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inflammatory arthritis summary and questions

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https://www.youtube.com/watch?v=ld8PhyAHov8&t=4s - great video to help understand the physiology of RA

I also used the crash course book in rheumatology and orthopaedics

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Rheumatoid Arthritis Pathophysiology (signs and symptoms)

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Here is a an old powerpoint I found from my uni during my pharmacy degree. I also like to use the BNF, highly recommend starting to use it as a source and getting used to it

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https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702073601000032

https://www.clinicalkey.com/student/content/book/3-s2.0-B978070207028000024X#hl0006126

I used both of the books given on sofia under this LO, they pretty much give the same info but equally as good, to the point and easy to understand.

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Only used the lecture as thought this was sufficient – but thought the below picture summarised it well.

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https://www.youtube.com/watch?v=viP5Ta0K-ho

https://www.clinicalkey.com/student/content/book/3-s2.0-B978032364186900039X - I liked the layout of this book, gave all the info needed

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Lyme Disease | Pathophysiology, Signs, and Treatment

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I thought that the 2 screencasts provided were sufficient as they were quite in depth but also easy to understand.
I have linked the second chronic inflammation screencast as there is a short animation near the end that is a really good summary of what we need to know for this LO

https://alt-5f47a5775541f.blackboard.com/bbcswebdav/courses/MED-0005Y-YEAR-21E/JG%20MURPHY/UEA%20WEBSITE%203/CHRONIC%20INFLAMMATION%202021/Chronic%20Inflammation%20and%20Wound%20Healing%20Part%202%20%28Published%29/index.html?one_hash=69B363A811576EBDBB877333231A3F6F&f_hash=7641CF0E41426D8A6EAE1857FDEF5E3C

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Chronic Inflammation and Wound Healing Part 2

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https://my.clevelandclinic.org/health/diseases/4924-rheumatoid-arthritis

This article outlines what rheumatoid arthritis is, what causes it (genetics, environment etc) how you can treat it with different medication and what the symptoms of the disease is.

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https://www.mayoclinic.org/diseases-conditions/lyme-disease/diagnosis-treatment/drc-20374655
https://www.mayoclinic.org/diseases-conditions/lyme-disease/symptoms-causes/syc-20374651

This clearly outlines what Lyme disease is, the early and late symptoms of it, how it is treated and how you can diagnose it.

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https://www.youtube.com/watch?v=yTIZpzoaIT0

This YouTube video clearly explained the concepts of acute inflammation, I recommend watching this and then Joe Murphy's lecture as it allows you to build the foundation knowledge you need first.

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https://www.mayoclinic.org/diseases-conditions/reactive-arthritis/symptoms-causes/syc-20354838

https://www.mayoclinic.org/diseases-conditions/reactive-arthritis/diagnosis-treatment/drc-20354843

These two links provide a great depth of detail into what Reactive arthritis is, the pathogens that cause it, what the symptoms are and how to diagnose and treat the condition.

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https://www.youtube.com/watch?v=fQCU7rQbovk
https://www.youtube.com/watch?v=a23A3nAaO0E&t=1s

This short video states what psoriatic arthritis is, the pathophysiology behind it, the symptoms, investigation and management.
The second link provides relevant information on ankylosing arthritis.

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https://www.youtube.com/watch?v=RlCoizT0L3M

This video states the obvious and main inflammatory markers and how they show signs of infection/disease. I couldn't find any more detail than this.

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https://www.nhs.uk/conditions/rheumatoid-arthritis/treatment/

The NHS website states the most common types of medication, e.g., methotrexate, leflunomide etc and the use of JAK inhibitors and biologics.

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https://www.youtube.com/watch?v=7abUCT0hnYY&t=3219s

Very long video but it demonstrates the comparison of inflammatory and degenerative arthritis and how to distinguish between them, it's worth a watch.

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Table that clearly shows common causes of polyarticular joint pain and they're presentation.  https://www.aafp.org/afp/2003/0915/p1151.html

https://www.msdmanuals.com/en-gb/professional/musculoskeletal-and-connective-tissue-disorders/pain-in-and-around-joints/pain-in-multiple-joints
Really useful website to see pathophysiology and treatment for the different diagnoses.
https://www.nhs.uk/conditions/joint-pain/
To understand how the differential diagnoses present.

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https://www.youtube.com/watch?v=2jEBTeAgtFY

I'm not sure if this entirely covers the question but it does explain very well how the T cells and MHC work together to prevent autoimmunity.

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https://www.youtube.com/watch?v=snjGL2x6Eus

https://www.ncbi.nlm.nih.gov/books/NBK499831/

I think these to sources give enough info to cover all the points, to the point and easy to understand

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Reactive Arthritis: Visual Explanation for Students

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Managing people with long-term conditions (kingsfund.org.uk)

page 16-24 has an entire section on Arthritis (OA and RA) and it clearly talks about the role of primary care and how they should treat and support patients with long term illnesses

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slightly off topic but when aspirating the joint in spetic or crystal arthropathies (which can be polyarticular) this clinical feature table is handy.

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this table is a nice summary of what central tolerance is/how it differs in T and B cells - becasue when the tolerance mechanism breaks down autoimmune effects are shown.

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https://www.everydayhealth.com/rheumatoid-arthritis/treatment/the-facts-on-methotrexate-for-ra-treatment/
The website I used to understand how MTX works.
Content (uea.ac.uk)
I mainly used Tanya Marshalls lecture on drugs for RA

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Content (uea.ac.uk)
I used Tanya Marshalls lecture on Lyme disease found on monoarticular joint pain week.

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Investigations - Crash Course Rheumatology and Orthopaedics - ClinicalKey Student
I used the book for information on areas I wasn't sure on like Anti-CCP and RF.

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ClinicalKey Student is an interactive education platform that supports students and faculty with tools to develop and assess the medical knowledge of aspiring professionals.

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I thought the RA and radiology lectures provided most of the required knowledge, whilst the pathology crashcourse textbook provided good visual and clear explanation of the pathophysiology of the disease.

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I only used the pathology lecture for this one as it was complete and detailed.

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*https://www.ncbi.nlm.nih.gov/books/NBK27156/*https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2291482/
Two links to help understand the role of MHCs in autoimmunity. (quite long,very in-depth)

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Elizabeth M. C. Fisher, Editor

Abstract

The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity.

Introduction

The major histocompatibility complex (MHC), located on the short arm of Chromosome 6, is one of the most extensively studied regions in the human genome because of the contribution of multiple variants at this locus in autoimmune, infectious, and inflammatory diseases and in transplantation. Historically, the murine MHC locus, H2, was identified and subsequently named for its role in histocompatibility almost 60 years ago by George Snell [1]. Shortly afterward, Jean Dausset recognized the human MHC, or human leukocyte antigen (HLA) region, so named because Dausset originally demonstrated MHC antigens on the surface of white blood cells [2]. Subsequently, Baruj Benacerraf described the importance of these antigens in the immune response [3]. The seminal work of Snell, Dausset, and Benacerraf garnered them the 1980 Nobel Prize for Medicine.

The classical MHC encompasses approximately 3.6 megabasepairs (Mb) on 6p21.3 and is divided into three subregions: the telomeric class I, class III, and the centromeric class II regions. The concept of the extended MHC (xMHC), spanning about 7.6 Mb of the genome, has been recently established by the finding that linkage disequilibrium (LD) and MHC-related genes exist outside the classically defined locus [4]. Of the 421 genes within the xMHC, 60% are expressed and approximately 22% have putative immunoregulatory function. The five subregions of the xMHC comprise the extended class I subregion, classical class I, classical class III, classical class II, and the extended class II subregions [4].

The MHC was first associated with disease in 1967 when HLA-B antigens were found at increased frequency in patients with Hodgkin's lymphoma [5]. Since then, variation within the MHC has been found to be associated with almost every autoimmune disease, as well as several infectious and inflammatory diseases. However, because of the extensive LD that exists among alleles throughout this locus, the causal MHC variant(s) have remained elusive for the great majority of diseases.

Nonrandom association (or LD) in the inheritance of alleles at multiple loci within the MHC was demonstrated as early as 1968 [6]. Upon determination of the physical size of the region, it appeared that LD extended more than 2 Mb in some cases, but not all. This differs from the LD pattern reported for other regions in the genome where strong LD exists in segments of approximately 22 kilobases (kb) [7]. However, closer inspection reveals that the "micro"-structure of LD is similar for the MHC [8],[9]. What appears to be different about a subset of MHC haplotypes is that there is a higher amount of LD observed between segments of strong LD. Such tight segment-to-segment LD can pose an important obstacle in MHC research: if one identifies a disease association with a variant in the region, it may not be possible to determine whether the variant is causal or whether its association simply reflects LD with the true causal variation. Several studies of the region to date have suffered from this caveat.

A further complication in the identification of disease-causing variants at the MHC is the great variability exhibited by some of the genes within the MHC (such as the classical class I genes, HLA-A, -B, and -C and the classical class II genes, HLA-DRB1, -DQA1, and -DQB1), which require typing strategies that are both labor- and time-intensive; indeed HLA-B is the most polymorphic gene known in the human genome.

The mechanisms underlying MHC association in autoimmune disease are not clearly understood. One long-held view suggests a breakdown in immunological tolerance to self-antigens through aberrant class II presentation of self or foreign peptides to autoreactive T lymphocytes. Thus, it seems likely that specific MHC class II alleles determine the targeting of particular autoantigens resulting in disease-specific associations.

For the reasons outlined above, most published studies of MHC disease association to date have been restricted to small cohorts, each testing a limited number of variants using a variety of typing methodologies. This problem has resulted in a literature base that can be complex and at times conflicting. We have therefore examined the past 30 years of research regarding MHC genetics in multiple autoimmune and inflammatory diseases using two different approaches-(1) a review of published data and (2) a pooled analysis of case-control association studies across the region-in order to consolidate and evaluate the current literature base. We chose to investigate six genetically complex disease traits: multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA). By relying on combined data, pooled analyses provide greater power for detecting disease-associated variants, so may be helpful in corroborating or refuting previous findings and establishing additional associations. Specifically, we performed PubMed literature searches and identified references from review sources to create a list of case-control association studies across the region for each disease up to and including September 2005 (see Table S1 for all disease-specific studies included in the pooled analysis and Text S1 for further search details). Only variants for which there were three independent studies examining more than 50 cases each were included in the final analysis. Phenotype and allele frequency data were included but analyzed separately in this study. In total approximately 390 studies were included across all diseases.

Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each serological, mixed lymphocyte reaction, or molecular specificity (see Text S1). These data were collated ( Table S2) and used to create and . The extended LD observed at the MHC does not allow differentiation between allelic and haplotypic association in the current pooled analysis. Thus, as it is vital to consider LD when interpreting association results at the MHC, our figures display statistically significant variants on the basis of "ancestral," also known as "conserved extended," haplotypes [10]-[12].

The following text is subdivided by disease; for each we provide a disease-specific review of the current literature on MHC genetics and then detail the results of the pooled analysis (illustrated in and ) with respect to the variants found to confer risk to disease (defined as a lower limit CI >1.0). A more comprehensive account of MHC association for each disease can be found in Datasets S1, S2, S3, S4, and S5. We also provide a brief explanation of HLA nomenclature and typing methodologies (with a mapping of serotypes to genotypes) because of the confusion that often surrounds these topics ( Text S2 and Table S3).

Multiple Sclerosis

MS (Online Mendelian Inheritance in Man [ http://www.ncbi.nlm.nih.gov/sites/entrezdbomim] accession number [MIM] 126200) is a chronic inflammatory demyelinating disorder of the central nervous system (reviewed in [13],[14]). The only region of the genome that has shown consistent evidence of linkage and association with MS is the MHC (reviewed in [15]). The association of the HLA-DR2 haplotype with MS was first noted in 1972 [16] and remains one of the most reproduced findings in MHC genetics. Due to strong LD across the associated haplotype, it remains unclear whether the primary driver for the association of the HLA locus to MS is the HLA-DQB1*0602 allele or the HLA-DRB1*1501 allele (reviewed in [15]). However, evidence is mounting that HLA-DRB1*1501 and the closely related HLA-DRB1*1503 allele are more strongly associated with MS in African-American [17] and possibly European populations (PLD, unpublished data) when compared to HLA-DQB1*0602. In addition, alleles within the MHC class I region show suggestive evidence of association independent of the DRB1*1501-DQB1*0602 haplotype, and include HLA-A*0201[18], HLA-A3[15],[18] and HLA-Cw05[19] as well as the HLA C1_3_2*354 microsatellite allele, although the latter is in strong LD with HLA-DR3[20].

There is support for allelic heterogeneity within the HLA-DRB1 gene, particularly in non-European MS populations [19],[21]. The best evidence for a second HLA-DRB1 risk allele in MS probably lies with HLA-DRB1*03 ( DR3) [19],[22],[23], although HLA-DRB1*0103 and HLA-DR4 alleles may also increase disease risk (reviewed in [13]) [19], [24]-[26].

As expected, our pooled analysis highlights the preeminent role of the extended haplotype defined by HLA-DRB1*1501 in MS (, top). Two other ancestral haplotypes containing HLA-DR3 and HLA-DR4 also appear to play a role in MS susceptibility, although the effect of these haplotypes on disease is more modest than that of the HLA-DR2 haplotypes. In comparison to the HLA-DRB1*1501 analysis, it is less clear whether the HLA-DRB1*0301 allele is primarily driving the association or whether one of the alleles of tumor necrosis factor ( TNF), for example, could be in stronger LD with a risk allele. On the other hand, the HLA-DR4 haplotypes seem to display their strongest association with their HLA-DRB1 alleles: four different HLA-DR4 alleles- 0402, 0403, 0404, and 0405-display significant association in our analysis. While the population risk of HLA-DR4 haplotypes on MS susceptibility may be relatively small, those rare individuals bearing these alleles may have a large increase in disease risk. In MS, our pooled analysis highlights the class II gene HLA-DRB1 as the primary candidate for MS susceptibility at the MHC, with a number of different alleles contributing to disease risk (see Dataset S1 for further information).

Type 1 Diabetes

T1D (MIM 222100) is a chronic autoimmune disease characterized by T cell-mediated destruction of pancreatic islet beta cells, resulting in irreversible insulin deficiency and long-term dysfunction of several organs and tissues. There is no doubt that the major genetic contribution to T1D susceptibility arises from the MHC [27], accounting for approximately 50% of the total genetic contribution to disease [28]. To date most evidence supports a role for variation at HLA-DQ as the major disease-predisposing locus [29],[30].

The predominant role of DRB1*04-DQA1*0301-DQB1*0302 and DRB1*03-DQA1*0501-DQB1*0201 haplotypes in susceptibility to T1D in European populations is borne out by several studies [31]. Heterozygosity for both risk haplotypes confers the greatest known genetic risk for T1D [31]. The formation of specific trans DQ dimers by transcomplementation between HLA-DQA1 and HLA-DQB1 alleles on homologous chromosomes ( DQA1*0301/DQB1*0201 and DQA1*0501/DQB1*0302) may be responsible for the increase in heterozygote risk [27],[32],[33]. HLA-DR4 ( DRB1*0405-DQB1*0401) and HLA-DR9 ( DRB1*0901-DQB1*0303) have shown association with T1D in Japanese and Korean populations [34]. The low frequency of the disease-associated HLA-DR3 and HLA-DR4 haplotypes may contribute to the reduced incidence of T1D in these non-European populations [31].

The nature of the HLA-DR association in T1D remains unclear. LD with HLA-DQ alleles may account for some of the association [27], while certain DRB1 alleles may also modify the risk present at the DQ locus. More recent studies, which require validation, suggest a role for a non-HLA locus, telomeric of class I [35], as well as polymorphism within HLA-DPB1[36],[37] in susceptibility to T1D.

Overall, studies to date suggest that both HLA-DR and HLA-DQ genes are important in determining disease risk, but the effects of individual alleles may be modified by the haplotypes on which they are carried [31]. There appears to be a hierarchy of risk alleles from the strongly protective HLA-DQB1*0602 to the highly predisposing HLA-DQB1*0302. Such a spectrum of risk is also borne out by TDT (transmission disequilibrium test) analysis showing that each HLA-DR/HLA-DQ haplotype has its own individual disease risk, which may result from transcomplementation and other haplotypic effects.

Our pooled analysis confirms association with HLA-DR3, HLA-DR4 and HLA-DR9-containing haplotypes in T1D (, middle). The HLA-DR9/ HLA-DRB1*0901 associations we observe arise from non-European cohorts only and concur with the published literature. With regard to HLA-DPB1, we find association with HLA-DPB1*0201, which maps to both disease-associated and unrelated haplotypes. A number of other, mainly class I alleles also show evidence for disease predisposition (see Dataset S2) and warrant further investigation.

Systemic Lupus Erythematosus

SLE (MIM 152700), or lupus, is the prototypic, multisystem autoimmune disease primarily affecting women of child-bearing age. Recent genome-wide association scans and a meta-analysis of linkage screens confirm the MHC as the greatest genetic risk factor in lupus susceptibility ([38]; TJV, unpublished data). However, the precise contribution attributable to the MHC with respect to overall genetic risk remains to be determined.

The most consistent HLA associations with SLE reside with the class II alleles, HLA-DR3 ( DRB1*0301) and HLA-DR2 ( DRB1*1501) and their respective haplotypes in predominantly white populations [39]. Studies in nonwhite populations have shown inconsistent results [40]-[44]. Inherited (and acquired) deficiencies of the early classical complement components, C2, C4A, and C4B, encoded within the class III region, are associated with the development of lupus [45]. In particular, C4A and C4B null alleles, which result in partial C4 deficiency, show association with disease [46],[47]. However, these alleles are in strong LD with specific ancestral haplotypes, so to date it has not been possible to establish whether C4 null alleles are causal in lupus. Recently the development of autoimmunity in patients treated with TNF-alpha antagonists has stimulated interest in the possible role of TNF in SLE [48]-[50]. However, the limited number of polymorphisms genotyped and the strong LD between certain TNF alleles and the B8-DR3 haplotype again restrict interpretation of these data.

In 2002, a family-based association study [51] identified three microsatellite-inferred risk haplotypes in European lupus families: DRB1*1501/DQB1*0602, DRB1*0301/DQB1*0201, and DRB1*0801/DQB1*0402. Further analysis of ancestral recombinants could only delimit the disease-associated region to 1 Mb of the MHC, encompassing class II and class III.

Taking the above into account, it is not surprising that our analysis demonstrates predominant association with variants linked to DR3- and DR2-bearing ancestral haplotypes in SLE (, bottom). The observed DRB1*0401 signal principally arises from Mexican Mestizo and Hispanic cohorts in whom this allele is uncommon (frequency ∼1%). This association has not been well described and warrants further study. Two further class II alleles, HLA-DQA1*0401 and HLA-DQB1*0402, reside on a DR8 haplotype, which is infrequent in European populations (frequency ∼2%). Our pooled analysis highlights the importance of polymorphism within HLA-DR3-containing haplotypes in lupus susceptibility. The remaining association signals largely arise from alleles of the class II genes HLA-DRB1, HLA-DQA1, and HLA-DQB1 (see Dataset S3 for further information).

Inflammatory Bowel Diseases: Ulcerative Colitis and Crohn's Disease

CD and UC are related inflammatory diseases of the gastrointestinal tract commonly known as inflammatory bowel diseases (IBD, MIM 266600). Several independent genome-wide scans in both CD and UC have shown evidence of linkage to the MHC ( IBD3 locus) [52]-[58]. It has been suggested that this region may exert a greater effect in susceptibility to UC rather than CD (with genetic contribution estimates of 60%-100% for UC and 10% for CD) [59].

The most consistent associations in UC are with the class II alleles HLA-DRB1*1502 and HLA-DRB1*0103[60]-[67]. HLA-DRB1*1502 has shown association to UC in the Japanese population, where it is highly prevalent (20%-25%) [61],[63],[65],[66], but also in European populations, where it is rare (less than 1%) [68]. HLA-DRB1*0103 represents the most reproducible association observed to date in UC [60], [62], [67], [69]-[72]; however, it has a low prevalence of less than 2% in Europeans.

In contrast to UC, four separate class II alleles show reproducible association with CD: HLA-DRB1*07, HLA-DRB1*0103, HLA-DRB1*04, and HLA-DRB3*0301[67]. HLA-DRB1*07 is the most consistently replicated association between the MHC and CD [67], [73]-[75], and more specifically with ileal disease [73]-[75]. DRB1*0103, also associated with susceptibility to UC [60], [67], [73]-[76], shows subphenotype specificity to colonic CD [73]-[75]. HLA-DRB1*04 has shown a weak but reproducible association [61],[67],[74],[77],[78] to CD, predominantly in patients of Japanese origin. Finally, HLA-DRB3*0301 was also identified in CD [67],[73]; however; this locus has been evaluated in only a few studies.

Our pooled analysis substantiates the association of UC to HLA-DRB1*0103 and HLA-DRB1*1502 (, top). We also detect a weak predisposing effect of the microsatellite allele MICA5.1, supporting previous non-replicated reports of association with polymorphisms of the MHC class I-related gene, MICA, and UC [66],[79],[80]. Other novel associations in UC are demonstrated for HLA-DR5 (and its subspecificities HLA-DR11 and -DR12), HLA-A19 and HLA-A24.

In CD, we confirm significant association signals arising from alleles/haplotypes related to HLA-DRB1*0103, HLA-DRB1*04, HLA-DR7, and HLA-DRB3*0301 (, middle). We also confirm previously reported association signals with HLA-B18 and HLA-B21, and identify novel associations to HLA-DR6 (encompassing HLA-DRB1*1401), HLA-DR8 (including HLA-DRB1*0802 and *0803), and HLA-DR10. Finally, we substantiate previous reports of association [81]-[85] of the TNF promoter polymorphism TNF-857T with CD, and further show association with TNF-1031C and TNF-863A (see Dataset S4 for further information).

Rheumatoid Arthritis

Rheumatoid arthritis (RA, MIM 180300) is a chronic systemic disorder, the hallmark of which is an inflammatory polyarthritis. It has been estimated that the MHC accounts for approximately one-third of the overall genetic component of RA risk [86],[87].

Much, but probably not all, of the risk attributable to the MHC is associated with variation at HLA-DRB1. When the susceptible HLA-DR subtypes were considered as a group, Gregersen et al. noted a shared amino acid sequence at positions 70-74 of the HLA-DRB1 protein [88]. These alleles are now known collectively as "shared epitope" alleles because of the related sequence composition in the third hypervariable region: the susceptibility alleles result in missense amino acid changes, where the shared susceptibility amino acid motif is ⁷⁰Q/R-K/R-R-A-A ⁷⁴. The most common (>5% population frequency) HLA-DRB1 shared epitope susceptibility alleles include *0101, *0401, and *0404 in individuals of European ancestry, and *0405 and *0901 in individuals of Asian ancestry. The strength of genetic association to RA susceptibility differs across the HLA-DRB1 alleles, there being at least two classes of HLA-DRB1 risk alleles, high and moderate. In general, the DRB1*0401 allele exhibits a high level of risk, with a relative risk (RR) of approximately 3. The DRB1*0101, *0404, *1001, and *0901 alleles exhibit a more moderate RR in the range of 1.5.

Several studies suggest that additional genes within the MHC likely contribute to disease susceptibility once the effect of HLA-DRB1 has been taken into consideration [89]-[93]. For example, an extended haplotype that includes HLA-DRB1*03 alleles may be associated with RA [89]. The associated haplotype spans ∼500 kb, and contains MHC class III genes, including the TNF locus implicated in other studies [92],[94],[95].

Genetic variation at the HLA-DRB1 gene is clearly associated with RA. Our pooled analysis (, bottom) also suggests the existence of high and moderate risk alleles. The *0401 and *0405 alleles have ORs in the range of 3.5, with lower-limit 95% CIs >3.0. The next class of HLA-DRB1 alleles have ORs in the 1.5-2.0 range. These alleles include: *0101, *0404, *0901, and *1001; additional DR4 alleles are also included in this group ( Dw14_0404-0408 alleles). Our analysis also supports the hypothesis that genetic variation located a significant genomic distance away from the HLA-DRB1 gene-and thus possibly not in LD with any of the HLA-DRB1 risk alleles-also appears associated with RA risk. For example, alleles near the TNF locus appear associated with RA (see Dataset S5 for further information).

Conclusions

Our review and pooled analysis of MHC association in MS, T1D, SLE, CD, UC, and RA corroborate established data and identify predisposing variants that have not been previously appreciated. Apart from IBD, this is the first time, to our knowledge, that the published literature regarding MHC genetics has been systematically analyzed in these diseases. Specifically, we corroborate established data showing that HLA-DR2 and -DR3 containing haplotypes harbor lupus and MS susceptibility alleles in European populations. We also demonstrate a putative predisposing effect of HLA-DR4 haplotypes in these diseases: HLA-DRB1*0401 (or a variant in LD with this allele) in non-European lupus cohorts and several different HLA-DRB1*04 alleles in MS. In RA we emphasize the high risk of both HLA-DRB1*0401 and *0405 despite apparent molecular heterogeneity. We confirm an established association with haplotypes containing DR3, DR4, and DR9 in T1D. Furthermore we find hitherto unidentified class I ( MICA5.1 and HLA-A19) and class II ( HLA-DR5, -6, -8, and -10) association signals in IBD.

The pooled analysis highlights a number of commonalities as well as differences across the six diseases (). The most frequently shared disease susceptibility alleles arise from HLA-DR4 haplotypes, which are observed in all cases except UC. HLA-DR3 haplotypes are clearly important in disease predisposition for SLE, MS, and T1D, while DR9 haplotypes are seen in T1D and RA. CD, UC, and RA share DR1 haplotypes, although the specific DR1 alleles differ, as is the case in SLE, MS, and UC, where different DR2 haplotypes are observed. The various TNF polymorphisms that show disease predisposition in RA, CD, MS, and SLE demonstrate an interesting paradox, as therapeutic TNF-alpha blockade for CD and RA is associated with the development of demyelination and antinuclear antibodies. The susceptibility alleles/haplotypes identified in this review therefore suggest both common and disease-specific pathogenetic mechanisms in autoimmunity.

We emphasize that nearly all association studies of the MHC in autoimmune and inflammatory disease to date have been limited to a subset of ∼20 genes and have been performed in small cohorts of predominantly European origin. These genes include the classical HLA loci ( HLA-A, -B, -C, -DRB, -DQA, -DQB, -DPA, and -DPB), TNF, LTA, LTB, the TAP genes, MICA, MICB, and the complement loci ( C2, C4, CFB). Moreover, most of these studies individually investigated only a small proportion of this limited subset of genes, thus impeding our ability to compare the strength of association across studies for this limited number of loci. Given that there are 421 genetic loci currently annotated to the xMHC, approximately 252 (60%) of which are thought to be expressed, it is necessary that a more comprehensive approach to the study of the MHC in disease is undertaken in conjunction with conditional analyses that address the issue of independent susceptibility loci within the region. In order to differentiate the effects of tightly linked loci, a dense map of variation is needed in large cohorts of ethnically (thus haplotypically) diverse populations, so that rare, distinguishing recombination events can be identified. Conditional analyses can then be applied to separate allelic from haplotypic association. Such statistical analyses are only now possible with respect to the MHC. Indeed, the recently published MHC single nucleotide polymorphism studies in MS [19], SLE [96] and T1D [97] and the forthcoming IMAGEN (International Major Histocompatibility Complex and Autoimmunity Genetics Network) consortium data prove the utility of these experiments. Fine-mapping and replication of the resulting independent association signals in appropriately powered European and non-European cohorts will present future challenges prior to moving forward with functional studies. Undoubtedly, the next one to two years will be witness to the identification of the causal variants within the MHC in autoimmune disease.

Supporting Information

Table S2

Complete pooled analysis results for each MHC allele or phenotype for all diseases indicating numbers of cases and controls, number of studies, odds ratio and 95% confidence interval. Variants highlighted in yellow are positively* associated with disease (defined as lower confidence interval >1.0) and are illustrated in and .

(0.11 MB XLS)

Acknowledgments

We would like to acknowledge the contribution of Dr. Mark Daly in the generation of the pooled analysis script.

Footnotes

The authors have declared that no competing interests exist.

MMAF and TJV were funded by an arthritis research campaign (arc) Clinical Research Fellowship and Wellcome Trust Senior Research Fellowship respectively. ECW was funded by a Cancer Research Institute Fellowship. PLD is funded through grant K08 NS46341 from the NINDS. RMP is funded through grant K08 AI55314-3. JDR is funded by grants from the National Institutes of Allergy and Infectious Diseases (AI065687; AI067152) and from the National Institute of Diabetes and Digestive and Kidney Diseases (DK064869; DK062432). The funders/sponsors played no role in the conduct or design of the study.

References

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Defining the Role of the MHC in Autoimmunity: A Review and Pooled Analysis

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Elizabeth M. C. Fisher, Editor The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases.

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Aside from the pathology lecture , I found this video (which figured during the lecture) as it has everything we really need to know:https://www.youtube.com/watch?v=1SvEdg94qUA
(uni of dundee, v good recap acute inflammation)

For a more detailed recap on inflammation: https://www.youtube.com/watch?v=Fbzb75HA9M8

More on blood clotting : https://www.youtube.com/watch?v=R8JMfbYW2p4 (best) https://www.youtube.com/watch?v=x8TLTTyyPfI

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Aside from the pathology lecture, I think that the Medical Sciences textbook (https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702073373000067#hl0005374) is fabulous.

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this website gave a lot of info about the inflammatory markers, you can just use the search bar to look for what you need. otherwise, I just used crash course 4th edition

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Acute phase reactants - CRP

C-reactive protein (CRP) is produced by the liver. The level of CRP rises when there is inflammation throughout the body. It is one of a group of proteins, called acute phase reactants, that go up in response to inflammation. The levels of acute phase reactants increase in response to certain inflammatory proteins called cytokines. These proteins are produced by white blood cells during inflammation.

This article discusses the blood test done to measure the amount of CRP in your blood.

Blood is drawn from a vein (venipuncture), usually from the inside of the elbow or the back of the hand. A needle is inserted into the vein, and the blood is collected in an air-tight vial or a syringe. Preparation may vary depending on the specific test.

How the Test is Performed

A blood sample is needed. This is most often taken from a vein. The procedure is called a venipuncture.

How to Prepare for the Test

No special steps are needed to prepare for this test.

How the Test will Feel

When the needle is inserted to draw blood, some people feel moderate pain. Others may feel only a prick or stinging sensation. Afterward, there may be some throbbing.

Why the Test is Performed

The CRP test is a general test to check for inflammation in the body. It is not a specific test. This means it can reveal that you have inflammation somewhere in your body, but it cannot pinpoint the exact location. The CRP test is often done with the ESR or sedimentation rate test which also looks for inflammation.

You may have this test to:

Check for flare-ups of inflammatory diseases such as rheumatoid arthritis, lupus, or vasculitis.

Determine if anti-inflammatory medicine is working to treat a disease or condition.

A more sensitive CRP test, called a high-sensitivity C-reactive protein (hs-CRP) assay, is available to determine a person's risk for heart disease.

Normal Results

Normal CRP values vary from lab to lab. The levels often increase slightly with age, female sex and in African Americans. The majority of healthy adults have levels less than 0.3 mg/dL.

However, a low CRP level does not always mean that there is no inflammation present. Levels of CRP may not be increased in people with rheumatoid arthritis and lupus. The reason for this is unknown.

Note: Normal value ranges may vary slightly among different laboratories. Talk to your health care provider about the meaning of your specific test results.

The examples above show the common measurements for results for these tests. Some laboratories use different measurements or may test different specimens.

What Abnormal Results Mean

It is unclear if a minor rise of 0.3 to 1 mg/dL in CRP levels is a cause for concern. The hs-CRP is more precise and may be used to further understand these results.

CRP levels from 1 mg/dL to 10 mg/dL are thought to be a moderate increase.

CRP Levels greater than 10 mg/dL are considered a marked increase.

A positive test means you have inflammation in the body. The cause of a high CRP cannot always be determined. Some include:

According to the American Heart Association, results of the hs-CRP can be interpreted as follows:

You are at low risk of developing cardiovascular disease if your hs-CRP level is lower than 1.0 mg/L.

You are at average risk of developing cardiovascular disease if your levels are between 1.0 mg/L and 3.0 mg/L.

You are at high risk for cardiovascular disease if your hs-CRP level is higher than 3.0 mg/L.

Note: Positive CRP results also occur during the last half of pregnancy or with the use of birth control pills (oral contraceptives).

Risks

Risks associated with having blood drawn are slight, but may include:

Excessive bleeding

Fainting or feeling lightheaded

Hematoma (blood accumulating under the skin)

Infection (a slight risk any time the skin is broken)

Dietzen DJ. Amino acids, peptides, and proteins. In: Rifai N, ed. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 6th ed. St Louis, MO: Elsevier; 2018:chap 28.

Haberman R, Fors Nieves CE, Cronstein BN, Saxena A. Acute phase reactants. In: Firestein GS, Budd RC, Gabriel SE, Koretzky GA, McInnes IB, O'Dell JR, eds. Firestein & Kelley's Textbook of Rheumatology. 11th ed. Philadelphia, PA: Elsevier; 2021:chap 60.

Ridker PM, Libby P, Buring JE. Risk markers and the primary prevention of cardiovascular disease. In: Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli GF, Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 11th ed. Philadelphia, PA: Elsevier; 2019:chap 45.

Version Info

Last reviewed on: 1/31/2021

Reviewed by: Diane M. Horowitz, MD, Rheumatology and Internal Medicine, Northwell Health, Great Neck, NY. Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Medical Director, Brenda Conaway, Editorial Director, and the A.D.A.M. Editorial team.

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Acute phase reactants - CRP C-reactive protein (CRP) is produced by the liver. The level of CRP rises when there is inflammation throughout the body. It is one of a group of proteins, called acute phase reactants, that go up in response to inflammation.

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https://www.england.nhs.uk/improvement-hub/wp-content/uploads/sites/44/2020/06/Productive-community-hospital-Multi-Team-Working.pdf
this is quite long but some a quick skim read of some slides s beneficial- just covers generic importance of MDT

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https://www.youtube.com/watch?v=s1zOLraHxyc
https://www.youtube.com/watch?v=snjGL2x6Eus
https://patient.info/doctor/reactive-arthritis-pro

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https://bestpractice.bmj.com/topics/en-gb/524?q=Psoriatic%20arthritis&c=suggested

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Polyarticular psoriatic arthritis distinguished from rheumatoid arthritis by the presence of dactylitis and the absence of anticyclic citrullinated peptide antibodies. Non-steroidal anti-inflammatory drugs (NSAIDs) usually sufficient to treat limited disease. Patients with progressive peripheral ...

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https://www.youtube.com/watch?v=POV9izM30LU

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https://www.youtube.com/watch?v=BR9_Tka_2PQ

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Biologics and DMARDs treatments of Rheumatoid arthritis

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https://www.youtube.com/watch?v=KeeIrY4BGWE

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https://www.nice.org.uk/guidance/ng95/chapter/Recommendations

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Recommendations | Lyme disease | Guidance | NICE

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This guideline covers diagnosing and managing Lyme disease. It aims to raise awareness of when Lyme disease should be suspected and ensure that people have

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https://pathways.nice.org.uk/pathways/rheumatoid-arthritis

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Referral

Quality statement

Adults with suspected persistent synovitis affecting more than 1 joint, or the small joints of the hands and feet, are referred to rheumatology services within 3 working days of presenting in primary care.

Rationale

Rapid referral of adults with suspected persistent synovitis is important to avoid delay in diagnosis and treatment. Rapid referral is particularly important for adults with inflammation of more than 1 joint, or the small joints of the hands and feet because they are likely to have a poor prognosis. Early diagnosis and treatment of rheumatoid arthritis improves long-term outcomes, physical function and quality of life.

Quality measures

Structure

a) Evidence that healthcare professionals in primary care can recognise persistent synovitis.

Data source: Local data collection, for example, training records and evidence of continuous professional development covering inflammatory arthritis.

b) Evidence that systems are in place for adults with suspected persistent synovitis to be referred to rheumatology services within 3 working days of presentation.

Data source: Local data collection, for example, agreed referral pathways.

Process

Proportion of adults presenting in primary care with suspected persistent synovitis affecting more than 1 joint, or the small joints of the hands and feet, who are referred to rheumatology services within 3 working days.

Numerator - the number in the denominator who are referred to rheumatology services within 3 working days of presenting in primary care.

Denominator - the number of adults presenting in primary care with suspected persistent synovitis affecting more than 1 joint, or the small joints of the hands and feet.

Outcome

Time from presentation in primary care to diagnosis for adults with rheumatoid arthritis.

Data source: Local data collection, for example, audit of patient records.

What the quality statement means for different audiences

Service providers (such as GP practices) ensure that healthcare professionals can recognise the signs and symptoms of inflammatory arthritis. They agree pathways for urgent referral to rheumatology services (within 3 working days of presentation in primary care) of adults with suspected persistent synovitis of more than 1 joint, or the small joints of the hands and feet.

Healthcare professionals (such as GPs, nurses or allied health professionals) recognise the signs and symptoms of inflammatory arthritis and are aware of local referral pathways. They refer adults with suspected persistent synovitis of more than 1 joint, or the small joints of the hands and feet, to rheumatology services within 3 working days of presentation in primary care.

Commissioners (such as clinical commissioning groups) ensure that service specifications include referral criteria and referral pathways for adults presenting with suspected persistent synovitis of more than 1 joint, or the small joints of the hands or feet, to be referred to rheumatology services within 3 working days of presentation in primary care.

Adults with pain, swelling and stiffness of more than 1 joint, or the small joints of the hands or feet, are referred within 3 working days of their GP appointment to a specialist in rheumatology. Early referral means that they can be diagnosed and start treatment sooner if they have rheumatoid arthritis.

Source guidance

Definition of terms used in this quality statement

Persistent synovitis

Signs and symptoms of persistent synovitis include persistent (not resolving within 3 to 4 weeks) pain, swelling, heat, early morning stiffness lasting more than 30 minutes and often recurring after longer periods of rest, and loss of function of the affected joint. Occasionally the joints may also be red, but this is unusual. The person may also have systemic symptoms of inflammation, which may include malaise, fever, sweats, fatigue and weight loss.

Treatment

Quality statement

Adults with active rheumatoid arthritis start conventional disease-modifying anti-rheumatic drug (cDMARD) monotherapy within 6 weeks of referral, with monthly monitoring until their treatment target is met.

Rationale

Starting treatment quickly give the best chance of improving long-term outcomes such as joint damage, joint function and quality of life for adults with active rheumatoid arthritis. Regular monitoring of C-reactive protein (CRP) and disease activity allows for the dose of cDMARDs to be adjusted as needed. Intensive treatment monitoring and adjustment, with the aim of maintaining remission, or low disease activity if remission cannot be achieved, results in better long-term function and quality of life for adults with rheumatoid arthritis.

Quality measures

Structure

a) Evidence of local arrangements to start treatment with cDMARD monotherapy for adults with active rheumatoid arthritis within 6 weeks of referral from primary care.

Data source: Local data collection, for example, service protocols and treatment strategies.

b) Evidence of local arrangements to measure CRP and disease activity monthly in adults with active rheumatoid arthritis until they are in remission or have low disease activity if remission cannot be achieved.

Data source: Local data collection, for example, service protocols and treatment strategies.

Process

a) Proportion of adults with suspected persistent synovitis who have specialist assessment within 3 weeks of referral from primary care.

Numerator - the number in the denominator who have specialist assessment within 3 weeks of referral.

Denominator - the number of adults with suspected persistent synovitis referred to rheumatology services.

b) Proportion of adults with active rheumatoid arthritis starting cDMARD monotherapy within 6 weeks of referral from primary care.

Numerator - the number in the denominator who start cDMARD monotherapy within 6 weeks of referral.

Denominator - the number of adults with active rheumatoid arthritis referred to rheumatology services.

c) Proportion of adults with active rheumatoid arthritis who have their CRP and disease activity score measured monthly.

Numerator - the number in the denominator who had their CRP and disease activity score measured within the past month.

Denominator - the number of adults with active rheumatoid arthritis.

Data source: Local data collection, for example, audit of patient records.

Outcome

a) Disease activity for adults with rheumatoid arthritis.

b) Health-related quality of life for adults with rheumatoid arthritis.

Data source: The National Early Inflammatory Arthritis Audit collects data on patient-reported quality of life, including symptoms, wellbeing, impact on daily life and work, in the patient questionnaire at baseline, 3-month and 12-month follow-up.

What the quality statement means for different audiences

Service providers (such as rheumatology services) ensure that systems are in place for adults with active rheumatoid arthritis to start cDMARD monotherapy within 6 weeks of referral from primary care. They also ensure that staff from the multidisciplinary team are trained to perform monthly monitoring of active rheumatoid arthritis.

Healthcare professionals (such as rheumatology consultants, rheumatology specialist registrars and specialist nurses) start cDMARD monotherapy for adults with active rheumatoid arthritis within 6 weeks of referral. They measure CRP and disease activity monthly until the target of remission, or low disease activity if remission cannot be achieved, is met.

Commissioners (such as clinical commissioning groups) commission rheumatology services that have capacity for adults with active rheumatoid arthritis to start treatment with cDMARD monotherapy within 6 weeks of referral. They check whether services undertake monthly monitoring for adults with active disease.

Adults with active rheumatoid arthritis start treatment within 6 weeks of seeing their GP. They also have monitoring each month until they have achieved their treatment target.

Source guidance

Definitions of terms used in this quality statement

Treatment target

A treat-to-target strategy should be used for adults with rheumatoid arthritis. This defines a treatment target (such as remission or low disease activity if remission cannot be achieved) based on a composite score such as DAS28 and applies tight control (such as monthly monitoring with treatment adjustment) to reach this target. The treatment strategy often follows a protocol for adapting treatment depending on the disease activity level and degree of response to treatment.

Equality and diversity considerations

Patient education

Quality statement

Adults with rheumatoid arthritis are given opportunities throughout the course of their disease to take part in educational activities that support self-management.

Rationale

It is important that adults with rheumatoid arthritis are involved in making decisions about their care and have a good understanding of their condition and its management. This enables them to get the best from their medicines, to better manage flare-ups, pain and fatigue, as well as improving their overall quality of life. To ensure they get the greatest benefit, it is essential that adults with rheumatoid arthritis are offered educational and self-management activities and signposting to resources provided by patient organisations, throughout the disease course and at times to suit individual needs.

Quality measures

Structure

Evidence of availability of educational activities for people with rheumatoid arthritis throughout the course of their disease.

Data source: Local data collection, for example, service protocols and treatment plans, or evidence of signposting to patient organisations documented in patient record.

Process

a) Proportion of adults with rheumatoid arthritis who are offered educational activities within 1 month of diagnosis.

Numerator - the number in the denominator who are offered educational activities within 1 month of diagnosis.

Denominator - the number of adults with rheumatoid arthritis.

Data source: Local data collection, for example, documentation in patient records or survey of adults with rheumatoid arthritis. The 2019/20 National Tariff Payment System collects data on adults with rheumatoid arthritis and early inflammatory arthritis who are offered education within 1 month of diagnosis.

b) Proportion of adults with rheumatoid arthritis who report at annual review that they have been given as much information as they want about their condition and its management.

Numerator - the number in the denominator who report that they have been given as much information as they want about their condition and its management.

Denominator - the number of adults with rheumatoid arthritis having an annual review.

Outcome

Proportion of adults with rheumatoid arthritis who are satisfied with their ability to self-manage their condition.

Numerator - the number in the denominator who are satisfied with their ability to self-manage their condition.

Denominator - the number of adults with rheumatoid arthritis.

Data source: Local data collection, for example, using patient surveys.

What the quality statement means for different audiences

Service providers (such as rheumatology services) ensure that adults with rheumatoid arthritis are offered educational and self-management activities throughout their disease course. They ensure that staff have access to and knowledge of educational materials, structured programmes, and patient organisations for rheumatoid arthritis, and know how to communicate effectively with adults with rheumatoid arthritis to allow for shared decision making.

Healthcare professionals (such as rheumatology consultants, specialist nurses, and allied health professionals) offer adults with rheumatoid arthritis structured educational and self-management activities throughout the course of the disease. They offer verbal and written information at each appointment to improve the person's understanding of their condition and its management. They provide opportunities for adults with rheumatoid arthritis to be involved in decisions on management of their disease and they signpost to relevant patient organisations.

Commissioners (such as clinical commissioning groups) commission services that provide educational and self-management activities for adults with rheumatoid arthritis and engage with patient organisations to provide additional support and resources.

Adults with rheumatoid arthritis take part in activities that help them to learn about their condition and what they can do to help themselves (self-management). These activities and resources should be available throughout the course of their disease. They are offered information to help them make decisions on managing their condition.

Source guidance

Definitions of terms used in this quality statement

Educational activities

Educational activities and self-management programmes can be provided 1-to-1 in a clinic setting, through self-study or computer-based interventions. They can also be provided in formal organised group sessions led by rheumatology healthcare professionals or trained lay leaders with arthritis or other chronic conditions. Different formats may be used, and should include patient information supported by written resources, to improve understanding of the condition and its management, and counter any misconceptions adults with rheumatoid arthritis may have. Educational activities may include lectures or facilitated interactive group discussions to increase knowledge and reduce concerns. Alternatively, regular skills practice, goal setting and home programmes may be used to facilitate behavioural change. The opportunity to take part in existing educational activities and self-management programmes should be offered to adults with rheumatoid arthritis throughout the course of their disease.

Equality and diversity considerations

Adults with rheumatoid arthritis should be provided with education and self-management materials and resources that they can easily read and understand themselves, or with support. Information should be in a format that suits their needs and preferences. It should be accessible to people who do not speak or read English, and it should be culturally and age appropriate. Adults with rheumatoid arthritis should have access to an interpreter or advocate if needed.

Adults with rheumatoid arthritis should be offered information about planning a pregnancy, pregnancy and breastfeeding at the time of diagnosis and throughout the course of their disease. The information should be appropriate to their age and circumstances.

Rapid access to specialist care

Quality statement

Adults with rheumatoid arthritis and disease flares or possible treatment-related side effects receive advice within 1-working-day of contacting rheumatology services.

Rationale

It is important that adults with rheumatoid arthritis and disease flares or treatment-related side effects can access rheumatology services rapidly to prevent any further joint damage. Rapid involvement of a specialist is essential for patient safety when there are side effects related to treatment. People may also need advice from members of the multidisciplinary team such as physiotherapists or occupational therapists, when they are having difficulties with activities of daily living.

Quality measures

Structure

a) Evidence of local arrangements for adults with rheumatoid arthritis to contact rheumatology services.

b) Evidence of availability of staff to give advice to adults with rheumatoid arthritis when they contact rheumatology services.

Data source: Local data collection, for example, staffing rotas.

Process

Proportion of adults with rheumatoid arthritis who receive advice from rheumatology services within 1 working day when experiencing a disease flare or possible treatment-related side effects.

Numerator - the number in the denominator who receive advice from rheumatology services within 1 working day.

Denominator - the number of adults with rheumatoid arthritis and a disease flare or possible treatment-related side effects who contact rheumatology services.

Outcome

a) Disease activity for adults with rheumatoid arthritis.

b) Functional ability of adults with rheumatoid arthritis.

What the quality statement means for different audiences

Service providers (such as rheumatology services) ensure that staff are available to give advice to adults with rheumatoid arthritis within 1 working day when they are experiencing disease flares or possible treatment-related side effects.

Healthcare professionals (such as rheumatology consultants, specialist nurses and allied health professionals) give advice within 1 working day when contacted by people with rheumatoid arthritis who have a disease flare or possible treatment-related side effects.

Commissioners (such as clinical commissioning groups) commission rheumatology services that have capacity to give advice when people with rheumatoid arthritis contact the service.

Adults with rheumatoid arthritis know who to contact and how to get advice quickly when they have a flare up of their condition or they have possible side effects from treatment.

Source guidance

Annual review

Quality statement

Adults with rheumatoid arthritis have a comprehensive annual review that is coordinated by rheumatology services.

Rationale

Annual review is important to ensure that all aspects of rheumatoid arthritis are under control and quality of life is maximised. It provides an opportunity to assess how the person is managing their condition and to identify any further support they may need. This includes support from individual members of the multidisciplinary team. It provides an opportunity to assess disease activity and measure functional ability, check for comorbidities, such as cardiovascular disease and osteoporosis, and complications of rheumatoid arthritis, including vasculitis and disease of the spine, lung or eyes. It also provides an opportunity to establish how the disease is affecting a person's life, including any effect on work and on psychological wellbeing.

Quality measures

Structure

Evidence of arrangements to ensure that adults with rheumatoid arthritis have a comprehensive annual review coordinated by rheumatology services.

Data source: Local data collection, for example, service specifications.

Process

Proportion of adults with rheumatoid arthritis diagnosed more than 12 months ago who had a comprehensive review within the past 12 months.

Numerator - the number in the denominator who had a comprehensive review within the past 12 months.

Denominator - the number of adults with rheumatoid arthritis diagnosed more than 12 months ago.

Outcome

Health-related quality of life for adults with rheumatoid arthritis.

Data source: The National Early Inflammatory Arthritis Audit collects data for patient-reported quality of life, including symptoms, wellbeing, impact on daily life and work at baseline, 3-month and 12-month follow-up as part of the patient questionnaire.

What the quality statement means for different audiences

Service providers (rheumatology services) coordinate comprehensive annual review for adults with rheumatoid arthritis. They ensure that systems are in place to invite adults with rheumatoid arthritis to attend an annual review and ensure that all elements of the review have been completed. This includes the use of protocols to refer to members of the multidisciplinary or surgical team when necessary.

Healthcare professionals (such as rheumatology consultants, specialist registrars, specialist nurses and GPs) provide a comprehensive annual review for all adults with rheumatoid arthritis. The review includes assessment of disease activity, functional ability and development of comorbidities or disease complications. They also assess the need for referral to other members of the multidisciplinary or surgical team. They have the expertise to assess the effect the disease is having on a person's life.

Commissioners (such as clinical commissioning groups) ensure that service specifications include the provision of a comprehensive annual review for adults with rheumatoid arthritis. They monitor services to check whether these annual reviews are being done.

Adults with rheumatoid arthritis have a check-up each year. The check-up includes an assessment of rheumatoid arthritis and complications, as well as a check for heart disease, bone disease and depression. They are asked about how the rheumatoid arthritis is affecting their day-to-day life and are referred to other services (such as physiotherapy and occupational therapy) if needed.

Source guidance

Definitions of terms used in this quality statement

Comprehensive annual review

A comprehensive annual review includes:

assessing disease activity and damage, and measuring functional ability (using, for example, the HAQ)

checking for the development of comorbidities such as hypertension, ischaemic heart disease, osteoporosis and depression

assessing symptoms that suggest complications such as vasculitis and disease of the cervical spine, lungs or eyes

organising appropriate cross-referral within the multidisciplinary team

assessing the need for referral for surgery

assessing the effect the disease is having on the person's life.

The multidisciplinary team

A multidisciplinary approach to managing rheumatoid arthritis incorporates various health professions such as specialist nurses, physiotherapists, occupational therapists and podiatrists. The composition of the team may vary in an individual centre, but emphasis should be placed on the tasks required to care for the individual's needs. The adult with rheumatoid arthritis can often be an active member of the team.

Equality and diversity considerations

Adults with rheumatoid arthritis should be offered information about planning a pregnancy, pregnancy and breastfeeding at annual review. The information should be appropriate to their age and circumstances.

Effective interventions library

Effective interventions library

Person-centred care

People have the right to be involved in discussions and make informed decisions about their care, as described in your care.

Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.

Your responsibility

Guidelines

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.

Technology appraisals

The recommendations in this interactive flowchart represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, health professionals are expected to take these recommendations fully into account, alongside the individual needs, preferences and values of their patients. The application of the recommendations in this interactive flowchart is at the discretion of health professionals and their individual patients and do not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Commissioners and/or providers have a responsibility to provide the funding required to enable the recommendations to be applied when individual health professionals and their patients wish to use it, in accordance with the NHS Constitution. They should do so in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities.

Medical technologies guidance, diagnostics guidance and interventional procedures guidance

The recommendations in this interactive flowchart represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, healthcare professionals are expected to take these recommendations fully into account. However, the interactive flowchart does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.

Commissioners and/or providers have a responsibility to implement the recommendations, in their local context, in light of their duties to have due regard to the need to eliminate unlawful discrimination, advance equality of opportunity, and foster good relations. Nothing in this interactive flowchart should be interpreted in a way that would be inconsistent with compliance with those duties.

Pathway created: April 2013 Last updated: September 2021

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Quality statement Adults with suspected persistent synovitis affecting more than 1 joint, or the small joints of the hands and feet, are referred to rheumatology services within 3 working days of presenting in primary care. Rationale Rapid referral of adults with suspected persistent synovitis is important to avoid delay in diagnosis and treatment.

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This website goes into great detail on the MHC II and immune tolerance

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Class II MHC Antigen Processing in Immune Tolerance and Inflammation

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Presentation of peptide antigens by MHC-II proteins is prerequisite to effective CD4 T cell tolerance to self and to recognition of foreign antigens. Antigen uptake and processing pathways as well as expression of the peptide exchange factors HLA-DM and ...

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https://www.niaid.nih.gov/research/immune-tolerance

https://clinicalkeymeded.elsevier.com/reader/books/9780702068010/epubcfi/6/84[%3Bvnd.vst.idref%3Did_chp0028]!/4/2/24/2[s0025]/8/2[s0030]/12[p0155]/1:396[the%2C%20de]

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Tolerance is the prevention of an immune response against a particular antigen. For instance, the immune system is generally tolerant of self-antigens, so it does not usually attack the body's own cells, tissues, and organs. However, when tolerance is lost, disorders like autoimmune disease or food allergy may occur. Tolerance is maintained in a number of ways:

When adaptive immune cells mature, there are several checkpoints in place to eliminate autoreactive cells. If a B cell produces antibodies that strongly recognize host cells, or if a T cell strongly recognizes self-antigen, they are deleted.

Nevertheless, there are autoreactive immune cells present in healthy individuals. Autoreactive immune cells are kept in a non-reactive, or anergic, state. Even though they recognize the body's own cells, they do not have the ability to react and cannot cause host damage.

Regulatory immune cells circulate throughout the body to maintain tolerance. Besides limiting autoreactive cells, regulatory cells are important for turning an immune response off after the problem is resolved. They can act as drains, depleting areas of essential nutrients that surrounding immune cells need for activation or survival.

Some locations in the body are called immunologically privileged sites. These areas, like the eye and brain, do not typically elicit strong immune responses. Part of this is because of physical barriers, like the blood-brain barrier, that limit the degree to which immune cells may enter. These areas also may express higher levels of suppressive cytokines to prevent a robust immune response.

Fetomaternal tolerance is the prevention of a maternal immune response against a developing fetus. Major histocompatibility complex (MHC) proteins help the immune system distinguish between host and foreign cells. MHC also is called human leukocyte antigen (HLA). By expressing paternal MHC or HLA proteins and paternal antigens, a fetus can potentially trigger the mother's immune system. However, there are several barriers that may prevent this from occurring: The placenta reduces the exposure of the fetus to maternal immune cells, the proteins expressed on the outer layer of the placenta may limit immune recognition, and regulatory cells and suppressive signals may play a role.

Read more about MHC proteins in Communication.

Transplantation of a donor tissue or organ requires appropriate MHC or HLA matching to limit the risk of rejection. Because MHC or HLA matching is rarely complete, transplant recipients must continuously take immunosuppressive drugs, which can cause complications like higher susceptibility to infection and some cancers. Researchers are developing more targeted ways to induce tolerance to transplanted tissues and organs while leaving protective immune responses intact.

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Tolerance is the prevention of an immune response against a particular antigen. For instance, the immune system is generally tolerant of self-antigens, so it does not usually attack the body's own cells, tissues, and organs. However, when tolerance is lost, disorders like autoimmune disease or food allergy may occur.

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Used crash course and the lecture
https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702073601000123

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ClinicalKey Student is an interactive education platform that supports students and faculty with tools to develop and assess the medical knowledge of aspiring professionals.