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Rheumatic Diseases

I’ve always been curious about the seemingly random symptoms of pain, inflammation, redness, or itchiness that pop up throughout people’s lives — sometimes magically disappearing and sometimes persisting and getting worse over time. The complexity of immunology is fascinating to me, and unraveling the clinical manifestations of a disturbed immune system is a major research interest of mine. This post will explore all the different types of rheumatic diseases, including links to review articles, basic summaries of the pathogenesis, and approaches for care and treatment.

In addition to the flagship Janeway’s Immunobiology text, there is a clinical companion, Case Studies in Immunology, both of which have been great references while learning about this broad subject area. Also, the Internal Medicine Pocket Medicine and OnRounds: 1000 Internal Medicine Pearls have been helpful books to learn concretely the different care algorithms for each condition.

A major goal of mind when learning about a new area is also getting a grasp of vocabulary. To this point, I’ll list upfront all the new and old vocabulary that I’ve had to learn and relearn. Hopefully, the next time I revisit I won’t forget all these terms! It is my hope to cover: ulcers, rashes, scaly skin, arthralgia, fever, fatigue, sore throat, mucocutaneous lesions, anti-Ro antibodies, C reactive protein, other autoantibodies (Smtih antigen, ds DNA), ANCA, hypocomplementemia, bursitis, uticaria, tophus, Rheumatoid Factor (RF), rheumatoid nodules, sacroiliitis, sicca, hyperuricaemia, NLRP3 inflammasome, TLR activation, DAMPs, Interferon (IFN), enthesitis, etc…

The general principles behind rheumatic and autoimmune diseases have been reviewed extensively. Briefly, they involve excessive and prolonged activation of immune cells, such as T and B lymphocytes, and overexpression of the master pro-inflammatory cytokine tumor necrosis factor alpha (TNF), together with other mediators such as interlukin-6 (IL-6), interlukin-1 (IL-1), and interferon gamma (IFN-γ). Non specific symoptoms of systemic inflammation include weight loss, fatigue, and joint and muscle pain.

Conditions

Rheumatoid Arthritis:

  • over production of TNF, IL-1, IL-6
  • treat with NSAIDs, glucocorticoids, DMARDs
  • strong genetic component with HLA-DRB1*01 and HLA-DRB1*04 highly associated with RA
  • Citrullination or other PTMs create altered peptides that bind MHC and generate autoantibodies including RF and ACPA
  • Interestingly, all targeted therapies have similar response rates

Osteoarthritis

  • chondrocytes replace GAG constituents which undergo turnover in response to external stimuli
  • Early in OA, chondrocytes exhibit increased synthetic activity and secrete SASP
  • Later, chondrocytes contribute to vascular invasion and hypertrophy
  • Dysfunctional chondrocytes generate pro-inflammatory cartilage degradation products, which act as damage-associated molecular patterns (DAMPs) that interact with Toll-like receptors (TLRs)

Sjögren’s syndrome

  • systemic autoimmune disease that primarily affects the exocrine glands (mainly the salivary and lacrimal glands) and results in the severe dryness of mucosal surfaces, principally in the mouth and eyes
  • characterized by immune activation in epithelial cells
  • patients are at increased risk of developing lymphoma

Gout

  • chronic disease caused by monosodium urate (MSU) crystal deposition, most common arthritis. Urate is the end product of human purine metabolism (beer, meat, seafood)
  • Allopurinol and colchicine are common medications used to lower urate levels
  • Symptoms occur in flares that self resolve but get more frequent over time, sometimes developing into tophaceous gout. During flares, neutrophil infiltration and IL-1beta have critical roles.
  • Altered urate transport has a central role in pathogenesis

Systemic Sclerosis

  • characterized by the distinctive pathogenetic triad of microvascular damage, dysregulation of innate and adaptive immunity, and generalized fibrosis in multiple organs
  • initiated by microvascular injury and endothelial activation, followed by immune cell infiltration. mechanisms unclear and no targeted therapies available. systemic immunosuppression and symptom relief are primary management strategies

Psoriasis

  • strong polygenic risk basis, cyclic evolution
  • abnormal keratinocyte proliferation and immune cell infiltration in the dermis and epidermis
  • in psoriatic lesions, CAMP (cathelicidin antimicrobial peptide) expression is uncontrolled which triggers pathological IFN signalling cascades and the activation of dendritic cells, which result in uncontrolled inflammation

Ankylosing Spondylitis

  • strong genetic association with HLA-B27
  • mechanical stress at specific tissue sites is a trigger
  • IL-23, IL-17, and TNF signaling pathways are important
  • leads to osteoproliferation and inflammation

Multiple Sclerosis

  • presents as muscle weakness, sensory deficits, cognitive impairment, and fatigue
  • Now known to be caused by EBV infection
  • infiltration of inflmmatory cells into CNS (breakdown of BBB), leads to inflammation demyelination, and neurodegeneration
  • pathological hallmark of MS is presence of demyelinating lesions in brain, spinal cord, and optic nerve

Myasthenia Gravis

  • presents as muscle weakness, ptosis, and double vision
  • ~80% of patients have autoantibodies against acetylcholine receptor (AChR), 1-10% of patients have MuSK antibodies which lead to reduced AChR clustering
  • treatments include anticholinesterases and immunosuppresants

Systemic Juvenile Idiopathic Arthritis

  • umbrella term for arthritis of unknown origin lasting > 6 weeks with onset before 16 weeks
  • treatment typically starts with NSAIDs and/or intra-articular corticosteroid injections
  • there is a need for improved classification, since this is a heterogenous group of disorders

Lupus (Systemic Lupus Erythematosus)

  • tissue damage driven by autoimmunity and excessive immune activation
  • viral infection, UV light, and certain drugs are known triggers of SLE initiation
  • Lupud nephritis (inflammation of the kidneys) is caused by SLE

Myositis

  • acute, subacute, or chronic symmetric muscle weakness, myalgia, low muscle endurance, and presence of auto-antibodies are used to diagnose and classify
  • thought to develop as a result of interactions between genetic and environmental risk factors in the relative absence of protective factors
  • several subtypes: dermatomyositis, immune-mediated necrotizing myopathy, includion body myositis, antisynthetase syndrome, polymyositis, overlap myositis,

Type I Diabetes

  • T cell mediated destruction of beta islet cells in the pancreas, with beta cell autoantibodies
  • chronic disease characterized by insulin deficiency, leading to hyperglycemia (presents as polyuria and thirst)

Allergies

  • breakdown of clinical and immune tolerance occurs when specific IgE antibodies bound to mast cells and basophils trigger the release of immune mediators like histamine
  • ‘first 1000 days’ between intrauterine development and first 2 years of post natal life have a lasting impact on susceptibility to developing allergies
  • environmental factors impact gut microbiota, conditions like atopic dermatitis increase risk of allergy development

ANCA associated vasculitis

  • comprises three autoimmune disorders: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA)
  • Anti-neutrophil cytoplasmic autoantibody (ANCA) are self-reactive antibodies that bind to neutrophils and overactivate them

Large-vessel vasculitis

  • inflammation of large blood vessels mainly consisting of two distinct conditions, giant cell arteritis (GCA) and Takayasu arteritis (TAK); most common vasculitis
  • may cause vision disturbance, which should be seriously monitored and treated with steroids

Behcet’s Disease

  • a systemic vasculitis affecting small and large vessels of venous and arterial systems which manifest in major vascular disease, eye disease, and central nervous system involvement
  • strong association with HLA-B*51, Th1 cells are thought to be mainly responsible for disease mechanisms
  • other hypotheses and associations include endothelial activation, hyperactive neutrophils (which potentially drive thrombosis), and reduced circulating haematopoietic progenitor cells

Chron’s Disease

  • defective intestinal barrier and dysregulated gut immune response causes chronic, progressive, and destructive inflammation usually presenting as abdominal pain
  • persistent immune cell activation, increased cytokine production, reduced anti-inflammatory responses
  • defective tight junctions, reduced antimicrobial peptide secretion and impaired bacterial clearance at intestinal barriers

Celiac Disease

  • indigestion of dietary gluten (gliadins and glutenins) causes peptides to be presented to CD4 T cells which leads to production of anti-gluten and anti-TG2 antibodies
  • intraepithelial lymphocytes kill intestinal epithelial cells, contributing to enteropathy
  • almost exclusively occurs in individuals with HLA-DQ2 and/or HLA-DQ8 haplotypes

Ulcerative Colitis

  • inflammation of the innermost layer of the intestine, resulting in ulceration and bloody diarrhea
  • decreased thickness of mucosal layer and reduced microbiota diversity causes barrier breach, activating immune cells and causing cytokine release (TNF, IL-13, IL-9, IL-23, IL-36)
  • symptom presentation includes blood and/or mucus in stool, increased frequency of bowel movements, etc

Autoimmune gastritis

  • progressive autoimmune disease characterized by the destruction of gastric parietal cells, leading to atrophy of oxyntic mucosa of the stomach
  • anti-parietal cell antibodies and anti-intrinsic factor antibodies are formed; autoimmunity is thought to be mediated by autoreactive T helper cells
  • anaemia and other hematological alterations, presence of autoantibodies, dyspepsia, and early satiety are common symptoms. diagnosis made via IHC

Drugs

NSAIDs (Non-steroidal anti-inflammatory drugs): analgesic, antipyretic, and anti-inflammatory effects by blocking COX which promotes the production of prostaglandins, a mediator which causes inflammation and pain. Cox-2 inhibitor (ibuprofen, naproxen, diclofenac, celecoxib, etoricoxib) Aspirin Paracetamol Capcaisin

DMARDs (conventional synthetic disease modifying antirheumatic drugs): treat root causes of inflammation Hydroxychloriquine (HCQ) Methotrexate Sulfasalazine Leflunomide (NF-kb inhibitor) TNF-alpha antibody (Adalimumab,certolizumab, etanercept, golimumab, infliximab) CD80/86 antibody (Abatacept) IL-1R antibody (Anakinra) IL-6R antibody (Tocilizumab, sarilumab) IL-12/23 antibody (Ustekinumab) IL-17 antibody (Secukinumab) Cyclosporine (and analogs) CD-20 antibody (Rituximab) BAFF blockade (Belimumab) JAK inhibitors (baracitinib, tofacitinib) PDE4 inhibitor (Apremilast)

Glucocorticoids: powerful anti-inflammatories Prednisone Dexamethasone

Future Drugs and Conclusions

My exploration into rheumatic conditions was both surprising and unsurprising. Firstly, there was a lot of new vocabulary and knowledge here that I expected to at least be exposed to during undergrad, but clearly had not. The knowledge base here is dense and hard to understand — clearly a lot to be unraveled here. One reason might be due to the lack of representative animal models. A lot of these conditions develop with old age and older mice are expensive. Maybe there is an opportunity for organoids or other cellular models to recapitulate old age or any of these age related inflammatory conditions.

One thing I was surprised about was that the cause of more than a few of these conditions isn’t exactly immune related. In other words, the issue isn’t the immune system per se, but rather something else is messed up and the immune system is responding to it. The immune system continously self-regulates, but for example in conditions like gout, barrier function disease like IBD, or chronic infections, it makes sense that the immune system is reacting to stimuli. Addressing these conditions upstream of the immune response is where the curative potential lies.

There is a lot of work to be done in this area. The very very few drugs that exist are effective in subsets of patients. Most rely on immunosuppression or other general mechanisms, making quality of life for some individuals a tradeoff. Future therapy might look like Treg cell therapy, protein degraders for tough inflammasome targets, complement blockade, tolerizing vaccines and biomaterials. Clinical trials in this area are inevitably quite expensive, but regardless lots of reasons to be optimistic.

Last thought is a link to an interesting case report published in NEJM where a differential is performed on a patient with autoimmune symptoms.