Rheumatic and Autoimmune Diseases

8/17/2019 Rheumatic and Autoimmune Diseases

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Rheumatic andAutoimmune Diseases

Autoimmune disorders can be categorized broadly into either systemic

or organ-directed diseases. The dominant clinical feature of organ-specic

autoimmune diseases is chronic inammation, generally localized in a single

organ specic for each individual disease. Within this group of autoimmune

disorders, familial clustering diseases occur with remarable fre!uency. The

relevant autoantibodies may or may not be species-specic but they do

e"hibit specicity for an antigen present in the diseased organ or tissue.

#heumatic diseases are characterized by the presence of one or more

autoantibodies that may be directed against components of the surface,

cytoplasm, nuclear envelope, or nucleus of the cell. The last group,

autoantibodies to nuclear antigens $A%As&, is a hallmar of systemic

rheumatic diseases.

There are several types of detection method. 'ne of it is (irect

)mmunouorescence *icroscopy $()+*&, which is the laboratory method





to the surfaces of the s!uamous epithelial cells in @:: of patients with

active disease. *oney esophagus is considered as the best substrate.

The subsets of pemphigus foliaceus include idiopathic pemphigus

foliaceus, endemic pemphigus foliaceus $fogo selvage&, drug-induced

pemphigus foliaceus and pemphigus erythematosus $1&. (esmoglein @ isthe ma6or antigen in pemphigus foliaceus. +or all forms of pemphigus

foliaceus e"cept pemphigus erythematosus, the ()+* pattern is similar to

pemphigus vulgaris. ))+* should detect circulating )g> )0 autoantibodies in

virtually @:: of pemphigus foliaceus patients with active disease.

1araneoplastic pemphigus, an uncommon disorder characterized by

painful blisters or erosion of mucous membranes and sin, is a condition of

patients with neoplasms. These blisters or erosions usually erupt in the

mouth, but other mucosal sites have been reported. *alignant neoplasms

that have been associated with paraneoplastic pemphigus include malignantlymphoma, chronic lymphocytic leuemia, thymoma, bronchogenic

s!uamous cell carcinoma and sarcomas.

)gA 1emphigus $)ntercellular )gA (ermatosis& is a rare intraepidermal

vesiculobullous disorder. (irect studies show linear )0 immunouorescence

for )gA that is suprabasillar, and particularly accentuated in the upper

epidermis. ))+* detects circulating )gA anti-)0 autoantibodies.

2ullous 1emphigoid is a subepidermal bullous disease of unnown

cause that can occur in patients of any age but mainly a8ects adults olderthan ;: years. This disorder typically involves e"or surfaces of the arms,

legs, groin, a"illa, and lower abdomen. The oral mucous membranes may be

a8ected but such lesions are rarely the presenting or predominant sign, a

point that di8erentiates pemphigoid from pemphigus vulgaris. The ma6or

antigens in bullous pemphigoid are two eratinocytic hemidesmosomal

proteins, an intracellular C<:(a protein $bullous pemphigoid antigen @& and

a transmembrane @D:(a protein $bullous pemphigoid antigen C&. ()+* of

unblistered, perilesional sin from the edge of a fresh blister is diagnostically

sensitive and typically demonstrates linear 2*5, immunoouorescence in

nearly @:: of patients. To help separate these disorders, salt-split direct

sin biopsies are useful, also nown as (omloge-3ultsch.

2enign *ucous *embrane 1emphigoid or cicatricial pemphigoid,

consistently a8ects oral and ocular mucosa. 'ther mucosal sites are

nasopharyn", laryn", genitalia, rectum and esophagus. 0carring follows the

healing of lesions and blindness is the most feared complication. hronic



localized scarring pemphigoid, also nown as cicatricial pemphigoid of

2runsting-1erry, is a variant of benign mucous membrane pemphigoid that is

localized to the head and nec region.

>estational 1emphigoid $3erpes gestationis& develops during or soon

after pregnancy. /esions are typically pruritic and located predominantly onthe abdomen and e"tremities. With ()+*, one typically nds linear < 2*5

deposits.

pidermolysis bullossa ac!uisita and bullous lupus erythematosus are

ac!uired subepidermal blistering diseases characterized by the presence of

autoantibodies to type 4)) collagen in 2*5 protein. All patients are aEicted

with a combination of blisters, erosions, scars, milia, and dyspigmentation of

sin, most often located on trauma-susceptible e"tensor sin surfaces such

as nees, elbows and dorsa of hands and feet. Fsing ()+*, patients with

epidermolysis bullosa ac!uisita and bullous lupus erythematosus have linear2*5 immunoreactants that most commonly consist of )g> and <.

(ermatitis 3erpetiformis is a severely pruritic subepidermal bullous

disease associated with gluten-sensitive enteropathy. )t is also associated

with 3/A-2D, (#< histocompatibility types. ()+* detects granular )gA in the

tips of dermal papillae in appro"imately D:-@:: of dermatitis herpetiformis

patients.

/inear )gA dermatosis is an uncommon ac!uired subepidermal

blistering disorder that is now considered a distinct clinical entity rather thanbeing a variant of dermatitis herpetiformis as was once thought. hronic

bullous dermatosis of childhood is similar to linear )gA dermatosis, both

clinically and immunopathologically.

/upus rythematosus is a disorder characterized serologically by the

presence of multiple autoantibodies, including antinuclear antibodies, anti-

native-(%A, antihistones, and anti-0m. With ()+*, one sees characteristic

course granular, continuous deposits of immunoglobulins and complement

along the epidermal 2*5 in B:-GB of 0/ patients.

4asculitis in the sin has a number of synonyms, including

leuocytoclastic vasculitis, allergic vasculitis and hypersensitivity

angiitis=vasculitis. 3istologically, small blood vessels of the dermis show

endothelial cell swelling, neutrophilic e"ocytosis, nuclear debris

$leuocytoclasis&, and necrosis in con6unction with e"travasated red blood

cells.



B. Liver

Autoimmune hepatitis, 12, and primary sclerosing cholangitis are the

chronic disorders dened by elevated concentrations of serum

transaminases for at least ; months.

Autoimmune hepatitis classically occurs in females around <B years

old, who present with high concentrations of serum aminotransferases,

hypergammaglobulinemiam amenorrhea, arthralgias and circulating

autoantibodies such as A%A, 0*A and /H*.

1rimary 2iliary irrhosis is a chronic, progressive, cholestatic disorder

typically occurring in young or middle-aged females. 1atients may be

asymptomatic or have symptoms of cholestasis $itch&. A*A are the most

specic and sensitive diagnostic marers for 12.

1rimary 0clerosing holangitis typically occurs in males with a history

of inammatory bowel disease and diarrhea. Flcerative cholitis is the

inammatory bowel disease lined with primary sclerosing cholangitis.

(iagnosis for it is cholangiography, which reveals a characteristic beading

pattern of bile ducts due to multifocal strictures at those sites. The hallmar

histologic lesion is brous cholangitis of large and small bile ducts.

Autoimmune holangitis=holangiopathy is a chronic cholestatic liver

disease that does not appear to be a variant of primary sclerosing

cholangitis. The clinical presentation resembles 12 but serologic ndingsmimic autoimmune hepatitis type @. A*As are not detected. And an

autoantibody to carbonic anhydrase has been detected.

C. Thyroid

Autoimmune thyroid diseases include >raves disease and 3ashimotos

thyroiditis.

>raves disease patients present with symptoms of hyperthyroidism

and di8use goiter. The pea incidence is in the third to fourth decades of life.

Also, there is a manifestations of ocular disturbances. /aboratory data shows

an increase in triiodothyronine $T<& and thyro"ine $T9&.

3ashimotos thyroiditis is the most common form of thyroiditis and is

functionally characterized by a slow progression to hypothyroidism. )n

patients with hypothyroidism, T< and T9 levels and T< uptae are low and



amount of T03 increase abnormally. 1ea is during third to fth decades with

a female ratio of @:7@.

D. Kidney

Autoimmune diseases found in idney are glomerulonephritis andantiglomerular basement membrane disease.

>lomerulonephritis is a ma6or cause of primary renal disease. )mmune

mediated mechanisms thought to have an important role in the pathogenesis

of glomerulonephritis, although e"perimental conrmation of such putative

autoimmune mechanisms is still lacing.

1atients with Antiglomerular basement membrane disease vary in

clinical presentation in that about B: have renal limited disease and the

other B: have both renal and pulmonary symptoms. This latterpresentation is often called >oodpasteur syndrome. (iagnosis of anti->2*

disease re!uires detection of anti->2* autoantibodies to the %@ domain of

type )4 collagen, the so called >oodpastures antigen.

. Adrena! g!ands

The common autoimmune disease found in the adrenal gland is

Addisons disease. %ontuberculous chronic adrenocortical insuIciency, or

Addisons disease, has an estimated prevalence of <-; cases per @::,:::

people. C@-3ydro"ylase and @JK-hydro"ylase are two autoantigens that havebeen identied as reactive with adrenocortical autoantibodies.

". #ancreas

(iabetes *ellitus is the diagnostic term applied to a group of metabolic

disorders that share hyperglycemia as their common lin. Aggressive blood

glucose control reduces the ris for development of and progression to

vascular complications. The ma6or clinical subgroups of diabetes mellitus are7

type @A for immune mediated diabetes and type @2 for non-immune

mediated diabetes with sever insulin deciency.

$. $astrointestina! tract

1ernicious anemia is characterized by histamine-fast achlorhydria,

hypergastrinemia, vitamin 2@C deciency. )t is associated with circulating



antiparietal cell $A1& autoantibodies in G: of patients and to intrinsic

factor.

>luten-0ensitive nteropathy or celiac sprue, is a small bowel disease

characterized by malabsorption of gastrointestinal fat. )t is considered as a

rare disease in the Fnited 0tates. 1atients might have nongastrointestinalmanifestations that dominate the clinical presentation, such as anemia,

neurological symptoms and autoimmune diseases. 3ypersensitivity to gluten

or gluten derivatives is the cause of >0.

Flcerative colitis and rohns disease are two of the most common

disorders within the group of idiopathic inammatory bowel diseases.

*a6or of the adult patients with ulcerative colitis have detectable p-

A%A that is sensitive to (%ase, which helps di8erentiate p-A%A in

inammatory disease.

%. &ervous system

*yasthenia gravis is a neuromuscular disorder characterized by use-

associated muscular weaness fatigue and the presence of antiacetylcholine

receptor autoantibodies. Ah#s, located in postsynaptic membranes of

seletal muscle bers, bind acetylcholine $Ach& from nerve endings, which

causes a muscle contraction when enough Ach has been released. Anti-Ah#

autoantibodies interfere with this neuromuscular function, resulting in

muscle weaness and fatigue.

*ultiple sclerosis is a relatively common demyelinating disease

involving the white matter of the brain and spinal cord. ause of it is still

unnown. "amination of 0+ does provide important information that

supports a diagnosis of multiple sclerosis in an appropriate clinical setting.

Systemic Rheumatoid diseases

#heumatic diseases are conditions characterized by the presence of auto antibodies directed against di8erent cellular components such as cellsurfaces, cytoplasm, and nuclear elements. The auto antibodies are notdirected to a specic organ.

0ystemic #heumatoid (isease are the following7

A. 0ystemic lupus erythematosus $0/&2. (iscoid lupus erythematosus $(/&. /upus-lie syndromes



(. (rug-induced lupus erythematosus. 06ogrenLs syndrome+. 0cleroderma=#0T syndrome $calcinosis cutis, #aynaudLs

phenomenon, esophageal dysmotility, sclerodactyly, andtelangiectasia&

>. #heumatoid arthritis $#A&3. (ermatomyositis and polymyositis

A. Systemic Lupus rythematosus 'SL(

0ystemic lupus erythematosus is a chronic inammatorymultiorgan disorder. The four etiological factors are endocrine-metabolic, environmental, genetic and viral. )t is characterized by anerythematous rash on the face when e"posed to sunlight anddeposition of immune comple"es in the idney that causesglomerulonephritis. 0creening test for antinuclear antibodies $this are

neutrophils that engulfed another antibody coated nucleus of anotherneutrophil& is the rst step in identifying the disease. +lorescentantinuclear antibody testing is the most accepted test for diagnosis.

Autoantibodies detected are not always specic to 0/. Anti-ds-(%A is specic to 0/ while Anti-ss-(%A, anti-histone, anti-00-A-#o,anti-00-2-/a are not specic to 0/. Anti-0m is diagnostic for 0/. The

table below shows the di8erent antigens and antibodies of 0/.



B.Dis coid

Lupus rythematosus

)t is a chronic sin disease characterized by red lesions on thechees and bridge of the nose that occurs primarily in women ages C:-9:. The sin lesions are the sin lesions of (/ are persistentlocalized erythema, adherent scales, follicular plugging, telangiectasis,

and atrophy,

C. Lupus !ike diseases

This are diseases that share similar clinical features with 0/ buthave di8erent etiologic agents and pathogeneses. this includes7vasculitis, cryoglobulinemia, relapsing polychondritis,lymphoproliferative diseases, rheumatic fever, glomerulonephritis,

syphilis, lupoid hepatitis,

drug-induced lupus, and occult malignancy.

D. Drug)induced !upus erythematosus

)t is characterized by the presence of histone antibodies. Anti-00-(%A could also be present and antichromatin gives the highestspecicity in detection of ()/. ()/ may develop on chonic use of certain drugs such as7 procainamide, hydralazine, )%3, phenytoin,mesantoin, d-penicillamine and ergot compounds. 0ymptoms mayinclude 6oint pain, pericarditis, and pleuritis.

. S*ogren+s syndrome

)t is a chronic progressive inammatory autoimmune disease inwhich the immune system attacs moisture producing glands such asthe tear and salivary glands that could cause severe dryness of eyesand mouth. 00 is classied into primary 00, which is not associatedwith other connective tissue disorder, and secondary 00, in which other



autoimmune diseases are present. These are the most commondisease associated with 007

@. #heumatoid arthritisC. 0ystemic lupus erythematosus

<. 1olydermatomyositis9. *i"ed connective tissue diseaseB. 1rimary biliary cirrhosis;. %ecrotizing systemic vasculitisJ. Autoimmune thyroiditis hepatitisG. *i"ed cryoglobulinemia@:. 3ypergammaglobulinemic purpura

Anti-00-A-#o and anti-00-2-/a are normally restricted to 00 butsometimes present in 0/ patients.

". Sc!eroderma,CRST syndrome

)t is a multisystem connective tissue disorder with unnownetiology characterized primarily by vascular lesions and tissue brosis. There are @@ possible auto antibodies that could be present in patientwith scleroderma, 0cl-J: being the most fre!uent auto antibody and%'#-G: being the rarest. The auto antibodies present in scleroderma

could also be present in #0T syndrome $calcinosis cutis, #aynaudLsphenomenon, esophageal dysmotility, sclerodactyly, andtelangiectasia& but anti-centromere antibody has the highest fre!uencyin #0T syndrome. The table below shows autoantigens andautoantibodies of scleroderma and #0T syndrome.



$. Rheumatoid arthritis

#A is a systemic autoimmune disorder characterized by chronic,

symmetric, and erosive arthritis of the peripheral 6oints, necroticareas are surrounded by granulation of tissue that eventually leads todisintegration of the 6oint. )ts etiologic factors are unnown. #A couldbe associated with other disease lie subcutaneous nodules, vasculitis,interstitial brosis, and anemia. The two most common diseaseassociated with #A are 06ogrenLs and +eltyLs syndromes. The mainimmunologic nding is the presence of #heumatoid factor $a @G0antibody against )g>&.

%. Dermatomyositis and po!ymyositis

1olymyositis is an inammatory disorder in which seletal muscletissue becomes inamed and deteriorates, causing weaness and pain.)t has unnown etiologic factors. When the disease has anaccompanying sin rash it is called dermatomyositis. 1resent autoantibodies targets transfer #%A synthetases, they are measuredserologically.



Over!ap syndromes

'verlap syndrome is a term used when patients e"hibit symptoms of more than one disease$1ope, C::C&. +or e"ample, patients who meet thediagnostic criteria for 0/ and also have typical manifestations suggestive of a

second diagnosis, such as #A, have been described$/azaro, @GDG&. )t is uncertain whether overlap syndromes may represent thecoe"istence of two or more di8erent diseases, or whether the syndrome is adistinct entity.

A.-ied Connective Tissue Disease '-CTD(



The concept of *T( was initially proposed by 0harp and colleagues in@GJC. The C: patients described in the initial report had a combination of features usually associated with 0/, systemic sclerosis, and polymyositis.

B.RA and SL 'Rupus(

)ts concept is when a patient who has 0/ develop rheumatoidarthritis-lie syndromes.

C. /egener+s granu!omatosis

)ts respective antigen is the >olgi Apparatus and the ytoplasmicpattern in the ))+ is >ranular poleMperinuclear, arrow-shaped, coarse,granular, corresponding tothe lamellar stacsof the >olgi comple" $3p-C&

D.#o!yarteritis nodosa and Churg0Strausssyndrome

)t is a condition associated with *onoclonal )mmunoglobulins.1olyarteritis nodosa is a rare autoimmune disease $immune system attacingits own body& featuring spontaneous inammation of the arteries $arteritis&.2ecause arteries are involved, the disease can a8ect any organ of the body. The most common areas of involvement include the muscles, 6oints,intestines $bowels&, nerves, idneys, and sin. 1oor function or pain in any of

these organs can be a symptom. Typically, one nds normochromic anemia,neutrophilic leuocytosis, hypoalbuminemia, hypergammaglobulinemia, anda maredly elevated 0#. *easurement of serum creatinine and blood ureanitrogen $2F%&, together with urinalysis to chec for proteinuria, hematuria,and abnormal sediment, are important for evaluating renal function. Thepositive A%A or #+ found in @:-9: of these patients may be associated withdecreased levels of complement components < and 9. 0erologic tests forhepatitis 2, hepatitis , and 3)4 should be obtained in all patients withpolyarteritis nodosa. 0eletal muscle biopsy reveals circumferential panmuralnecrotizing arteritis of a small muscular artery with mi"ed cell inammation,brinoid necrosis, and proliferative endarteritis.

hurgM0trauss syndrome, also called allergic angiitis andgranulomatosis, is a systemicnecrotizing vasculitis characterized by vascular and e"travasculargranulomatous inammation,multiple organ involvement, and associations with allergic rhinitis, severeasthma, fever, and



hypereosinophilia.

The clinical course of hurgM0trauss syndrome is often divided intothree distinct phases,although in reality these three phases are not always identiable or may

overlap $/angford,@GGB, C::< N9CO N<GO&7 $@& a prodromal phase characterized by allergicrespiratory disease, $C&an eosinophilic phase characterized by peripheral blood and tissuehypereosinophilia, and $<&a vasculitic phase. ardiac involvement, either transmural eosinophiliccarditis or coronaryvasculitis, occurs in CB-;C of patients and is the ma6or cause of death.

A hallmar of hurgM0trauss syndrome is striing peripheral bloodeosinophilia, which may be seen at any phase of the disease. The peripheral

blood eosinophil count reaches @:::eosinophils per P/ in D: or more of patients. 'ther laboratory ndings arenonspecic. Anemia, leuocytosis, and increased 0# fre!uently accompanythe vasculitic phase. 0erum )g levels may be elevated. 0erum #+ may beidentied but the titer is usually low.

.Leukocytoc!astic vascu!itis

/euocytoclastic vasculitis $/4&, also nown as hypersensitivityvasculitis and hypersensitivity angiitis, is a histopathologic term commonly

used to denote a small-vessel vasculitis. /euocytoclastic vasculitis may belocalized to the sin or may manifest in other organs. The internal organsa8ected most commonly include the 6oints, the gastrointestinal tract, and theidneys.

". #oor!y defned connective tissue disease

syndromes

The term Qundi8erentiated connective tissue diseaseQ $FT(& is used

to describe people who have symptoms and certain lab test results that loo

lie a systemic autoimmune disorder or connective tissue disease. 2ut theydonLt have enough of such characteristics to meet the diagnosis for a well-

dened connective tissue disease, such as rheumatoid arthritis, lupus, or

scleroderma. Thus, they seem to have another, similar disorder that doctors

call undi8erentiated connective tissue disease.Q

• arthralgia $6oint achiness&R



• arthritis $6oints that are swollen and hot, often with redness of the

overlying sinR

• rashes, usually on the face, which can worsen due to sun e"posureR

• alopecia $hair loss&R

•

#aynaudLs phenomenon $color changes in your hands and feet inresponse to cold&R

• oral ulcers $sores inside the mouth&R

• "erophthalmia $dryness of the eyes due to decreased tears&R

• "erostomia $dry mouth due to decreased saliva&R

• low-grade fever $usually under @::o f&R

• photosensitivity $ development of rashes or other symptoms after sun

e"posure&.

0ome people also develop7

• leuopenia - decreased numbers of white cells $cells that help ght

infection& in your bloodR

• anemia - decreased numbers of red blood cells $cells that carry o"ygen

to tissues in the body& in your bloodR

• thrombocytopenia - an abnormal decrease in the number of platelets

$the parts related to blood clotting&R

• pleuritis or pericarditis - inammation of the lining surrounding the

lungs or heart, respectively, which may cause pain in the chest,

especially with breathingR• neuropathy - abnormal nerve sensations, usually in the ngers or toes,

ranging from numbness to tingling to pain.

La1oratory "indings '2mmuno!ogic&

0ome marers in your blood indicate possible abnormal function of

your immune system. While most studies note that the ma6ority of patients

with FT( are have antinuclear antibodies $A%A&, a broad range of

immunologic abnormalities can be seen in people with FT(. These mayinclude7

• elevated erythrocyte sedimentation rate $0# - an indicator of

inammation&R

• antiphospholipid antibodies $which can a8ect blood clotting and may

increase your ris of miscarriage&,



• hypergammaglobulinemia $an e"cess of gamma globulin, often called

)g>, a protein in the blood thatLs involved in resistance to infection&R

• hypocomplementemia, $a decreased level of complement -- proteins

that help destroy bacteria and other cells -- commonly referred to as <

and 9&R• a false positive blood test for syphilis, nown as Q#1#Q $meaning the

lab test indicates you have syphilis but you really donLt, which can be

proven by a more comple" test&R

• positive evidence of other marers of autoimmune disease, such as

anti-ds(%A $double-stranded (%A& antibodies, anti-#o=00A, anti-0*

$0mith&, anti-#%1, rheumatoid factor $#+&R and anti-Hu antibodies.

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Rheumatic and Autoimmune Diseases