen with monotherapy.

A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis.

OBJECTIVES: To review the available evidence for the efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and biological drug therapies for the different clinical manifestations of psoriatic arthritis (PsA) in order to provide data for the development of treatment recommendations by the European League Against Rheumatism (EULAR) taskforce. METHODS: A systematic literature review (SLR) of available treatments for PsA was performed using the largest electronic databases (MEDLINE, EMBASE and COCHRANE) by two working groups formed within the EULAR taskforce. This comprised a comprehensive sample of rheumatologists, dermatologists, epidemiologists and patients. The available evidence was reviewed for NSAIDs, synthetic disease modifying antirheumatic drugs (DMARDs), local and systemic corticosteroids and biologic drugs. All articles and abstracts published between 1962 and January 2010 were reviewed and considered and a meta-analysis of data on biological therapies was performed. RESULTS: While little data are available on NSAIDs, glucocorticoids and synthetic DMARDs, the available evidence suggests an acceptable efficacy and safety profile of both NSAIDs and synthetic DMARDs (methotrexate, cyclosporine A, sulfasalazine and leflunomide) in PsA. More evidence is available (level 1B) supporting the efficacy of anti-tumour necrosis factor (anti-TNF) agents (adalimumab, etanercept, golimumab and infliximab) in treating the signs and symptoms of PsA as well as reducing radiographic progression. Registry data show no new safety concerns, although the numbers studied to date are relatively small. CONCLUSIONS: This SLR reveals some evidence to support the use of NSAIDs and synthetic DMARDs and good evidence for the efficacy of anti-TNF therapy in PsA.

Psoriasis patients with nail disease have a greater magnitude of underlying systemic subclinical enthesopathy than those with normal nails.

OBJECTIVE: Enthesopathy is a major feature of psoriatic arthritis (PsA), which is supported by imaging studies. Given that nail disease often predates PsA and that the nail is directly anchored to entheses, the authors asked whether nail involvement in psoriasis equates with a systemic enthesopathy. METHODS: Forty-six patients with psoriasis (31 with nail disease) and 21 matched healthy controls (HC) were recruited. 804 entheses of upper and lower limbs were scanned by an ultrasonographer blinded to clinical details. RESULTS: Psoriasis patients had higher enthesitis scores than HC (median (range) 21 (0-65) vs 11 (3-39), p=0.005). Enthesopathy scores were higher in patients with nail disease (23 (0-65)) than in patients without nail disease (15 (5-26), p=0.02) and HC (11 (3-39), p=0.003). Inflammation scores of patients with nail disease (13 (0-34)) were higher than patients without nail disease (8 (2-15), p=0.02) and HC (5 (0-19), p<0.001). Modified nail psoriasis severity index scores were correlated to both inflammation (r(2)=0.45, p=0.005) and chronicity scores (r(2)=0.35, p=0.04). No link between the psoriasis area and severity index and enthesitis was evident. CONCLUSION: The link between nail disease and contemporaneous subclinical enthesopathy offers a novel anatomical basis for the predictive value of nail psoriasis for PsA evolution.

Optical coherence tomography: a new tool to assess nail disease in psoriasis?

BACKGROUND: Nail disease is a characteristic manifestation of the psoriatic disease spectrum but is poorly understood. OBJECTIVE: Given the intrinsically high spatial resolution imaging capabilities of optical coherence tomography (OCT), we assessed its value in psoriatic nail disease compared to high-resolution ultrasonography (US). METHODS: All fingernails in a psoriatic arthritis patient with nail changes were scanned with OCT, and findings were compared with high-resolution US. RESULTS: US showed loss of trilaminar appearance in all nails, resulting in the nail plate being visualized as a single hyperechoic layer with inhomogeneous thickness. The OCT images showed much higher-resolution changes with prominent thickening in the ventral plate at the nail bed which was grossly inhomogeneous, 'eroded' and irregularly fused with the underlying epidermis, which correlated with the clinical observation of subungal hyperakeratosis. CONCLUSION: OCT has considerable potential for the evaluation of psoriatic nail disease and may be superior to US.

Structural damage in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: traditional views, novel insights gained from TNF blockade, and concepts for the future.

Structural changes of bone and cartilage are a hallmark of inflammatory joint diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Despite certain similarities - in particular, inflammation as the driving force for structural changes - the three major inflammatory joint diseases show considerably different pathologies. Whereas RA primarily results in bone and cartilage resorption, PsA combines destructive elements with anabolic bone responses, and AS is the prototype of a hyper-responsive joint disease associated with substantial bone and cartilage apposition. In the present review we summarize the clinical picture and pathophysiologic processes of bone and cartilage damage in RA, PsA, and AS, we describe the key insights obtained from the introduction of TNF blockade, and we discuss the future challenges and frontiers of structural damage in arthritis.

The early phase of psoriatic arthritis.

Evaluation of the preclinical phases of the classic autoimmune diseases including rheumatoid arthritis has been facilitated by the availability of autoantibody and genetic markers that point firmly towards the early dysregulation of the adaptive immune responses. The association of psoriatic disease with the human leucocyte antigen-Cw0602 (HLA-Cw0602) gene has likewise led to the perception that autoimmunity has a pivotal role in early psoriatic arthritis (PsA). However, this HLA-Cw0602 genetic association does not appear to hold for PsA or associated nail, scalp and intergluteal skin involvement. Of note, these three sites of psoriasis are predictive of PsA evolution. For initiation of both skin and nail disease there is a link with Koebnerisation, or site-specific trauma. Nail disease is most common in the dominant hand thumbnail, pointing towards local tissue factors as disease initiators Likewise, for PsA, there is also good evidence for a history of previous joint trauma and histological studies showing microdamage in normal entheses which are typical locations where PsA frequently occurs. Furthermore, subclinical enthesopathy including osteitis is common in subjects with psoriasis but without arthritis. Collectively, these findings indicate that the classic model of adaptive immune dysregulation does not generally hold for the early stages of PsA. The way in which knowledge pertaining to tissue-specific factors in PsA, combined with the emerging data relating to monogenic disorders and animal models, points towards perturbation in the healing response and dysregulation of innate immune responses in early PsA is discussed. The way in which this model explains the clinical disconnect between skin and joint disease and the emerging human data that support it are demonstrated.

Golimumab - a new tool in the armoury against inflammatory arthritis.

The development of biological drugs blocking tumour necrosis factor-alpha (TNF-α) has had a dramatic impact on the treatment of inflammatory arthritis in recent years. Golimumab is a fully human monoclonal antibody which inhibits TNF-α. It is licensed for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this review we evaluate the results of phase III studies using golimumab and explore the place of golimumab in the treatment of these diseases.

MRI for the assessment and monitoring of RA--what can it tell us?

The past 15 years has seen an exponential rise in the use of MRI for the assessment of rheumatoid arthritis (RA). In this Perspectives article, we review the current and potential future role of MRI in the diagnosis, prognosis and monitoring of RA. We also review the impact of MRI research on the understanding of disease mechanisms. In our view, the pivotal role of synovitis in RA and its predilection for sonographically accessible joints makes it likely that MRI will be used diagnostically in joints that are inaccessible to ultrasonography or where the differential diagnosis is unclear. Additionally, MRI will probably assume an even more prominent role in clinical trials where the aim of therapy is the complete ablation of synovitis. Given the ever-increasing sophistication of MRI, we anticipate that it will continue to be a key research tool in the coming years.