Box 10.6 Differential diagnosis of early rheumatoid arthritis

Postviral arthritis – rubella, hepatitis B or parvovirus Seronegative spondyloarthropathies Polymyalgia rheumatica Acute nodal osteoarthritis (PIPs and DIPs involved)

Box 10.7 Typical presentations of rheumatoid arthritis

Palindromic – Monarticular attacks lasting 24-48 hours; 50% progress to other types of RA. Transient – A self-limiting disease, lasting less than 12 months and leaving no permanent joint damage. Usually seronegative for IgM rheumatoid factor. Some of these may be undetected postviral arthritis. Remitting – There is a period of several years during which the arthritis is active but then remits, leaving minimal damage. Chronic, persistent – The most typical form, it may be seropositive or seronegative for IgM rheumatoid factor. The disease follows a relapsing and remitting course over many years. Seropositive patients tend to develop greater joint damage and long-term disability. They warrant earlier and more aggressive treatment with disease-modifying agents. Rapidly progressive – The disease progresses remorselessly over a few years and leads rapidly to severe joint damage and disability. It is usually seropositive, has a high incidence of systemic complications and is difficult to treat.

A seronegative, limited synovitis initially affects the wrists more often than the fingers and has a less symmetrical joint involvement. It has a better long-term prognosis, but some cases progress to severe disability. This form can be confused with psoriatic arthropathy, which has a similar distribution. There may be a family history of psoriasis or the patient may develop psoriasis later.

Palindromic rheumatism is unusual (5%) and consists of short-lived (24-72 h) episodes of acute monarthritis. The joint becomes acutely painful, swollen and red, but resolves completely. Further attacks occur in the same or other joints. About 50% go on to develop typical chronic rheumatoid synovitis after a delay of months or years. The rest remit or continue to have acute episodic arthritis. The detection of IgM rheumatoid factor predicts conversion to chronic, destructive synovitis.

Typical presentation

The most typical presentation of rheumatoid arthritis (approximately 70% of cases) begins as a slowly progressive, symmetrical, peripheral polyarthritis, evolving over a period of a few weeks or months. Women are affected three times more often than are men. The patient is usually in her thirties to fifties, but the disease can occur at any age. Less commonly (15%) a rapid onset can occur over a few days (or explosively overnight) with a severe symmetrical polyarticular involvement. These patients often have a better prognosis. A worse than average prognosis (with a predictive accuracy of about 80%) is indicated by being female, a gradual onset over a few months, and a positive IgM rheumatoid factor, and/or anaemia within 3 months of onset. The differential diagnosis of early RA is shown in Box 10.6.

Symptoms and signs

The majority of patients complain of pain and stiffness of the small joints of the hands (metacarpophalangeal, MCP), proximal and distal interphalangeal (PIP, DIP) and feet (metatarsophalangeal, MTP). The wrists, elbows, shoulders, knees and ankles are also affected. In most cases many joints are involved, but 10% present with a monarthritis of the knee or shoulder or with a carpal tunnel syndrome. The hips are rarely affected early in the disease.

The patient feels tired and unwell and the pain and stiffness are significantly worse in the morning and may improve with gentle activity. Sleep is disturbed.

The joints are usually warm and tender with some joint swelling. There is limitation of movement and muscle wasting. Deformities develop as the disease progresses. Nonarticular features develop (see below).

Other presentations

The presentation and progression of RA is variable. Presentations are shown in Box 10.7. Relapses and remissions occur either spontaneously or in response to drug therapy. In some patients the disease remains active, producing progressive joint damage. Rarely the process may cease (’burnt-out RA’).

Rheumatoid arthritis is typified by widespread persisting synovitis (inflammation of the synovial lining of joints, tendon sheaths or bursae). The cause of this is unclear, but the production of rheumatoid factors (RFs, see below) by plasma cells in the synovium and the local formation of immune complexes play a part. In RA, the normal synovium becomes greatly thickened to the extent that it is palpable as a ‘boggy’ swelling around the joints and tendons. There is proliferation of the synovium into folds and fronds, and it is infiltrated by a variety of inflammatory cells, including polymorphs, which transit through the tissue into the joint fluid, and lymphocytes and plasma cells. There are disorganized lymphoid follicles that are responsive to exogenous antigens. The normally sparse surface layer of lining cells becomes hyperplastic and thickened. There is marked vascular proliferation. Increased permeability of blood vessels and the synovial lining layer leads to joint effusions that contain lymphocytes and dying polymorphs.

The hyperplastic synovium spreads from the joint margins on to the cartilage surface. This ‘pannus’ of inflamed synovium damages the underlying cartilage by blocking its normal route for nutrition and by the direct effects of cytokines on the chondrocytes. The cartilage becomes thinned and the underlying bone exposed. Local cytokine production and joint disuse combine to cause juxta-articular osteoporosis during active synovitis.

Fibroblasts from the proliferating synovium also grow along the course of blood vessels between the synovial margins and the epiphyseal bone cavity and damage the bone. This is shown by MRI to occur in the first 3-6 months following onset of the arthritis, and before the diagnostic, ill-defined juxta-articular bony ‘erosions’ appear on X-ray. This early damage justifies the use of DMARDs within 3-6 months of onset of the arthritis. Low-dose steroids delay and anti-TNF-α agents halt or even reverse erosion formation. Erosions lead to a variety of deformities and contribute to long-term disability.

Rheumatoid factors (RFs)

These are circulating autoantibodies, which have the Fc portion of IgG as their antigen. The nature of the antigen means that they self-aggregate into immune complexes and thus activate complement and stimulate inflammation, causing chronic synovitis. Transient production of RFs is an essential part of the body’s normal mechanism for removing immune complexes, but in RA they show a much higher affinity and their production is persistent and occurs in the joints. They may be of any immunoglobulin class (IgM, IgG or IgA), but the most common tests employed clinically detect IgM rheumatoid factor. Around 70% of patients with polyarticular RA have IgM rheumatoid factor in the serum.

The term seronegative RA is used for patients in whom the standard tests for IgM rheumatoid factor are persistently negative. They tend to have a more limited pattern of synovitis.

IgM rheumatoid factor is not diagnostic of RA, nor does its absence rule the disease out; but it is a useful predictor of prognosis. A persistently high titre in early disease implies more persistently active synovitis, more joint damage and greater disability eventually, and justifies earlier use of DMARDs.

RF and the antibody to CCP together are more specific, and anti-CCP indicates a worse prognosis.

Nodal OA

Joints of the hand are usually affected one at a time over several years, with the distal interphalangeal joints (DIPs) being more often involved than the proximal interphalangeal joints (PIPs). The onset may be painful and associated with tenderness, swelling and inflammation and impairment of hand function. The inflammation often occurs around the female menopause. PIP-predominant nodal OA has a superficial similarity to early rheumatoid arthritis. Even if a weakly positive rheumatoid factor is found, it is of no significance. The inflammatory phase settles after some months or years, leaving painless bony swellings posterolaterally – Heberden’s nodes (DIPs) and Bouchard’s nodes (PIPs), along with stiffness and deformity. Functional impairment is slight for most, although PIP osteoarthritis restricts gripping more than DIP involvement. On X-ray, the nodes are marginal osteophytes and there is joint space loss.

Carpometacarpal and metacarpophalangeal OA of the thumb coexist with nodal OA and cause pain, which decreases as the joint stiffens. The ’squared’ hand in OA is caused by bony swelling of the carpometacarpal joint and fixed adduction of the thumb. Function is rarely severely compromised.

Polyarticular hand OA is associated with a slightly increased frequency of OA at other sites.

Osteoarthritis affects many joints, with diverse clinical patterns. Hip and knee OA is the major cause of disability. Early OA is rarely symptomatic unless accompanied by a joint effusion, whilst advanced radiological and pathological OA is not always symptomatic.

Box 10.5 Factors predisposing to osteoarthritis

Obesity – Predicts later risk of radiological and symptomatic OA in population studies. Heredity – Familial tendency to develop nodal and generalized OA. Gender – Polyarticular OA is more common in women; a higher prevalence after the menopause suggests a role for sex hormones. Hypermobility – Increased range of joint motion and reduced stability lead to OA. Osteoporosis – There is reduced risk of OA. Other diseases – See Table 10.11. Trauma – A fracture through any joint. Meniscal and cruciate ligament tears cause OA of the knee. Congenital joint dysplasia – Alters joint biomechanics and leads to OA. Mild acetabular dysplasia is common and leads to earlier onset of hip OA. Joint congruity – Congenital dislocation of the hip or a slipped femoral epiphysis or Perthes’ disease; osteonecrosis of the femoral head in children and adolescents causes early-onset OA. Occupation – Miners develop OA of the hip, knee and shoulder, cotton workers OA of the hand, and farmers OA of the hip. Sport – Repetitive use and injury in some sports causes a high incidence of lower-limb OA.

Table 10-11. Causes of osteoarthritis

Primary OA	No known cause
Secondary OA	Pre-existing joint damage:
	Rheumatoid arthritis
	Gout
	Seronegative spondyloarthropathy
	Septic arthritis
	Paget’s disease
	Avascular necrosis, e.g. corticosteroid therapy
	Metabolic disease:
	Chondrocalcinosis
	Hereditary haemochromatosis
	Acromegaly
	Systemic diseases:
	Haemophilia – recurrent haemarthrosis
	Haemoglobinopathies, e.g. sickle cell disease
	Neuropathies

Some flare-ups are due to inflammation but are not associated with an increased ESR or CRP. Focal synovitis is caused by fragments of shed bone or cartilage. Radiological OA is usually, but not inevitably, progressive. This progression may be stepwise or continual. Radiological improvement is uncommon but has been observed, suggesting that repair is possible. This may be the basis for effective drug treatments in the future.

Symptoms

• Joint pain
• Joint gelling (stiffening and pain after immobility)
• Joint instability
• Loss of function.

Table 10-12. Features of nodal OA

Familial

Has a higher incidence in women

Typical pattern of polyarticular involvement of the hand joints

Develops in late middle age

Has a generally good long-term functional outcome

Associated with OA of the knee, hip and spine

Signs

• Joint tenderness
• Crepitus on movement
• Limitation of range of movement
• Joint instability
• Joint effusion and variable levels of inflammation
• Bony swelling
• Wasting of muscles.

X-rays can be diagnostic in certain conditions (e.g. rheumatoid arthritis), but remember the following points: (a) In acute low back pain, X-rays are indicated only if the pain is persistent, recurrent, associated with neurological symptoms or signs, or worse at night. They should also be performed if the pain is associated with such symptoms as fever or weight loss, which might indicate a more sinister underlying pathology. (b) Radiological changes are common in older people and may not indicate symptomatic osteoarthritis or spondylosis. (c) X-rays are of little diagnostic value in early inflammatory arthritis but are useful as a baseline from which to judge later change. Ultrasound (US) is particularly useful for periarticular structures, soft tissue swellings and tendons. It is increasingly used to examine the shoulder and other structures during movement. This visualizes shoulder impingement syndrome. US can be used to guide local injections. Quantitative ultrasound of the heel may prove a convenient and portable means of assessing bone density. Magnetic resonance imaging (MRI) shows bone changes and intra-articular structures in striking detail. It is more sensitive than X-rays in the early detection of articular disease. It is the investigation of choice for most spinal disorders but is inappropriate in uncomplicated mechanical low back pain. Gadolinium injection enhances inflamed tissue. MRI can also detect muscle changes, e.g. myositis. Computerized axial tomography (CT) is useful for detecting changes in calcified structures. Bone scintigraphy utilizes radionuclides, usually 99mTc, and detects abnormal bone turnover and blood circulation and, although non-specific, helps in detecting areas of inflammation, infection or malignancy. It is best used in combination with other anatomical imaging techniques. DXA scanning uses very low doses of X-irradiation to measure bone density and is used in the screening and monitoring of osteoporosis. Positron emission tomography (PET) scanning uses radionuclides which decay by emission of positrons. Fluorine-18 in deoxyglucose indicates areas of increased glucose metabolism, locates tumours, demonstrates large vessel vasculitis, e.g. Takayasu’s arteritis. PET scans are combined with CT or MRI to improve anatomical details. Arthroscopy is a direct means of visualizing a joint, particularly the knee or shoulder. Biopsies can be taken, surgery performed in certain conditions (e.g. repair or trimming of meniscal tears), and loose bodies removed.

Examination of synovial fluid is described in Box 10.1.

Gender

Gout, reactive arthritis and ankylosing spondylitis are more common in men. Rheumatoid arthritis and other autoimmune connective tissue diseases are more common in women.

Age

• Is the person young, middle-aged or older? Injury is common in young people but can occur at any age.
• How old was the patient when the problem first started? Osteoarthritis and polymyalgia rheumatica rarely affect the under-fifties. Rheumatoid arthritis starts most commonly in women aged 20-50 years.

General health

• Is there any associated ill-health or other worrying feature, such as weight loss or fever? Systemic illness is a common feature of many rheumatic diseases. If there is weight loss and/or fever, think of autoimmune rheumatic disease, sepsis (joint infection may be due to septicaemia and is a medical emergency) or malignancy.
• Are there other associated medical conditions that may be relevant? Psoriasis or inflammatory bowel disease is associated with asymmetrical arthritis. Charcot’s joints are seen in diabetics.

Medication

Could a drug be a cause? Diuretics may precipitate gout in men and older women. Hormone replacement therapy or the oral contraceptive pill may precipitate systemic lupus erythematosus (SLE). Steroids can cause avascular necrosis. Some drugs cause a lupus-like syndrome.

Race

Is this relevant? Sickle cell disease causes joint pain in young black Africans, but osteoporosis is uncommon in older black Africans.

Past history

Have there been any similar episodes or is this the first? Are there any clues from previous medical conditions? Gout is recurrent; the episodes settle without treatment in about 10 days. Acute episodes of palindromic rheumatism may predate the onset of rheumatoid arthritis.

Family history

Does anyone in the family have a similar problem or another related disorder? Osteoarthritis may be familial. Sero-negative spondyloarthropathies is seen in families with a history of arthritis, psoriasis, ankylosing spondylitis, iritis or inflammatory bowel disease. Autoimmunity has a familial tendency.

Occupational history

What job does the patient do? This can be a factor in soft tissue problems and osteoarthritis (e.g. in heavy labourers and dancers). Work-related problems are becoming more common and are complained of more.

Psychosocial history

• Has there been an injury for which a legal case for compensation is pending?
• Has there been any recent major stress in family or working life? Could this be relevant? Stress rarely causes rheumatic disease but may precipitate a flare-up of inflammatory arthritis. Stress also tends to reduce a person’s ability to cope with pain or disability. Remember that the diagnosis of a chronic arthritis has a major influence on the lifestyle of patients and their families. The extent of disability should be noted.

Eosinophils in host defence

In developed countries eosinophils are most commonly associated with allergic disease, but their physiological function is in parasite control. Eosinophils have receptors for IgE which is the major antiparasite antibody, particularly against nematodes. Eosinophils bind IgE via the FcεR, and toxic metabolites are released from the eosinophil granules directly onto the parasite surface. Examples are major basic protein (MBP), which produces ballooning and detachment of the helminth tegumental membrane, and eosinophil cationic protein (ECP), which is present in smaller amounts but is eight to ten times more toxic than MBP, producing complete fragmentation and disruption of the parasites.

Mast cells and basophils

Mast cells consist of two populations, which are distinguished by their enzyme content. The T mast cells contain trypsin alone (also termed mucosal mast cells owing to their location). The TC mast cells contain both trypsin and chymotrypsin and are called connective tissue mast cells. Mast cell function appears to be in the initiation of inflammatory responses (increased vascular permeability, bronchoconstriction) by the release (following degranulation) of pro-inflammatory mediators such as histamine, leukotrienes, platelet-activating factor (PAF), prostaglandins and some cytokines (e.g. IL-4). Basophils are morphologically similar to mast cells but are found in very small numbers in the blood. These cells bear high-affinity IgE receptors FcεR1 (CD23) which rapidly absorb any local IgE and participate in immediate-type hypersensitivity reactions.

Dendritic cells/Langerhans’ cells

These are derived from the lymphoid and myeloid cell lines; dendritic cells in the skin are called Langerhans’ cells. Their major function is to present antigen to T cells when stimulated. Dendritic cells link innate immunity to the adaptive immune system by being the only cell that can activate naive T cells to initiate an adaptive immune response. They are activated by signals from PAMP, heat shock proteins and TNF-α, and IFN-α (secreted from host cells) reacting to injury. When activated, dendritic cells can change their expression of chemokine receptors and migrate from tissue to the T cell zones of lymph nodes.

Complement

The complement system comprises a series of at least 20 glycoproteins that are activated in a cascade sequence, with proenzymes that undergo sequential proteolytic cleavage to their active forms. It is a major part of the innate immune system.

Three main pathways of complement activation exist, termed the classical, alternative and mannan-binding lectin (MBL) pathways. The terminology of the complement proteins is that components of the classical pathway are named by ‘C’ followed by a number (the numbering sequence is in order of their discovery not position in the sequence). Alternative pathway components are called factors followed by a specific letter. During activation some components are initially cleaved into fragments. The smaller fragment, designated ‘a’, is released; the larger ‘b’ fragment is usually deposited on the surface of the activating cell. Further fragmentation may occur to ‘c’, ‘d’ and ‘g’ fragments.

The complement pathways are triggered by different factors:

- Classical pathway by antigen-antibody immune complexes, apoptotic cells, C-reactive protein bound to ligand and certain viruses and bacteria.
- Alternative pathway by bacterial endotoxin, fungal cell walls, viruses and tumour cells.
- Mannan-binding lectin (MBL) pathway is activated by microbes with terminal mannose groups. MBL has a similar structure to C1q and activates through the classical pathway without the requirement for antibody.

The pathways converge in the activation of C3 (by the formation of either classical or alternative C3 convertase). This leads into a final common pathway with the assembly of components C5-C9 to form the membrane attack complex (MAC) which assembles into a ‘doughnut-like’ transmembrane channel leading to cell lysis by osmotic shock.

Complement activation is focused at cell membranes. Host cells are protected from complement-mediated lysis by inhibitory surface molecules, for example decay accelerating factor (DAF). Most organisms lack any protective molecules and are therefore susceptible to complement.

Functions of complement

- Anti-infective function:
opsonization by C3b and C4b
chemotaxis – attraction of phagocytes by chemoattractant activation products
activation of leucocytes by anaphylatoxins (C5a, C3a and C4a); via receptors on leucocytes
lysis of bacteria and cells (C5b-C9).

-Interplay between innate and adaptive immune system. Immunomodulation of B-cell responses to specific antigen through binding of complement receptors on B-cell surface, thus augmenting antibody responses and immunological memory.

-Clearance of:
immune complexes (C1q, C3 and C4)
apoptotic cells (C1q, C3 and C4).

Other cells or factors active in non-specific immunity
Natural killer (NK) cells

These non-phagocytic cells have the morphology of lymphocytes but do not bear the markers for T or B cells. They are distinguished by the presence of numerous cytoplasmic granules. They have non-specific antiviral and antitumour activity, causing lysis of cells with which they react.

NK cells recognize abnormal cells in two ways. Firstly, they bear immunoglobulin receptors (FcR) and bind antibody-coated targets leading to antibody-dependent cellular cytotoxicity (ADCC). Secondly, they have surface receptors for MHC (major histocompatibility complex) class I. If these MHC receptors are not bound on interaction with a cell, the NK cell is programmed to lyse this target cell. It does this by making holes in its cell membrane by secreting ‘perforins’; granzymes are injected through these pores and cause the induction of apoptosis. As normal host cells are MHC class I positive, the ‘death pathway’ is inhibited by the NK cell binding to this receptor. However, tumours on affected cells and viruses often cause downregulation of class I and thus it leaves them open to NK cell attack.

NK cells may also shape the adaptive T cell responses to Th1 or Th2 type depending on the balance of the NK receptor activation during the early stage of an immune response.

Cytokines

Cytokines are small soluble intercellular messengers that exert their effect by binding to specific receptors on target cells. They act as autocrine, paracrine or endocrine messengers. Cytokines are produced by any cell. Their biological effect varies according to the cytokine and the cell involved (Table 4.5), but typically these molecules will signal certain cell populations to activate, divide or home in on a particular site in the body. Cytokines include:

- Interleukins produced by and signal between white cells.
- Chemokines have a chemoattractant function.
- Colony-stimulating factors cause differentiation and proliferation of stem cells.
- Interferons (see below).
- Tumour necrosis factors. TFN-α increases phagocyte function.

Interferons (IFN) are a major class of cytokine. They are divided into type I (alpha and beta) and type II (gamma or ‘immune’ interferon). Type I interferons are antiviral agents produced mainly by fibroblasts, monocytes and infected cells as a reaction to viral infection. Alpha and beta IFN bind the same cellular receptor and protect uninfected cells by inducing the intracellular production of molecules that inhibit viral RNA and DNA production. They also increase the expression of MHC class I molecules, leading to enhanced lysis of virally infected cells by specific cytotoxic T lymphocytes. Type I interferons also have antiproliferative function. IFN-α is used in the treatment of chronic hepatitis B and C infections as well as in some forms of leukaemia. IFN-β reduces the relapse rate in some forms of multiple sclerosis.

Gamma-interferon has different functions, acting mainly on the immune response. It activates macrophage and neutrophil intracellular killing, stimulates natural killer cells and enhances T-cell responses by increasing MHC class II expression on antigen-presenting cells. IFN-γ uses a separate receptor from the type I interferons. It is used therapeutically in the congenital neutrophil defect (chronic granulomatous disease), in patients with defects in IFN-γ production or receptor expression, and in the adjunct therapy of some infections (leishmaniasis, atypical mycobacterial disease).

Other cytokines are also involved in innate immunity. Interleukin-6 mediates the acute-phase reaction through hepatic induction. Interleukin-8 is a powerful chemoattractant. Granulocyte and macrophage-granulocyte colony-stimulating factors (G- and GM-CSF) increase phagocyte numbers.

Heat-shock proteins (HSP)

Heat-shock proteins are a family of highly conserved proteins which act as immunodominant antigens in many infections. They are molecular chaperones, housekeeping proteins within cells, preserving the cell’s protein structure. They are similar in configuration to antigens found on certain microorganisms and may induce autoimmunity through molecular mimicry.
HSPs are also released and may act on cells to modulate function by inducing cytokines, adhesion molecules and maturation signals.

Pattern recognition receptors (PRRs)

The innate immune response is essential for host survival as it is immediately active. It is not antigen specific but can detect tissue damage and discriminate foreign molecules from ’self’ (sometimes called ‘danger-stranger’ recognition). Phagocytic cells (macrophages, dendritic and B cells – antigen-presenting cells) bear pattern-recognition receptors with lectin-like activity which recognize pathogen-associated molecular patterns (PAMPs) present on microbes but not host cells. PRRs include:

– Mannan-binding lectin, which initiates complement activity inducing opsonization.
– Endocytic pattern recognition receptors, which act by enhancing antigen presentation on macrophages, by recognizing microorganisms with mannose-rich carbohydrates on their surface or by binding to bacterial cell walls and scavenging bacteria from the circulation. All lead to phagocytosis.
– Signalling receptors that initiate nuclear factor kappa B induction (e.g. toll-like receptors) and immune response genes leading to cell activation. These may have some specificity, e.g. TLR4 binds Gram-negative bacterial endotoxin and TLR2 binds Gram-positive bacterial lipoteichoic acid. TLR3 and TLR9 detect nucleic acid. TLR5 recognizes a protein on bacterial flagella. Innate immunity critically depends on toll-like receptor signalling. These receptors act through a critical adaptor molecule, myeloid differentiation factor 88 (MyD88), to regulate the activity of NFκB pathways and the expression of many of the cytokines necessary to mount an innate defence response.
– TREM-1 (triggering receptor expressed on myeloid cells), a member of the aminoglobulin superfamily, is a cell surface receptor which, when bound to its ligand, triggers secretion of proinflammatory cytokines. It is upregulated by bacterial lipopolysaccharides (e.g. pseudomonas), but not in non-infective disorders. It is a mechanism that links bacteria on the outside of the cell membrane with gene transcription of cytokines in the cell nucleus.

Nuclear factor kappa B (NFκB)

Table 4-5.
Origins and biological functions of cytokines (including chemokines)

Cytokine	Source	Mode of action
Haemopoietins
IL-1	Macrophages/monocytes	Immune activation: induces an inflammatory response
IL-2	Primarily Th1 cells	Activates T (and NK) cells and supports their growth
IL-3	T cells	Primarily promotes growth of haemopoietic cells
IL-4	Th2 cells	Lymphocyte growth factor; involved in IgE responses
IL-5	Th2 cells	Promotes growth of B cells and acute phase response eosinophils
IL-6	Th2 cells and macrophages	Promotes B-cell growth and antibody production
IL-7	Stromal cells	Lymphocyte growth factor, important in the growth of immature cells
IL-10	CD4 cells, activated monocytes	Inhibits the production of IFN-γ, IL-1, IL-6, TNF-α and antigen presentation
IL-11	Macrophage	Maintains epithelial integrity of gastrointestinal tract and megakaryocyte differentiation
IL-12	Monocytes/macrophages	Augments Th1 responses and induces IFN-γ
IL-13	Activated T cells	Stimulates B cells
IL-15	Many tissues, not T cells	Similar action to IL-2
G-CSF	Primarily monocytes	Promotes growth of myeloid cells
M-CSF	Primarily monocytes	Promotes growth of macrophages
GM-CSF	Primarily T cells	Promotes growth of monomyelocytic cells
Interferons
IFN-α	Leucocytes	Immune activation and modulation (following viral infection)
IFN-β	Fibroblasts	Immune activation and modulation (following viral infection)
IFN-γ	Th1 and NK cells	Immune activation and modulation (inhibits Th2 cells, activates macrophages)
Tumour necrosis factors
TNF-α	Macrophages, NK, T, B and mast cells	Stimulates generalized immune activation as well as tumour necrosis; formerly known as cachectin
TNF-β	T and B cells, macrophages, mast cells	Stimulates immune activation and generalized vascular effects; also known as lymphotoxin
TGF-β	Platelets	Immunoinhibitory but stimulates tumorigenesis, angiogenesis and fibrosis
Chemokines*
‘CC chemokines’
MCP1-MCPS	Monocytes, macrophages, fibroblasts, keratinocytes	Attracts monocytes and memory T cells to inflammatory sites
MIP-1α	Macrophages	Attracts monocytes and T cells
MIP-1β	Monocytes, macrophages, endothelial cells, T and B cells	Attracts monocytes and CD8+ T cells
Eotaxin	Macrophages, activated leucocytes, endothelial cells	Attracts eosinophils, basophils
RANTES	Platelets and T cells	Attracts monocytes, T cells, eosinophils
‘CXC chemokines’
IL-8	Macrophages	Attracts neutrophils, naive T cells
CINC	Macrophages	Attracts neutrophils
MIP2	Kupffer cells	Attracts neutrophils
ENA78	Epithelial cells, Kupffer cells	Activates neutrophils
GROα	Macrophages, hepatocytes, endothelial cells	Unknown
IP10	Hepatocytes, endothelium	Unknown
MIG	Monocytes/macrophages, hepatocytes	Attracts lymphocytes

NFκB is a pivotal transcription factor in chronic inflammatory diseases. It is a heterodimer of two proteins (p. 157) and is found in the cytoplasm bound to an inhibitor (IκB), which prevents it from entering the nucleus. It is released from IκB on stimulation of the cell and passes into the nucleus where it binds to specific sequences in the promoter regions of target genes. It is stimulated by, for example, cytokines, protein C activators and viruses, and itself regulates various proteins (e.g. pro-inflammatory cytokines, chemokines, adhesion molecules, inflammatory enzymes and receptors).

The importance of regulation of the inflammatory response is demonstrated in sepsis when overwhelming activation, by for example, endotoxin, leads to induction of a ‘cytokine storm’ with organ failure, shock and death as a result. Proteosome inhibitors are being developed which inhibit the degradation of ubiquinated proteins including the cell cycle regulating proteins like cyclins and cyclin-dependent kinases. For example, bortezomib, a proteosome inhibitor inhibits activation of NFκB.

Dysregulated chronic inflammation is also associated with clinical disease, in particular an increased risk of cardiovascular complication in conditions with chronically elevated CRP such as rheumatoid arthritis. The inflammatory process is thought to contribute to the atheromatous lesions.