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.
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)
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
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
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
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
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
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,
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
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
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
defective intestinal barrier and dysregulated gut immune response causes chronic, progressive, and destructive inflammation usually presenting as abdominal pain
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
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
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.