Block 8 - Musculoskeletal Flashcards

Question

**BENIGN BONE TUMOURS - What is a** **Unicameral bone cyst?** * Description? (1) * Epidemiology? (1) * Location? (1) * Characteristics? (2) * Treatment? (2) * Diagnostics? (3)

Answer 1

**Unicameral bone cyst**

Answer 2

**Aneurysmal bone cyst**

Answer 3

**_SOFT TISSUE CYSTS -**_ _**Popliteal/Baker cyst (Synovial cyst)_** * **Diagnostics** * Usually, a clinical diagnosis * Plain x-ray or ultrasound are commonly used as initial imaging modalities and reveal a soft tissue mass (x-ray) or an anechoic lesion (ultrasound). * MRI can be helpful in some case * **Treatment** * Asymptomatic cysts do not require treatment. * Symptomatic cysts * Treat underlying pathology of the knee joint * If symptoms persist, intra-articular injection of glucocorticoids can control inflammation. * Surgical resection for symptomatic cysts that persist despite treatment.

Answer 4

**_SOFT TISSUE CYSTS -**_ _**Popliteal/Baker cyst (Synovial cyst)_** **Complications** 1. Cyst enlargement and rupture → leakage of synovial fluid caudally into the lower leg muscles 2. Rupture of a popliteal cyst may mimic a deep vein thrombosis! 3. Positive Homan’s sign (calf pain during foot dorsiflexion)

Answer 5

1. Ewings sarcoma 2. Osteosarcoma 3. Chondrosarcoma 4. Malignant Fibrous Histiocytoma (Soft Tissue Sarcoma) 5. Chordoma 6. Mets/Secondary

Answer 6

**_MALIGNANT BONE TUMOURS -**_ _**Ewing’s Sarcoma_** * **Conventional X-ray** * Lytic bone lesions * Onion skin appearance of the periosteum * **Biopsy** * Very little cytoplasm and few mitotic figures * Very little matrix produced * PAS positive cells * Leu-7 and neuron-specific enolase positivity * Anaplastic small-blue-round-cell malignancy * Tumour cells resemble lymphocytes. * Differential diagnoses include lymphoma and chronic osteomyelitis. * Chromosomal translocation t(11;22)(q24;q12) which leads to expression of fusion protein EWS-FLI1 * Cells contain glycogen accumulations and are usually CD99-positive. * **Laboratory findings:** ↑ ESR, ↑ LDH (lactate dehydrogenase), leucocytosis

Answer 7

**_MALIGNANT BONE TUMOURS -**_ _**Osteosarcoma_** **1 - Imaging** * **Conventional x-ray** * Sunburst appearance of lytic bone lesions and/or Codman triangles * Signs of osteolysis adjacent to osteosclerosis (moth-eaten appearance) * **MRI**: assesses the involvement of soft tissue, evaluation in cases of unclear radiographic findings **2 - Biopsy** * Pleomorphic, malignant osteoblasts that produce osteoid * Osteosarcomas always feature woven bone matrix (compared to chondrosarcomas and fibrosarcoma) **3 - Laboratory** * ↑ Alkaline phosphatase, ↑ LDH, ↑ ESR

Answer 8

**_MALIGNANT BONE TUMOURS -**_ _**Chondrosarcoma_** * **Conventional X-ray or CT** * Osteolysis with a moth-eaten appearance * Intralesional calcifications (rings and arcs calcification, popcorn calcification) * Endosteal scalloping and cortical breach with infiltration of soft tissue * **MRI**: rim-like contrast enhancement * **Biopsy** * Malignant chondrocytes * Lobulated appearance (hyaline cartilage nodules with peripheral calcification) * **Grading** * Grade I: low cellularity, mostly chondroid matrix * Grade II: increased cellularity, decreased chondroid matrix with localized myxoid changes * Grade III: high cellularity, prominent nuclear atypia, myxoid matrix

Answer 9

**_MALIGNANT BONE TUMOURS -**_ _**Malignant Fibrous Histiocytoma (Soft Tissue Sarcoma)_** * **Definition** * Fibrogenic tumour with cells producing collagen fibres but no osteoid * **Epidemiology** * Commonest soft tissue sarcoma * 15% of soft tissue sarcomata * Age 20 – 60 years * **Localisation** * Predilection for femur, humerus and tibia * Eccentrically placed close to joint * **Clinical Features** * Soft tissue mass with bone erosion but without periosteal reaction or sclerotic change

Answer 10

**_Congenital and Developmental Bone Disorders_** * **Dysostoses** 1. Amelia 2. Phocomelia (“seal extremity”) * **Dysplasias** 1. Achondroplasia 2. Osteogenesis imperfecta (brittle bone disease)

Answer 11

**_DYSPLASIAS - Achondroplasia_** **Diagnostics** * Physical examination * DNA test * X-ray findings * Lateral skull: frontal prominence, midface hypoplasia * Spine: spinal canal stenosis, scoliosis * Extremities: short, thick bones * CT/MRI head: indicated in patients with signs of cervicomedullary compression * Assessment of brain stem compression * Measurement of the size of the foramen magnum **Therapy** * Early initiation of growth hormone therapy (between 1–6 years of age) * Surgical correction of spinal stenosis, secondary scoliosis, genu varum, brain stem compression

Answer 12

**Osteogenesis imperfecta type I (the mildest and most common form)** * Growth delay * Skeletal deformities, brittle bones * Bowing of bones and saber shins * Fractures during childbirth and recurrently from minimal trauma thereafter * Blue sclerae (choroidal veins show through the thin, translucent sclera) * Progressive hearing loss due to deformation, fracture, and/or atrophy of the ossicles * Brittle, opalescent teeth (dentinogenesis imperfecta; due to a lack of dentin) * Ligamentous laxity and joint hypermobility **Osteogenesis imperfecta type II** * Most severe form; lethal perinatally or within the first year * Multiple intrauterine and/or perinatal fractures * Underdeveloped lungs and subsequent respiratory problems * Laboratory tests: ↑serum alkaline phosphatase & ↑Ca2+ in urine

Answer 13

**_Metabolic Bone Diseases -**_ _**Classification:_** * **Disorders with OSTEOCLAST DYSFUNCTION** 1. Paget’s Disease 2. Osteopetrosis * **Disorders with ABNORMAL MATRIX** 1. Osteogenesis imperfecta (I-IV) 2. Mucopolysaccharidoses 3. Osteoporosis * **Disorders with ABNORMAL MINERAL HOMEOSTASIS** 1. Rickets & Osteomalacia 2. Hyperparathyroidism 3. Renal Osteodystrophy

Answer 14

**_Paget Disease of Bone (Osteitis deformans)_** **Diagnostics - Laboratory tests** * **Blood work** * Normal calcium, phosphate, and parathyroid hormone ([PTH](https://next.amboss.com/us/article/Hg0K92#Z82b80df8e4df1330c0aa8506a5aa4525)) levels * ↑↑ Serum alkaline phosphatase ([ALP](https://next.amboss.com/us/article/Ln0wFg#Z78c098e284dee4ae95afddad9ababaa4)) = most common cause of isolated elevated ALP in patients \>40 years old. * Hyperuricemia * **Urinalysis**: ↑ markers of collagen degradation * Deoxypyridinoline * N-telopeptide, C-telopeptide * Hydroxyproline

Answer 15

**_Paget Disease of Bone (Osteitis deformans)_** **Imaging -** **X-ray** * Deformed bones with both sclerotic and osteolytic lesions * Sclerotic lesion: focus/foci of ↑ density (usually the result of increased mineralization and/or thickening). * Osteolytic lesion: focus/foci of ↓ density (usually the result of decreased demineralization). * Thickened cortical bone * Coarsened trabeculae; expansion or enlargement of a region of the bone. * **Skull x-ray:** thickening of the diploe; osteoporosis circumscripta (cotton wool appearance). * **Vertebral x-ray:** thickening of the upper and lower plates of the vertebral body gives rise to a “picture frame” appearance; diffuse enlargement of the vertebrae (ivory vertebra) * **Pelvic x-ray:** disruption/fusion of sacroiliac joints; thickened iliopectineal line (brim sign) * **Bone scans** (skeletal scintigraphy): to test for additional bony lesions

Answer 16

**_Disorders with ABNORMAL MINERAL HOMEOSTASIS - Rickets_** * **Laboratory tests** * ↓ Calcium and ↓ phosphate * ↑ Alkaline phosphatase and ↑ PTH * Vitamin D-dependent rickets type 1: ↓ calcitriol concentration * Vitamin D-dependent rickets type 2: ↑ calcitriol concentration * **Imaging** * ↓ bone density * Cortices thinning * Growth plates in the metaphysis of the long bones are less defined and show cupping, stippling, and fraying * Wide epiphysis * In severe cases, Looser zones and fractures * Chest X-ray: prominent costochondral junctions * Evidence of bone deformities

Answer 17

* **Sclerotic Lesion**: An abnormal increase in density and hardening/thickening of bone, usually from a slow - growing lesion (gain of bone), looks like 'crazy paving' * **Lytic Lesion**: Destruction of an area of bone (loss of bone), looks 'moth-eaten' * **Periosteal Reaction (Periostitis):** The formation of new bone in response to injury or other stimuli of the periosteum surrounding the bone. Will occur whenever the periosteum is irritated by a malignant tumour, benign tumour, infection or trauma. * **Benign Periosteal Reaction**: Thick, wavy and uniform callus formation resulting from chronic irritation. The periosteum has time to lay down thick new bone and remodel it into a more normal -appearing cortex. * **Aggressive Periosteal Reaction**: Multilayered, lamellated or bone formation perpendicular to the cortical bone which may be spiculated and interrupted. Sometimes there is a Codman's triangle which is elevation of the periosteum away from the cortex, forming an angle where the elevated periosteum and bone come together. In aggressive periostitis the periosteum does not have time to consolidate.

Answer 18

**Staging Investigations for Bone Tumours:** * **X-Ray:** To evaluate the primary lesion and the joint above and below * **MRI:** To plan surgery or biopsy (or sometimes CT) * **Bone Scan (Technetium):** To assess for bony secondaries (+/- PET) * **CT Chest Scan:** To assess for lung mets (osteosarcoma usually spreads to lungs, not LNs) * **NB:** Do staging before biopsy! Biopsy is either CT-guided core or open biopsy by orthopaedic surgeon, not FNA!

Answer 19

**Risk factors for poor fracture healing**: 1. Unstable 2. Comminuted 3. Severely displaced 4. Infected 5. Poorly vascularised fracture

Answer 20

**Types of Fractures:** 1. **Acute Traumatic**: Fracture caused by an accident, fall or other kind of force e.g. MVA 2. **Pathological**: Fracture caused by a disease process e.g. tumour, osteomyelitis, osteonecrosis, Paget disease or osteoporosis 3. **Stress**: Fracture due to normal bone but abnormal (repetitive) stress e.g. runners or obese people 4. **Insufficiency**: Fracture due to normal stress (physiological load) but abnormal weak bone e.g. osteoporosis or long-term bisphosphonate use commonly causing lumbar crush and sacral/pelvic fractures

Answer 21

**Mechanism of Fractures:** * **Impacted Fracture**: When the broken ends of the bone are jammed together by the force of the injury * **Compression Fracture**: When an excessive axial load compresses the bone beyond its limits (vertebral bodies) * **Depressed Fracture**: A localised force breaks and depresses one segment below the level of surrounding bone

Answer 22

**Myeloid Progenitor Cells** 1. Neutrophils 2. Eosinophils 3. Basophils 4. Mast cells 5. Monocytes 6. Dendritic cells 7. Macrophages

Answer 23

**_Cells of Innate Immune Response - Myeloid Progenitors_** ## Footnote **Macrophages/Monocytes:** A large mononuclear phagocytic cell type important as scavenger cells, pathogen recognition cells, source of pro-inflammatory cytokines in innate immunity, antigen presenting cells and as effector phagocytic cells in humoral and cell-mediated immunity. MOs derive from bone marrow precursors and are found in most tissues of the body. Precursors found in the blood are known as monocytes.

Answer 24

**_Cells of Innate Immune Response - Myeloid Progenitors_** **Dendritic Cells:** Bone marrow derived cells found in most tissues, including lymphoid tissues. Conventional DCs take up antigen in peripheral tissues and travel to the peripheral lymphoid organs, where they are the most potent stimulators of T-cell responses. * phagocytes, antigen-presenting cells * release cytokines to recruit other cells * circulate in lymph, blood tissue * consume large proteins in interstitial fluid * break blood-borne pathogens into small amino-acid chains → move to lymph node → present antigen to T cells

Answer 25

**_Cells of Innate Immune Response - Myeloid Progenitors_** ## Footnote **Neutrophils:** The most numerous type of WBC in human peripheral blood. NOs are phagocytic cells with multilobed nucleus and granules that stain with neutral stains (light pink). They enter infected tissues and engulf and kill extracellular pathogens.

Answer 26

**_Cells of Innate Immune Response - Myeloid Progenitors_** ## Footnote **Eosinophils:** A type of WBC containing granules that stain eosin (red). It is thought to be important chiefly in defence against parasitic infections, but is also important as an effector cell in allergic reactions.

Answer 27

**_Cells of Innate Immune Response - Myeloid Progenitors_** ## Footnote **Basophils**: A type of WBC containing granules that stain with basic dyes (blue-purple). It is thought to have a function similar to mast cells.

Answer 28

**_Cells of Innate Immune Response - Myeloid Progenitors_** ## Footnote **Mast Cells:** A large granule-rich cell found in connective tissues throughout the body, most abundantly in the submucosal tissues and the dermis. The granules store bioactive molecules including vasoactive amine histamine, which are released on mast-cell activation. Mast cells are thought to be involved in defences against parasites and they have a crucial role in allergic reactions.

Answer 29

**_Cells of Innate Immune Response - Myeloid Progenitors_** ## Footnote **Natural Killer Cells:** Large granular lymphocytes which kill virus-infected cells and some tumour cells. NK cells bear a wide variety of invariant activating and inhibitory receptors, but do not rearrange immunoglobulin or T-cell receptor genes. NK cells are important in innate immunity to viruses and other intracellular pathogens and in antibody-dependent cell-mediated cytotoxicity (ADCC).

Answer 30

**Lymphocytes:** A class of WBC that bear variable cell-surface receptors for antigen and are responsible for adaptive immune responses, which include B and T cells. On antigen recognition, a lymphocyte enlarges to form a lymphoblast and then proliferates and differentiates into an antigen-specific effector cell.

Answer 31

**_Cells of Innate Immune Response - Lymphoid Progenitors_** ## Footnote **B Cells/Lymphocytes:** Generated in the bone marrow and mediate humoral immunity. Antigens bind to a B cell receptor (BCR) causing B cells to proliferate and differentiate into plasma cells which produce antibody.

Answer 32

**_Cells of Innate Immune Response - Lymphoid Progenitors_** **T Cells/Lymphocytes:** Originate in the bone marrow, but develop and mature in the thymus and are responsible for cell-mediated immunity. The highly variable T cell receptor (TCR) recognises peptide-antigen complexes bound to MHC molecules on cell surfaces. Effector T cells perform a variety of functions including activation of macrophages (Th1), activation of B cells (Th2) and the killing of virus-infected cells (CTL). * **Types** 1. CD4 Type 1 T Helper (Th1) Cell 2. CD 4 Type 2 T Helper (Th2) Cell 3. CD8 Cytotoxic T Cell (CTL) 4. Suppressors (Treg) Cells

Answer 33

**_Cells of Innate Immune Response - Lymphoid Progenitors_** 1. **CD4 Type 1 T Helper (Th1) Cell:** Part of cell-mediated immunity which acts to secrete cytokines such as INF-y, IL-2 and TNF-b to activate CLT and macrophages 2. **CD 4 Type 2 T Helper (Th2) Cell:** Part of humoral immunity and acts to promote B cell maturation following antigen-MHC II complex recognition and costimulatory signals 3. **CD8 Cytotoxic T Cell (CTL):** Part of cell-mediated immunity which act to kill cells expressing anitgen- MHC I complex by releasing granules that contain perforin and granzyme for cell lysis and proteases to induce an apoptosis response within the cell 4. **Suppressors (Treg) Cells:** Have an immunosuppressive effect that inhibits cell-mediated immunity at the end of a response and destroys autoimmune T cells that aren’t filtered out by negative selection in the thymus (induced by IL-10, IL-35 and TGF-b)

Answer 34

**Memory Cells:** B and T lymphocytes that mediate immunological memory. They are more sensitive than naïve lymphocytes to antigen and respond rapidly on re-exposure to the antigen that originally induced them.

Answer 35

**NB:** Order of Cell Abundance in Plasma is Neutrophils -\> Lymphocytes -\> Monocytes -\> Eosinophils -\> Basophils (Never Let Monkeys Eat Bananas)

Answer 36

**Adaptive Immune Response:** * **Antigen Presentation (Exogenous/Extracellular Antigens):** Dendritic cells recognise extracellular pathogenic proteins and internalise, process and present Ag on MHC II to CD4 T cells at the lymph nodes, activating T helper cells. * **Antigen Presentation (Endogenous/Intracellular Antigens):** Intracellular antigens (viruses or intracellular bacteria) are processed by pathogen 'target cells' for the eventual presentation on MHC I to CD8 T cells, activating T killer cells (CTL). * **T-Cell Dependent Response (Protein Antigen)** * **T-Cell Independent Response (Carbohydrate/Lipid/DNA Antigen):** 1. B cells are able to pick up and present soluble Ag in the lymph node independent to T cell interaction. 2. Carbohydrate or lipid Ag bind to IgM or IgD of naïve B cell. 3. Highly repetitive structures cause BCR crosslinking (strong clustering) which provides a signal to activate the B cell. 4. B cell upregulates production and release of IgM. No T helper cell means no class switching, only monoclonal Abs, no memory and only modest affinity.

Answer 37

**_T-Cell Dependent Response (Protein Antigen):_** 1. Peptide Ag binds to BCR of B cell in lymph node 2. Ag is internalised and processed and peptide antigens are presented on MHC II for Th2 cell recognition at paracortex of lymph node (here BCR acts as APC) 3. Th2 recognises antigen-MHC complex via TCR 4. CD80/86 (or B7) binds to CD28 on T cells and provides a signal to activate T cell 5. T cell upregulates expression of CD40L which binds to CD40 to activate B cells and also expresses cytokines IL-4, IL-5, IL-6, IL-10 and IL-13 for B cell activation and differentiation 6. Activated B cell migrates to germinal centre of lymph node for proliferation and differentiation into Ab-secreting B cells (plasma cells) and memory cells 1. **Clonal Expansion:** Proliferation of activated B cell in dark zone of germinal centre of secondary lymphoid tissue. 2. **Somatic Hypermutation (SMH):** The phenomenon in which a high frequency of point mutations are generated within the variable region of expressed immunoglobulin genes in response to the presence of an antigen, in the dark zone of germinal centres. Produces functional and non- functional Ab with a range of high/low affinity for Ag, so Ab must go through a selection process to determine those with greatest affinity to Ag. 3. **Affinity Maturation:** The positive selection of Ab with greatest affinity for Ag via a process in which follicular dendritic cells (FDCs) or Th2 cells (follicular T helper cells) present Ag to light zone germinal centre B cells and B cells with highest/improved affinity Ab-Ag complexes compete more effectively for survival signals from FDCs. FDCs and Th2 interact via costimulatory signals (CD80/86-CD28 and CD40-CD40L) and cytokines IL-4, IL-5, IL-6, IL-10 and IL-13 which induce B cell activation, growth and differentiation (same as initial interaction with Th2) 4. **Class Switch Recombination (CSR):** B cell with improved Ag affinity undergo change in Fc region of chain to change into a different immunoglobulin (IgM to IgG, IgE or IgA) in light zone germinal centre, influenced by cytokine environment produced by T helper cells. B cells differentiate into plasma cells or memory cells.

Answer 38

**Inflammatory ("Seropositive") Joint Disease:** 1. Rheumatoid Arthritis (RA) 2. Systemic Lupus Erythematosus 3. Sjögren’s Syndrome 4. Idiopathic Juvenile Arthritis 5. Progressive Systemic Sclerosis & CREST Syndrome 6. Inflammatory Myopathies

Answer 39

**Pathogenesis of Inflammatory ("Seropositive") Joint Disease:** Autoimmune! * There is persistent synovitis, causing chronic symmetrical polyarthritis and systemic inflammation. * Initially, non-specific inflammation affects the synovial tissue, which is later amplified by activation of T cells (autoimmune response). * With time, it may lead to inflammatory joint effusion and synovial hypertrophy, as well as progressive destruction and deterioration of cartilage and bone. * Synovial lining hyperplasia * Pannus formation (proliferative granulation tissue) along the synovial tissue, production of proteinases and destruction/erosion of cartilage extracellular matrix (articular cartilage and bone) * Extra-articular manifestations

Answer 40

**NB1:** The triggering antigen, which leads to self-maintained inflammation in RA, remains unclear. Triggers for anti- citrullinated peptide antibodies (ACPA) production include filaggrin, type II collagen and vimentin. There is little evidence that collagen type II is the triggering antigen, although it is a cause of arthritis in animal models of RA. Smoking is a potential trigger, particularly in ACPA positive RA. **NB2:** Citrullination is the process where arginine amino acid residues can be enzymatically converted into citrulline residues in proteins such as vimentin or fibrinogen during inflammation.

Answer 41

Extra-articular effects of Rheumatoid Arthritis 1. Acute phase response 2. Normochromic normocytic anaemia 3. Vasculitis 4. Lymphadenopathy 5. Serositis – includes pericarditis 6. Granuloma Rheumatoid nodules 7. Amyloidosis 8. Pulmonary fibrosis 9. Felty’s syndrome - hypersplenism

Answer 42

**_Role of Immune System in Inflammatory Joint Disease (Example of RA)_** * **Plasma (B) Cells:** Produce autoantibodies to Fc portion of IgG (rheumatoid factor) and to citrullinated cyclic peptide. * **CD4+ T Helper Cells:** May initiate the autoimmune response by reacting with an arthritogenic agent, perhaps microbial or a self-antigen * **TH1 Cells:** Produce IFN-y to activate macrophages and resident synovial cells * **TH17 Cells:** Produce IL-17 to recruit neutrophils and monocytes * **Macrophages:** Produce TNF-a and IL-1 to stimulates resident synovial cells to secrete proteases that destroy hyaline cartilage. Overproduction and overexpression of TNF-a is a key inflammatory element in RA, leading to synovitis and joint destruction. Interaction of macrophages and T and B lymphocytes drives this overproduction. TNF-α stimulates overproduction of interleukin-6 and other cytokines. * **Osteoclasts:** RANKL expressed on activated T cells stimulates bone resorption * **Synovial Cells:** In chronic rheumatoid synovitis, are predominantly abnormally behaving fibroblast-like Synoviocytes and macrophage-like synoviocytes which produce pro-inflammatory cytokines.

Answer 43

**_Role of Immune System in Inflammatory Joint Disease (Example of RA)_** * **Abnormal Fibroblast-Like Synoviocytes:** Appear to circulate between joints and may be the trigger for the polyarthritis * **Synovial Fibroblasts:** Have high levels of the adhesion molecule, vascular cell adhesion molecule (VCAM-1: a molecule which supports B lymphocyte survival and differentiation), decay accelerating factor (DAF: a factor that prevents complement-induced cell lysis) and cadherin-II (which mediates cell to cell interactions). These molecules may facilitate the formation of ectopic lymphoid tissue in synovium. * **Complement:** Activated by immune complexes of RF and anti-CCP antibodies in synovial joints. As RFs have the Fc portion of IgG as their antigen they have the potential for self-aggregation and immune complex formation in the synovium. These may then trigger complement (classical pathway) and macrophages via IgGFc receptors and potentiate the inflammatory response. * **Mast Cells:** Release of histamine which contributes to increased vascular permeability and vasodilation, potentiating the inflammatory response.

Answer 44

**Type I Hypersensitivity** * Specific IgE is constitutively present bound to its receptor on mast cells * One new element results in pathology - *antigen* * One class of antibody - IgE

Answer 45

**Clinical features of Type I hypersensitivity reactions** 1. Anaphylaxis 2. Angioedema 3. Bronchospasm 4. Urticaria (hives) 5. Hypotension

Answer 46

**Type II Hypersensitivity** * The antigen is part of the target cell or tissue * Two things are needed - antibody + an effector * Can be one of 2 sorts of Ig - IgG or IgM * Can be one of 2 sorts of effector - cell or complement * Type II hypersensitivity is mediated by antibodies of the IgG and IgM classes * Antibodies are directed against cellular or ECM proteins * Antigen-bound immunoglobulin induces 1. Effector cell activation via Fc receptors 2. Complement activation * Intracellular antigens mainly do not provoke a Type II hypersensitivity response.

Answer 47

**Type III Hypersensitivity** * Disease is caused by deposition of immune complexes in tissues that are or may be unrelated to the antigen * Three new things are needed 1. Antigen 2. Antibody 3. Complement * Antibodies may be produced against free and/or soluble antigen * Microbial * Self antigens * Inhaled antigens * Usually but not exclusively IgG and fix complement. * Damage to tissues is initiated by complement. * Circulating immune complexes (CICs) are solubilised by complement * Circulating immune complexes are removed by complement binding especially to CR1 on RBCs * Clearance mainly occurs in liver and spleen * Clearance is mediated by tissue macrophages. * Failure of clearance may occur with * Over-production of CICs * Complement deficiency * CR abnormalities * Excess CICs are deposited in tissues * Complement induces an inflammatory response with tissue damage

Answer 48

**Type IV Hypersensitivity** * Different to I, II and III * T cell mediated response * Variously mounted by cells and cytokines that result in pathological changes

Answer 49

**Hypersensitivity** = Any immune response that gives rise to an excessive or inappropriate reaction or that is more damaging than the antigen or pathogen that induced the response.

Answer 50

**Goodpasture syndrome** * Antibodies are directed against the basement membrane – collagen type IV * N terminus region of collagen type IV shared by lung and kidney (especially glomerulus) after alternate RNA splicing * Goodpasture described the association of lung haemorrhage with severe necrotising GN.

Answer 51

**Type II hypersensitivity reactions - Pemphigus** * Antibody is directed against the intercellular junctions of skin and mucous membrane (desmoglein-1 and -3). * Antibodies cause loss of intercellular adhesion (acantholysis) and breakdown of the epidermis or epithelium. * Vesicular disorder that may lead to death.

Answer 52

**Myasthenia gravis** * Mediated by an antibody directed against the AChR at the neuromuscular synapse. * Neurotransmission results in internalisation of the receptor which is then not re-expressed in an appropriate time frame. * The result is fewer and fewer functional synapses with use & progressive weakening = fatiguability.

Answer 53

**Serum sickness** * Follows administration of foreign Immunoglobulin * Symptoms develop 7 -10 days after injection * Clinical features are due to tissue deposition of insoluble immune complexes 1. Chills, fever 2. Rash, especially urticaria 3. Arthritis 4. Glomerulonephritis

Answer 54

**_Inflammatory Joint Diseases:**_ _**Rheumatoid Arthritis_** * Chronic, systemic autoimmune disease (type III HSR) which classically arises in women of late childbearing age and associated with HLA-DR4. * Hallmark is synovitis leading to formation of a pannus (inflamed granulation tissue) which leads to destruction of cartilage and ankylosis (fusion) of the joint. * Clinical features include arthritis with morning stiffness that improves with activity, symmetrical involvement of PIP joints of the fingers (deformities), wrists (radial deviation), elbows, ankles and knees, and joint-space narrowing, loss of cartilage, and osteopenia seen on x-ray. * Also includes fever, malaise, weight loss, and myalgias, Rheumatoid nodules (central zone of necrosis surrounded by epithelioid histiocytes in skin and visceral organs), vasculitis, Baker cyst, pleural effusions, lymphadenopathy, and interstitial lung fibrosis. Important to diagnose early to prevent joint deformity! * Diagnose via serology (rheumatoid factor and anti- CCP), elevated ESR/CRP, joints involved and duration of synovitis.

Answer 55

**Septic Arthritis:** Due to an infectious agent, usually bacterial such as *N. gonorrhoeae* in young adults (most common) or *S. aureus* in older children and adults. Classically involves a single joint, usually the knee. Presents as a warm joint with limited range of motion with fever, increased WCC, elevated ESR and purulent synovial fluid. Requires joint aspiration for urgent diagnosis!

Answer 56

**Crystal-Induced Arthritis (Gout/Pseudogout):** * Deposition of monosodium urate (MSU) crystals in tissues, especially the joints due to hyperuricemia related to overproduction or decreased excretion of uric acid. Uric acid is derived from purine metabolism and is excreted by the kidney. * Primary gout is the most common form but etiology of hyperuricemia is unknown. * Secondary gout is seen with leukemia and myeloproliferative disorders (increased cell turnover leads to hyperuricemia), Lesch-Nyhan syndrome-X-Iinked deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (presents with mental retardation and self- mutilation), renal insufficiency (decreased renal excretion of uric acid). * Acute gout classically manifests as painful MTP joint of big toe (podagra) because MSU crystals deposit in the joint, triggering an acute inflammatory reaction. Alcohol, red meat, seafood, dehydration often lead to acute attacks. * Chronic gout leads to development of tophi-white, chalky aggregates of uric acid crystals with fibrosis and giant cell reaction in the soft tissue and joints, and renal failure as urate crystals may deposit in kidney tubules (urate nephropathy). Synovial fluid shows needle-shaped crystals with negative birefringence under polarised light. * **NB:** Pseudogout resembles gout clinically, but is due to deposition of calcium pyrophosphate dihydrate (CPPD), where synovial fluid shows rhomboid-shaped crystals with weakly positive birefringence under polarised light.

Answer 57

**Seronegative Spondyloarthritis:** Group of joint disorders characterised by lack of rheumatoid factor, axial skeleton involvement and HLA-B27 association. 1. Psoriatic Arthritis 2. Ankylosing Spondylitis 3. Reactive Arthritis (Reiter Syndrome) 4. Inflammatory Bowel Disease

Answer 58

**Psoriatic Arthritis:** Associated with skin psoriasis and nail lesions (pitting). Involves axial and peripheral joints, asymmetric and patchy involvement. Dactylitis (sausage fingers and toes) and “pencil-in-cup” deformity of DIP of hands and feet on x-ray. Seen in fewer than 1 ⁄3 of patients with psoriasis.

Answer 59

**Ankylosing Spondylitis:** * Presents with low back pain due to involvement of vertebral bodies and joint fusion (ankylosis) of the vertebrae (looks like 'bamboo spine'). * Patients may be unable to rotate spine. * Involves symmetric involvement of spine and sacroiliac joints. * Extra-articular manifestations include uveitis and aortitis (leading to aortic regurgitation). * Can cause restrictive lung disease due to limited chest wall expansion (costovertebral and costosternal ankylosis). * More common in young males.

Answer 60

**Reactive Arthritis (Reiter Syndrome):** Characterised by the triad of arthritis, urethritis and conjunctivitis. Arises in young adults (usually males) weeks after a GI or *Chlamydia trachomatis* infection (can’t see, can’t pee, can’t bend my knee).

Answer 61

**Sjögren Syndrome** * Autoimmune disorder characterised by destruction of exocrine glands (especially lacrimal and salivary) by lymphocytic infiltrates. * Predominantly affects females 40–60 years old. * Associated with HLA-DRW52, DQA1 and DQB1 genes and exocrine (salivary and lacrimal) gland infections. * Normally presents with xerostomia (dry mouth), parotitis, dysphagia, xerophthalmia (dry eyes), red, itching and burning eyes and blurred vision, as well as nasal (nosebleeds, rhinitis), pharyngeal, tracheal, bronchial (persistent cough) and vaginal dryness (dyspareunia). * Findings include inflammatory joint pain, keratoconjunctivitis sicca (decreased tear production and subsequent corneal damage), xerostomia (decreased saliva production), presence of antinuclear antibodies, rheumatoid factor, antiribonucleoprotein antibodies SS-A (anti-Ro) and/or SS-B (anti-La), bilateral parotid enlargement. * A common primary disorder or a secondary syndrome associated with other autoimmune disorders (RA, SLE, systemic sclerosis). * Complications include dental caries and mucosa-associated lymphoid tissue (MALT) lymphoma (may present as parotid enlargement). Labial salivary gland biopsy can confirm diagnosis.

Answer 62

**Systemic Lupus Erythematosus:** * Chronic, systemic autoimmune disease where flares and remissions are common. * Classically arises in middle‐aged females, especially African American and Hispanic women. May also arise in children and older adults (less dramatic gender bias). * Antigen‐antibody complexes damage multiple tissues (type III HSR). * Classic presentation is rash, joint pain, and fever and almost any tissue can be involved (RASH OR PAIN). * Findings include: 1. Antinuclear antibodies (ANA) 2. Anti-dsDNA antibodies 3. Anti-Smith antibodies 4. Antihistone antibodies 5. Low C3 and C4 due to immune complex formation. * Treat with NSAIDs, steroids, immunosuppressants and hydroxychloroquine. * Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the production of numerous autoantibodies and involvement of skin, joints, kidneys, brain, serosal surfaces, blood vessels, blood cells, lungs and heart. * SLE in humans is heterogeneous and affects different individuals with a wide range of disease courses and manifestations are believed to emerge from a more global abnormality in immunoregulation * In situ immune complex formation → Deposition of autoantibody (anti-dsDNA) in tissues followed by local complement activation, especially in renal glomerulus * Direct antibody induced tissue damage → Anti-SSA (anti-Ro) antibodies may bind to skin in subacute cutaneous LE or in neonatal LE.

Answer 63

**Most Common Degenerative Joint Disease = Osteoarthritis** * Progressive degeneration of articular cartilage. Wear and tear destroys articular cartilage resulting in inflammation with inadequate repair. * Specifically, joint damage/stress results in inflammation which activates proteases, causing cartilage destruction. * Major risk factors include age (common after 60 years), obesity and trauma (i.e. previous joint injury). * Affects a limited number of joints (oligoarticular) including hips, lower lumbar spine, knees, and the distal interphalangeal joints (DIP) and proximal interphalangeal joints (PIP) of fingers are common sites. * Classic presentation is joint stiffness in the morning that worsens during the day. Also includes joint pain, muscle wastage, joint effusion, reduced joint movement and crepitations. Pathologic features include disruption of the cartilage that lines the articular surface, fragments of cartilage floating in the joint space called 'joint mice', joint space narrowing, subchondral sclerosis and cysts, eburnation of the subchondral bone and osteophyte formation (reactive bony outgrowths, bone spurs) which classically arises in the DIP (Heberden nodes) and PIP (Bouchard nodes) joints of the fingers.

Answer 64

**_Anti-Inflammatory Drugs_** * **Non-Selective NSAIDs:** Block COX-1 and COX-2 enzymes which lowers the levels of circulating prostaglandins and thromboxanes thus reducing prostanoid-mediated inflammation and pain. Has analgesic, antipyretic, anti-inflammatory and antiplatelet actions by preventing synthesis of prostaglandins by non-competitively and non-selectively inhibiting both COX-1 and COX-2 (preventing prostaglandin synthesis inhibits inflammatory mediators which inhibits pain (from odeama and chemoreceptors) * **Examples:** Aspirin (salicylates), diclofenac, sulindac and indomethacin (arylalkanoic acids), ibuprofen, ketoprofen, naproxen and ketorolac (profens), mefenamic acid (fenamic acids) and piroxicam (oxicams). * **Selective NSAIDs:** Selectively inhibit COX-2 enzymes which results in anti-inflammatory and analgesic action. Although selective COX-2 inhibitors have little or no effect on COX-1 at therapeutic doses, they are still associated with GI adverse effects. * **Examples:** Celecoxib, Etoricoxib and Parecoxib (coxibs) and Meloxicam (oxicam). * **Acetaminophen (Paracetamol):** Generally considered to be a weak inhibitor of the synthesis of prostaglandins in the CNS. Does not appear to inhibit the function of COX enzymes outside the CNS which is why it is not useful as an anti-inflammatory.

Answer 65

**Glucorticosteroids**: Regulate gene expression, which results in gluconeogenesis, proteolysis, lipolysis, suppression of inflammation and immune responses. Some corticosteroids (hydrocortisone) also have mineralocorticoid effects which include hypertension, sodium and water retention, potassium loss. Inhibit phospholipase A2 and reducing the levels of arachidonic acid **Examples:** Prednisolone and Dexamethasone

Answer 66

**_Disease Modifying Antirheumatic Drugs (DMARDs)_** ## Footnote **Methotrexate (Immunosuppressant):** Folic acid antagonist. Inhibits the enzyme dihydrofolate reductase, and hence the final production of tetrahydrofolate. Mechanism of immunomodulatory effects in autoimmune diseases is unclear and may differ from its action as a folic acid antagonist in cancer treatment. It suppresses inflammation and immune responses. Indicated for RA, psoriasis, JIA and Chron's disease. Give with folic acid!! **Leflunomide (Immunosuppressant):** Inhibits pyrimidine synthesis in leucocytes and other rapidly dividing cells by inhibiting activity of dihydro-orotate dehydrogenase. It has immunosuppressive, immunomodulating and antiproliferative properties. Also has uricosuric effects. Indicated for RA and psoriatic arthritis. **Hydroxychloroquine:** Anti-inflammatory. May also have immunosuppressive effects. Indicated for RA, SLE and JIA. **5-Aminosalicylates (Sulfasalazine/Mesalazine):** Anti-inflammatory, immunosuppressant. Exact mechanism unknown. Indicated for ulcerative colitis and Chron's disease (limited role). **TNF-α Inhibitor (Biological Agent/Cytokine Modulator):** Bind to TNF-α and inhibit its activity. TNF alpha is a cytokine involved in inflammatory and immune responses and in the pathogenesis of rheumatoid arthritis, psoriasis and inflammatory bowel disease. Indicated for RA, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. **Examples:** Infliximab and Adalimumab

Answer 67

**_Urate-Lowering Agents (Prevent Attacks):_** * **Xanthine Oxidase Inhibitors**: Inhibit xanthine oxidase which reduces production of uric acid, lowering serum urate concentration and allowing acute flares and crystal deposits to resolve if long-term serum urate \<0.36 mmol/L. * **Examples:** Allopurinol or Febuxostat (is allopurinol cannot be taken) * **Uricosurics:** Reduce serum urate by increasing renal excretion of uric acid. They require an adequate fluid intake to prevent formation of uric acid stones; avoid use with a history of urolithiasis. If unable to reach target serum urate with xanthine oxidase inhibitor treatment, a uricosuric may be added to increase its effect. * **Examples:** Probenecid or Benzbromarone

Answer 68

**Acute Flares (Treat Attacks):** **Colchicine:** Relief of pain in acute gout and prophylaxis of gout flares (preferred prophylaxis). Reduces inflammation as it inhibits neutrophil migration, chemotaxis, adhesion and phagocytosis in inflamed tissue. In gout it reduces inflammatory reaction to urate crystals. **NSAIDs (Except Aspirin):** For acute attacks. Consider risks from long-term treatment. Note, aspirin competes with uric acid for the organic acid secretion mechanism in the proximal tubule of the kidney **Corticosteroids:** For acute attacks. Consider only if colchicine and NSAIDs are contraindicated.

Answer 69

**Treat High Uric Acid Caused by Cytotoxic Drugs:** • **Rasburicase:** Recombinant urate oxidase enzyme that catalyses the enzymatic oxidation of uric acid into allantoin, which is more water soluble than uric acid and less likely to precipitate in the renal tubules.

Answer 70

**Diagnosis of Inflammatory Arthritis:** 1. Number of joints and specific joints involved 2. Pattern of joint involvement (symmetrical or asymmetrical and large or small) 3. Associated features 4. Presence of non-articular disease 5. Past medical history 6. Family history 7. Periodicity of the arthritis (single acute, relapsing, chronic and progressive) 8. Evidence of recent viral illness (rubella, hepatitis B or erythrovirus), rheumatic fever or a tick bite and skin rash (Lyme disease) 9. Pain and stiffness is worse in the morning (often for 30 minutes to several hours) 10. Inflammatory markers (ESR and CRP) are often raised and there is often normochromic, normocytic anaemia

Answer 71

**Investigations of Monoarthritis and Polyarthritis:** * **Examination:** Clinical examination of joints is key to diagnosis and distinguishing between monoarthritis and polyarthritis. * **Synovial Fluid Analysis:** Acute monoarthritis is a medical emergency, where joint aspiration and synovial fluid (SF) analysis are mandatory to exclude septic arthritis and gout. Both conditions can produce turbid SF. Macroscopic examination of the SF is also helpful in excluding a haemarthrosis, as in the case of trauma and haemophilia. Microscopy is essential to determine the white cell count, to detect bacteria by gram stain and to look for uric acid crystals under polarised light. Synovial fluid culture is indicated in cases where infection is suspected. * **Bloods:** 1. **FBC and Iron Studies:** Anaemia is common in inflammatory arthritis, mostly due to anaemia of chronic disorders, but can also result from iron deficiency secondary to non-steroidal anti-inflammatory drug-induced peptic ulcer disease, and rarely Coomb’s positive haemolytic anaemia as in systemic lupus erythematosus (SLE). Leucocytosis is a feature of septic arthritis, acute gout and juvenile arthritis. Leucopaenia, and especially lymphopaenia, in a patient presenting with polyarthritis, is very suggestive of SLE. Reactive thrombocytosis is common with active chronic inflammatory arthritis, like RA and juvenile idiopathic arthritis, whereas thrombocytopaenia can be a presenting feature of SLE. 2. **ESR and CRP:** Elevation of acute phase reactants aids in the differentiating inflammatory from non- inflammatory arthritis. It generally lacks specificity, except when the CRP is greater 100 mg/L, in which case septic arthritis or gout should be excluded. 3. **Autoantibodies:** Screening for rheumatoid factor and antinuclear antibodies (ANA) is indicated in the patient presenting with polyarthritis to assess for rheumatoid arthritis or SLE. 4. **Hyperuricaemia:** A feature of gout, however 30–45% of patients have a normal serum uric acid level during an acute attack of gout. * **Imaging:** 1. **X-Ray:** The imaging method of choice to distinguish between inflammatory arthritis (RA) and degenerative arthritis (OA). 2. **Ultrasound:** Can confirm presence and size of joint effusion. 3. **MRI:** Only in exceptional cases is MRI indicated to better define the nature and the extent of joint, bone and surrounding soft tissue changes.

Answer 72

**Fibromyalgia:** * A neurosensory disorder characterised by chronic musculocutaneous pain. * The pathophysiology of is still not fully understood, but its aetiology is likely multifactorial including genetic predisposition, environmental triggers (stress) and neuroendocrine and autonomic nervous system dysregulation. * Most commonly seen in women 20–50 years old. It is commonly associated with SLE, RA, functional syndromes such as IBS and chronic fatigue, and depression and generalised anxiety disorder. * It is a clinical diagnosis (characteristic tender points often allow for diagnosis) and treatment includes lifestyle modification (diet recommendations, sleep hygiene and regular exercise), education of coping strategies, medication (TCAs, SSNRIs and anticonvulsants) and multidisciplinary pain management. Although the syndrome is benign, it causes the patient significant psychological strain and discomfort.

Answer 73

**Symptoms of fibromyalgia** 1. Chronic, widespread pain, primarily at points where muscles and tendons attach to bone (tender points) 2. Headache 3. Fatigue 4. Morning stiffness 5. Non-refreshing sleep 6. Cognitive dysfunction such as poor memory, attention and clarity of thought (“fibro fog”) 7. Paresthesias 8. Symptoms of autonomic dysfunction such as digestive problems, weight fluctuation, palpitations, sexual dysfunction and night sweats

Answer 74

**Fibromyalgia Features Contrary to Organic Pathology:** 1. Functional complaints (symptoms above) 2. On physical examination, there is no notable swelling, deformity, or erythema 3. Laboratory values and imaging are normal (no inflammation) **Differential Diagnosis:** 1. Myofascial pain syndrome 2. Polymyalgia rheumatica 3. Complex regional pain syndrome 4. Hypothyroidism 5. Sleep apnea 6. Rheumatoid arthritis 7. Systemic lupus erythematosus 8. Malignancy

Answer 75

**Joint Aspiration:** * Examination of joint (or bursa) fluid is used mainly to diagnose septic, reactive or crystal arthritis. * The appearance of the fluid is an indicator of the level of inflammation. * The procedure is often undertaken in combination with injection of a corticosteroid. Corticosteroids are believed to modify the vascular inflammatory response to injury, inhibit destructive enzymes, and restrict the action of inflammatory cells. * Aspiration alone is therapeutic in crystal arthritis. * To establish a diagnosis, relieve discomfort, drain off infected fluid or deliver medication **Indications for Joint Aspiration:** 1. **Acute/Unexplained Monoarthritis:** To diagnose/exclude septic arthritis (medical emergency!). Produces a turbid SF and allows for microscopy. 2. **Crystal-Induced Arthropathy**: To diagnose/exclude gout and other diseases. Produces a turbid SF and allows for microscopy and the observation of uric acid crystals under polarised light. 3. **Hemarthrosis:** To determine presence of RBCs upon macroscopic examination. Can be due to trauma or haemophilia and indicate the presence of a fracture or other anatomic disruption. 4. **Symptomatic Relief of Large Effusion:** Allows for drainage and deliverance of medication. 5. **Unexplained Joint Effusion:** Allows for macroscopic, microscopic and laboratory analysis to confirm diagnosis. 6. **Limiting Joint Damage from an Infectious Process:** Allows for microscopy, culture and sensitivity. Prompt treatment of a joint infection can preserve the joint integrity. **Contraindications for Joint Aspiration:** 1. Bacteremia 2. Inaccessible joints 3. Joint prosthesis 4. Overlying infection in the soft tissue

Answer 76

**Cyclosporin** * It is a natural metabolite produced by the fungus species *Beauveria nivea* * Is an immunosuppressive drug used to prevent graft rejection, and to treat some autoimmune diseases e.g. rheumatoid arthritis * It inhibits the actions of calcineurin by binding to intracellular proteins called immunophilins * By inhibiting the actions of calcineurin it reduces the production of interleukin 2, and reduces the growth, activation and differentiation of T cells * Increases the risk of developing lymphomas and other malignancies, particularly those of the skin * Predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens * Regular monitoring of renal function, hepatic function, blood pressure, potassium and cyclosporin blood levels * Drug interactions - CYP3A4 and p-glycoprotein inhibitors (note grapefruit juice) and inducers

Answer 77

**Methotrexate** * **Class of Drug:** Methotrexate is a DMARD and DMARD therapy is often commenced with methotrexate e.g. treatment of rheumatoid arthritis * **MOA** * Methotrexate is a folic acid antagonist. It inhibits the enzyme dihydrofolate reductase which is the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolic acid results in interference with DNA synthesis and cellular reproduction. * **Indications**: Can be used in the treatment of a number of cancers * When used in the treatment of cancer it is often taken on a daily basis (with rest periods) * In the treatment of autoimmune diseases such as rheumatoid arthritis it is taken on a weekly basis * Both GPs and pharmacists must stress to the patient the importance of the weekly dosage - mistaken daily use may cause life-threatening toxicity and death * DMARDs reduce or eradicate synovial inflammation and thus prevent joint damage in rheumatoid arthritis. * **Adverse effects:** 1. Methotrexate has a Black Box warning - May depress the bone marrow and reduce both red and white blood cell counts 2. Malignant lymphomas may occur in patients taking methotrexate 3. Potentially fatal opportunistic infections, especially *Pneumocystis carinii* pneumonia, may occur with methotrexate therapyClose monitoring is mandatory

Answer 78

**Infliximab** * bDMARDS primarily inhibit the actions of tumour necrosis factor alpha (TNF-α) * Infliximab is an example of a bDMARD * It is a chimeric human murine monoclonal antibody that binds to human tumour necrosis factor alpha (TNFα) * They exert an anti-inflammatory effect and produce a reduction in the number of T cells * Infliximab is used in the treatment of * Crohn's disease * psoriasis * rheumatoid arthritis * Therapy with tumour necrosis factor alpha (TNF-α) inhibitors may - increase the risk of lymphoma and leukaemia-increase the risk of skin cancers-increase the risk of infection (bacterial, fungal and viral)

Answer 79

**Corticosteroids** * Examples include hydrocortisone, dexamethasone and prednisolone * Produce an anti-inflammatory effect * Mechanism of action is complex: * Inhibit phospholipase A2 and the release of arachidonic acid leading to reduced levels of prostaglandins and leukotrienes * Bind to intracellular nuclear receptors and modulate gene transcription and protein synthesis * Reduce the synthesis of cytokines and tumour necrosis factor alpha (TNF-α)

Answer 80

**_Long-term corticosteroid therapy_** 1. Masking of the signs of infection 2. Increase in blood pressure (salt and water retention) 3. Worsening of heart failure (salt and water retention) 4. Increase in blood glucose levels (hyperglycaemia) 5. Reduced bone mineral density and osteoporosis 6. Cushing syndrome 7. Adrenocortical insufficiency

Answer 81

**Monoclonal Antibodies (mAbs)** * A monoclonal antibody is an antibody made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell * They are used to treat some autoimmune diseases, cancer and infections * Secukinumab binds to interleukin-17A and is used in the treatment of psoriasis * Tocilizumab binds to interleukin-6 receptors and is used in the treatment of rheumatoid arthritis