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Compartmentsyndrome
Cellulitis
Deepvenousthrombosis
Ischemia/infarctionduetothrombus
Raynaudphenomenonassociatedwithgangrene
Fracture
Spinalcordcompression
Mononeuritismultiplex
Vasculitis
Erythema
Erythema of a joint is rarely seeninpatientswithsystemic inflammatorydisorders such as
rheumatoidarthritis orspondyloarthropathy.Thepresenceoferythema raises suspicionfora
septic joint, gout,or cellulitis. When acellulitis lies over a joint, itcanbe a challenge to
distinguishitfromgoutorsepticarthritisbecauseitmayalsolimitrangeofmotionofthejoint
owingtopaincausedbystretchingoftheskinandsubcutaneoustissues.Anobviousportalof
entryoranoff-centerdistributionoferythema(relativetothejointspace)canbehelpfulclues
to cellulitis, if present. Although gout is often thought of as a condition isolated to joints,
tenosynovium and subcutaneous tissue are commonly involved, and when this occurs itcan
also cause anoff-center distributionoferythema on thejoint. Point-of-care musculoskeletal
ultrasound (MSKUS) can be valuable in these situations, as it will show edema in the
subcutaneousfatinthecaseofcellulitisorcanshowjoint/tendoninvolvementinthecasesof
goutorsepticarthritis.
ConstitutionalSymptoms
Althoughmanysystemicautoimmuneconditionsand evencrystallinearthropathycanpresent
withconstitutionalsymptoms,thepresenceoffever,malaise,weightloss,and/oranelevated
leukocytecountshouldpromptthecliniciantoruleoutinfection.Bloodcultures,synovialfluid
cultures, and culture of other distant symptomatic sites are necessary. Patients with known
underlying conditions that can cause fever such as systemic lupus erythematosus (SLE) or
systemic vasculitis often take immunosuppressive drugs, increasing the risk of infection.
Therefore,whenthesepatientspresentwithafever,itisdifficulttodiscernwhetherthereisa
flare ofdisease,an infection,orboth. Also, itis important to note thatcorticosteroidswill
oftencauseanelevationintheWBCcount,confoundingasituationwhereinfectionneedstobe
ruledout.Moreover,patientswhoareoncorticosteroids,especiallydosesgreaterthan30mg
ofprednisonedaily(ortheequivalent),maynotmountafeverevenwhenseptic,ortheymay
have reduced symptoms in the setting of an infection. In a patient taking high doses of
corticosteroids,anyinfectionhaslikelybeenpresentlongerthanonemightsuspectbasedon
theirsymptoms;therefore,onemusthavealowthresholdtoinitiateantibiotictherapyassoon
asispossible.
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NeurologicSymptoms
Weakness,numbness,paresthesia,andaburningqualityofpaincanallbecluestoneurologic
involvement such as radiculopathy, myelopathy, compartment syndrome, or mononeuritis
multiplex/vasculitis. Itis importanttokeep in mind that painina joint will often resultin
weakness,makingassessmentofstrengthchallenging.Furthermore,inflammationinaregionin
whichaperipheralnervepassesthrough(suchasthetarsaltunnelorvolarwrist)canleadto
compressionofthenerveandresultantparesthesiaornumbness.
DiffuseEdema
Diffuseedema,especiallywhenunilateral,mayraisesuspicionforthepresenceofaDVT.The
typicalpresentationofaDVTisthatofpain,swelling,anderythemaonthelowerextremity;
however,allofthesesymptomsneednotbepresent,andtherearemanyotherconditionssuch
as venous insufficiency, popliteal cysts, cellulitis, and muscle injury that may present in a
similarfashion.Furthermore,arthritisorperiarthritisoftheankle,whichmaybeseeninany
type ofsystemic inflammatoryarthritis, maypresent this way. Riskfactors forDVTinclude
statesthatpromotehypercoagulabilitysuchasrecentsurgeryorinjury,pregnancy,malignancy,
genetichypercoagulablestatessuchasFactorVLeiden,andautoimmuneconditionssuchasthe
antiphospholipidantibodysymptomsandgranulomatousangiitis.5Apersonalorfamilyhistory
ofDVTisalsoariskfactor.Diagnosiscanbemadewithultrasoundofthelowerextremity;the
locationoftheclotoftendoesnotcorrelatewiththelocationofsymptoms.TreatmentofDVT
withanticoagulationiscriticaltoreducetheriskofpulmonaryembolus.
ArticularversusPeriarticularDisorders
Patientswhopresentwithacomplaintofjointpainoftenfinditdifficulttodistinguishbetween
atruearticularproblemandaperiarticulardisorder.Ingeneral,anarticulardisorderwillbe
associated with pain throughout the range of motion of the joint involved, whereas a
periarticular disorder (e.g., tendonitis, bursitis) willbeassociatedwithpainthrough only a
segmentofthefullrangeofmotion.Well-localizedtendernessoveratendonorbursafurther
supportstheconclusionofaperiarticulardisorder.Itisnotonlypossible,butrathercommon
for both processes to occur simultaneously during an inflammatory illness. Therefore, the
presenceofperiarticularpaindoesexcludetheexistenceofasystemicinflammatorydisorder.
Forexample,rheumatoidarthritisfrequentlyaffectstendonsinadditiontojoints6and mayin
factbecommoninearlypresentationofthedisease. In gout,uric acid crystalsmaynotonly
deposit in joints and tendons but also disperse to surrounding soft tissue. In
spondyloarthropathy,themajortargetoftheautoimmuneattackistheenthesis:theattachmentof
tendonsandligamentstobone.7Therefore,patientswilloftenpresentwithbothclearsynovitis
manifestedbytendernessandswellingofajointwithpainthroughouttherangeofmotionand
also localizedtenderness overanearbytendonsuch as theAchilles,quadriceps,orpatellar
tendons.
MonoarticularArthritisversusOligo-/PolyarticularArthritis
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Septicarthritis,traumaticarthritis,andcrystallinearthritis(i.e.,gout,pseudogout)arethemain
entities to consider when a patient presents with monoarticular joint pain. However, it is
importanttokeepinmindthatgoutand pseudogoutcaninvolve morejoints in a significant
proportionofpatients,andcanevenpresent,albeitrarely,asasymmetricpolyarthritisofthe
small jointsofthehandsandfeet,mimickingrheumatoidarthritis.Furthermore,anytypically
polyarticular process such as rheumatoid arthritis and spondyloarthropathy can present as
monoarticulardisease,especiallyearlyinthediseasecourseandespeciallywithonsetinthe
elderly.Afterworkingupamonoarticulararthritisforinfection,injury,andcrystallinedisease,
itisimportanttogiveconsiderationtosystemicinflammatorydisease.Thefailuretorecognize
asystemicconditionthathasmanifestedatypicallyasamonoarticulararthritis mayresultin
multipleunnecessaryprocedures,includingsurgery.Increasingly,MSKUShasbeenfoundtobe
usefulindistinguishingbetweenmono-andoligo-/polyarticulardisordersandarticularversus
periarticulardisorders.
UseofUltrasoundinRheumatology
Overthelast10to15years,MSKUShasbecomeanestablishedtechniqueforevaluationand
follow-up of patients with rheumatic diseases. Technologic advances, including faster
computersandprobesthatcanseegreaterdetail,alloweventoday’slow-budgetmachinesto
detect tinyfluid collections within joints, resolve small defects in bone and cartilage, and
providecolormapsofthejoint,indicatingwhereinflammationistakingplace.Theadvantages
ofultrasoundoverotherimagingmodalitiesincludethefollowing:portabilityduetothesmall
sizeofthemachines,noninvasiveness,lackofradiation(allowingforfrequentrepeatimaging),
relativeinexpensiveness,theabilitytoscanmultiplejointsinabriefperiod,andtheabilityto
lookatthejointwhileitisinmotion(i.e.,dynamicimaging).Thesefeaturesmakeultrasound
particularlywellsuitednotonlyforthediagnosisofrheumaticdiseasebutalsoformonitoring
the progress of therapy. Therefore, a rheumatologist with a clinical understanding of the
patient’sproblemcanscanandinterpretimagesatthebedside,ratherthansendingthepatient
for a second appointment. Treatment decisions can be made immediately, thereby greatly
improving the efficiency of medical care. Finally, ultrasound at the bedside hastremendous
educationalvalueforthepatientastheystruggletounderstandtheirowndiseaseprocess.With
only brief explanations, the patients can see real-time images of the inflammatory process
damagingtheirjoint,makingaconcretenotionofwhatwaspreviouslyonlyabstract.Thisisof
great utilitytothe practitioner when discussing the reasons for medical therapy, which are
oftenimmunosuppressiveorchemotherapeuticdrugswithnumeroustoxicities.
Indeed, a large body of literature supports the above assertions. For example, studies
examining the utility ofultrasound inthe rheumatologyclinic have shown thatultrasound is
moreaccuratethanclinicalexaminationatdetectingjointfluidandinflammation.
8,9
Inastudy
of 100 consecutive patients, Karim et al.10 have shown that use of ultrasound in a busy
outpatient rheumatology clinic changed the management plan that was made prior to the
performanceofultrasound56%ofthetimeandthatoveralldiagnosiswaschanged5%ofthe
time. Several studies
11–13
haveshown that,in rheumatoid arthritis, baseline power Doppler
signalisastrongpredictorofjointdamage1yearlater.
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Forseveraltypesofinflammatoryarthritis,studieshaveexaminedtheroleofperforming
ultrasound inrheumatic disease patients with thefollowing aims: clarifyingthe differential
diagnosisinearly, undifferentiatedrheumaticdisease,definingthe number ofjointsinflamed
and/ordamaged, monitoring thesuccess of therapyin establisheddisease, guidance ofjoint
aspirationsandinjections.Indeed,therehavebeenagrowingnumberofrheumatologistsusing
point-of-careultrasoundtoenhancepatientcareinrecentyears.
14
WHENANDWHYTOREFERAPATIENTWITH
SUSPECTEDINFLAMMATORYARTHRITIS
Inthepastseveraldecades,studiesincohortsofpatientswithearlyinflammatoryarthritis(not
fulfillingtheAmericanCollegeofRheumatologycriteriaofrheumatoidarthritisatonset)have
shownthatwhilemanyofthesepatientshaveaself-limitedillness,asignificantproportionof
thesepatientsgoontodeveloprheumatoidarthritis(RA).
15,16
Severalobservationshaveledto
the conclusionthatRApatientsshouldbeidentifiedearlyandtreatedaggressively.Machold
andcolleagues15haveshowninastudyofpatientswithinflammatoryjointdiseaseoflessthan
3months’durationthat61.1%ofpatientswentontodeveloprheumatoidarthritis,12.8%had
erosionsontheirfirstX-rays,and27.6%haderosionsbytheirfirstyear.Thishighlightsthe
factthatpermanentjointdamagecanbeginveryearlyinthediseaseprocess.Inaddition,many
patientswithRAareforcedtoleaveworkwithin5to10yearsofdiseaseonset,andlifespans
ofRApatientsaresignificantlyshortened.Thepersistentinflammatoryburdenassociatedwith
RAcanleadtoprematureatherosclerosisanddeathduetocardiacevents.Datasuchasthese
have led investigators to compare treatment strategies in patients with early inflammatory
arthritis.
There is now clear evidence that patients who have early rheumatoid arthritis have
significantlybetter outcomes whenthey are treated withinthe firstfew weeks to months of
their illness.Forexample, Lard andcolleagues17haveshown(utilizingmedicationsthat are
now considered relatively weak disease-modifying antirheumatic drugs (DMARDs)) that
treatmentinitiatedwithinafewweeksofsymptomonsetresultedinlessradiographicdamage
(as measuredby Sharpscore) andless overall disease activity (asmeasuredbythe disease
activityscore).
Furthermore, overthe last15years, theintroductionofbiologic medications,especially
those that block tumor necrosis factor α (TNF-α), has revolutionized the practice of
rheumatology, allowing for greater control of the inflammation of RA than was previously
possible.TheTNF-αblockers,whichincludeetanercept,infliximab,adalimumab,golimumab,
and certolizumab pegol, not only greatly reduce disease activity but also can slow the
progression of joint destruction. Because early treatment results in better outcomes and
becausewenowhaveveryeffectiveagentsfordoingso,earlyinflammatoryarthritisshouldbe
treatedwithasenseofurgency.WhileRAistheclassicinflammatoryarthritis,therearemany
other conditionsthat are virtuallyindistinguishable from RA early in their course, some of
which can be equally destructive, but may require different or additional therapies. These
diseasesinclude(butarecertainlynotlimitedto)thefollowing:SLE,psoriaticarthritis(PsA),
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ankylosing spondylitis, systemic sclerosis, relapsing polychondritis, inflammatory myositis,
granulomatous angiitis, adult-onset Still disease, polymyalgia rheumatica, and giant cell
arteritis.
Emery and colleagues18 suggest the following guidelines for referral of a patient with
arthritis andany of the following to a rheumatologist: (a) ≥3swollenjoints; (b) a positive
“squeeze test” (transverse compression of the metatarsophalangeal (MTP) or
metacarpophalangeal(MCP)joints);(c)morningstiffnesslastinggreaterthan30minutes;(d)
elevated acute-phase reactants including erythrocyte sedimentationrate(ESR)or C-reactive
protein (CRP); (e) positive serologies including rheumatoid factor (RF) or anti-cyclic
citrullinatedprotein(anti-CCP);(f)jointsymptomslastinggreaterthan6weeks.
COMMONLYOBSERVEDRHEUMATICDISEASESOF
THELOWEREXTREMITY
RheumatoidArthritis
Rheumatoid arthritis is a systemic inflammatory disease affectingapproximately 1% of the
population.Itisprimarilycharacterizedbyanimmune-mediatedattackonthejoints;indeed,
tissuetakenfromthejointsofRApatientsshowsthatleukocyteshavemigratedfromtheblood
tothesynovialtissueandsynovialspace.Althoughjointsandtendonsaretheprimarysiteof
inflammation,otherorganssuchastheeye,lungs,skin,andbloodvesselscanalsobeaffected.
Peakincidenceisbetween25and50yearsofage,butanyagecanbeaffected.Thecondition
affectswomenmorethanmenataratioofapproximately3:1.
Rheumatoid arthritis is a disease of unknown cause; however, both genetic and
environmentalinfluenceshavebeensuggested.Inthecaseofmonozygotictwins,whereoneof
thetwinpairhasrheumatoidarthritis,theincidenceofthesecondtwindevelopingrheumatoid
arthritisis15%to30%.BecausetheincidenceofRAinthegeneralpopulationisonly1%,this
suggests a strong genetic influence on disease; however, the incidence of the second twin
developingRAisnot100%,suggestinganenvironmentalcomponentaswell.Inaddition,there
isageneticassociationwithanalleleofthemajorhistocompatibilitycomplex(MHC)classII
receptor, HLA-DR4. Suggestions of environmental influences include an association with
periodontaldiseaseand theassociationofmoreaggressivediseaseinpatientswhohavethe
anti-CCPantibodyandwhoconcomitantlysmoke.
19
Atthecellularlevel,thesynovialliningofthejointsofpatientswithrheumatoidarthritis
becomesinfiltratedwithimmunecellssuchas Tlymphocytes,Blymphocytes,plasmacells,
andmacrophages(Fig.2-1).Immunecomplexesandneutrophilsarefoundwithinthesynovial
fluid. Furthermore, proinflammatory cytokines have been shown to be upregulated in the
synoviumofpatientswithrheumatoidarthritis,andtheseincludeTNF-α,interleukin-6(IL-6),
IL-1,andIL-17.Thethickenedsynovialliningcontaininginflammatorycellsandmediatorsis
known as a pannus. The chronic, unregulated inflammatory response of the pannus has the
ability to degrade both bone and cartilage, leading to the destructive arthropathy seen in
rheumatoidarthritis.Whenboneandcartilageofthejointaredestroyed,thiscanbevisualized
onX-ray,ultrasound,orMRIasanerosion(Fig.2-2).
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Manylaboratorytestsmaybeabnormalinpatientswithrheumatoidarthritis.TheESRand
CRP are both nonspecific markers of inflammation that may be elevated but can also be
normal;thus,theirabsencecannotbetakenastheabsenceofdisease.Inaddition,thepatient
mayhaveananemiaofchronicdiseasethatmayimproveasthediseaseiscontrolled.Synovial
fluidaspiratedfromaclinicallyswollenortenderjointoftenwillbeinflammatoryandcontain
numerous neutrophils, but will be negative for culture and crystals. RF and anti-CCP are
autoantibodiesthatarehighlyassociatedwithrheumatoidarthritis.RFrecognizestheFcregion
of immunoglobulin G, while anti-CCP antibodies recognize citrullinated proteins usually
present within connective tissue. Patients may have one of these autoantibodies, both, or
neither.Anti-CCPantibodiesarepresentin50%to70%ofpatientswithrheumatoidarthritis,
butareonlypresentinless than2%ofthe population. In contrast,RFismuch morewidely
seen in the general population, with a prevalence of about 10%. Interestingly, anti-CCP
antibodies may appear years before the patient displays symptoms,20 suggesting that the
abnormality which is autoimmunity exists long before the patient can even sense the first
symptom.
The classic clinical presentation of rheumatoid arthritis is a symmetric polyarthritis
involvingthesmalljointsofthehandsandfeet,butabout25%ofpatientsmayhaveoligo-or
monoarticulararthritis.Thehandsandfeetwillbeinvolvedinthevastmajorityofpatientsat
somepointinthediseasecourse.Whenapatientpresentswithmonoarticulararthritis,theknee
will be involvedapproximately50%ofthetime.Older patients haveatendencytopresent
withanonclassicpresentationsuchasmonoarticulararthritisorepisodicdisease.Inthehands,
theusualinvolvedjointsaretheMCPjointsandtheproximalinterphalangealjoints.Inthefeet,
theMTPjointsandintertarsaljointsaremostoftenaffected;however,anyjointofthefootcan
be involved. The cervical spine may also be affected in severe cases and maypresent as
weakness of the legs due to atlantoaxial subluxation or basilar invagination, causing
impingementonthe cervical spinalcord.These patients maynotpresentwithneckpainbut
ratherweakness(suchasdifficultyarisingfromachairorascendingsteps)ordifficultywith
ambulating. Therefore, in rheumatoid arthritis patients scheduled to undergo general
anesthesia, it is reasonable to first obtainlateral view X-rays of the cervical spinein both
flexionandextensiontoassessforinstabilityofthesecondcervicalvertebraerelativetothe
first cervical vertebrae. Rheumatoid arthritis, if untreated, has a high likelihoodofcausing
jointdamageordestruction.Manypatients,ifuntreated,willaccumulatedisabilitywithinthe
first 1 to 3 years of disease onset. It has become clear over the last decade that early
aggressive therapy is important for theprevention of long-term joint destructionand patient
disability.
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FIGURE2-1.Rheumatoidarthritis.Lymphocytesandmonocytesmigrateintotherheumatoidsynoviumfromthe
vasculature,causingittobecomethickened.Neutrophilsmigrateintothesynovialspace,andimmunecomplexes
canbefoundhereaswell.Theproinflammatorymediatorsproducedbythesecells,includingcytokinessuchas
TNF-αanddegradativeenzymes,cancausedestructionoftheboneandcartilage,whichcanbeseenonimaging
asanerosion.
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FIGURE2-2.Typicalultrasoundfindingsinrheumatoidarthritis.Grayscale(AandB)andpowerDoppler(C)
imagesoftheproximalinterphalangealjointofapatientwithrheumatoidarthritisinlongitudinal(AandC)andshort
axisviews(B).Theleftsideoftheimageisproximalin(AandC);medialin(B).Adarkregionemanatingfromthe
joint(A;arrowheads)indicatessynovialthickening,andanerosionisalsoseen(star).Thesynoviumdemonstrates
powerDopplersignal(redcolor),indicatinginflammation.
Becauseitisasystemicdisease,rheumatoidarthritiscanaffectotherorgansinadditionto
thejoints.Systemicdiseasemanifestationsareseenlessfrequentlytodaybecauseoverthelast
decade and a half, improved therapies, which have been deliberately engineered to target
different components of the inflammatory response, have revolutionized the treatment of
rheumatoidarthritis.Theseimprovedtherapieshavemadetheextraarticularmanifestationsof
rheumatoidarthritisrare.Whenpresent,manypotentialorgansystemscanbeaffectedbythe
autoimmuneprocess. Pulmonaryinvolvementmayincludeeffusions,nodules,interstitial lung
disease, and vasculitis. Cardiac involvement may include pericarditis or amyloidosis. The
patientmaydeveloprheumatoidnodules,whichareusuallyfoundovertheextensorsurfaceof
the forearmbutcanalsobepresentinthelung.Eyeinvolvement maytaketheformofeither
scleritis or uveitis. The presence of scleritis is an emergency because, if untreated, it can
rapidly lead to melting of the sclera. Neurologic involvement may include an entrapment
syndrome such as carpal tunnel syndrome or ulnar nerve entrapment, or mononeuritis
multiplex:avasculitisofthevasanervoruminwhichthepatientmaypresentwithahanddrop
orfootdrop.Ofnote,patientsmayalsopresentwithadropofthefourthandfifthfingersnot
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related to neurologic cause but rather secondary to rupture of the fourth and fifth extensor
tendonsonajaggedlyerodedulnarstyloid.FeltysyndromeisapresentationofRAinwhich
thepatienthasleukopenia,splenomegaly,andlowerextremityulcerations.
Patients with rheumatoid arthritis, similar to patients with other systemic inflammatory
diseasessuchasSLE,haveahigherincidenceofatherosclerosisandcoronaryevents,andthis
leads to earlier mortality in this population. When compared with age-matched controls,
coronary artery disease occurs in patients with rheumatoid arthritis at younger ages.
Furthermore, the control of rheumatoid arthritis with disease-modifying agents such as
methotrexate leads to a decreased incidence of coronary artery disease, linking the
inflammationcausedbyrheumatoidarthritistothepresenceofatherosclerosis.21Thissuggests
that the inflammatory burden of RA impacts on the vasculature in ways that promote
atherosclerosis; therefore, lowering the inflammatory burden of the disease with medical
therapysignificantlyreducestheburdenofatherosclerosisaswell.
Thedifferentialdiagnosisforrheumatoidarthritis,especiallyearlyinthediseasecourse,is
quite broad because many inflammatory conditions can present in a similar fashion. Other
conditionstoconsiderincludepolymyalgiarheumatica,PsAandotherspondyloarthropathies,
crystalline arthropathy such as gout and pseudogout, SLE, Sjögren syndrome, systemic
sclerosis, and sarcoidosis. Infections such as Lyme disease, parvovirus infection, and a
poststreptococcalreactivearthritiscanpresentsimilarlytorheumatoidarthritisaswell.
X-rayfindingsthatmaybesuggestiveofinflammatoryarthritisincludesofttissueswelling,
periarticularosteopenia,andjointspacenarrowing.Thepresenceoferosionsincharacteristic
locationssuchastheulnarstyloidandlateral5thMTPjointcanbeacluetothepresenceof
rheumatoid arthritis. Ultrasound findings may include synovial hypertrophy, effusions,
erosions,andpowerDopplersignal(Fig.2-2). Inearlyrheumatoidarthritis,powerDoppler
signalatbaselineispredictiveofdamageat1year.12Inaddition,itisclearthatmanypatients
whoarefelttobeinclinicalremissionstillhavepowerDopplersignalonultrasound,andthis
isassociatedwithjointdamage.
13
Many years ago, standard of care for treatment of rheumatoid arthritis included the
initiationofnonsteroidalanti-inflammatorydrugs(NSAIDs).Sincethen,ithasbeenshownthat
eventhough NSAIDs have theability to reduce pain, the destructive process of RA is not
altered: patients may have less joint pain but will continue to undergo joint destruction.
Therefore, the treatment paradigm has shifted to early initiation of DMARDs and biologic
agents.Earlyaggressivetherapywiththesedrugsresultsinaslowingofdiseaseprogressionin
addition to reduction in daily pain and disability. Furthermore, there is a reduction in
atherosclerosis,whichleadstoanimprovementinmortalityofpatients.Thegeneralapproach
totreating patientswithrheumatoidarthritishasrecentlybeenoutlined,andguidelineswere
publishedin2015.22 The general treatmentapproachis to startwithaDMARDas soonas
possible once the diagnosis of rheumatoid arthritis is made. Adding a biologic agent or
switching toa biologic agentis then considered ifthepatientdoesnothavea greatenough
response to the DMARD. Combinations of two or three DMARDs and combinations of a
DMARDandbiologicareroutinelyemployed.
DMARDs includethefollowingagents: hydroxychloroquine, sulfasalazine,methotrexate,
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leflunomide, andcyclosporine.Thesearesmallmoleculesthatwork,inpart,bysuppressing
the immune system by interfering with the activation and proliferation of the cells of the
adaptiveimmuneresponse.Theyaretypicallygivenbymouth,althoughmethotrexatecanbe
injectedsubcutaneously. They tend to workslowly, usuallyrequiring 6to12 weeks before
seeingaresponse.Patientsmustbe monitoredfrequentlywith bloodtests forhepatotoxicity
andmarrowsuppression.
Biologicagentsaremoleculesthathavebeenengineeredtospecificallytargetmoleculesor
cellsthathavebeenshowntoplayacrucialroleindysregulatedinflammatoryresponsethat
takes place in rheumatoid arthritis. One of thefirst biologic agents introduced includes the
group of molecules that blockTNF-α (infliximab,adalimumab, etanercept, golimumab, and
certolizumab), a critical proinflammatory molecule found to be elevated in patients with
rheumatoidarthritis. Abataceptisamoleculethatblocksthecostimulatory pathwaybetween
antigen-presenting cells and T lymphocytes. Thepurpose of this molecule is to prevent the
propagationofan adaptive immune responseby interferingwith this signal. Rituximab is a
chimericmonoclonalantibodythatrecognizesandrapidlydepletesBlymphocytes,the cells
responsible for antibody production, and thus autoantibody production. Tocilizumab is a
humanizedmonoclonalantibodythatbindstotheIL-6receptorandpreventssignalingbythis
potent proinflammatory molecule through its receptor. Tofacitinib is a small molecule that
blocks signaling of immune cells through the Janus kinase pathway. This is an important
pathwayfor proinflammatorycytokinesignaling.All ofthebiologic agents described above
have been studied in patients with rheumatoid arthritis (usually in combination with
methotrexate)andhavebeenshowntobeextremelyeffectiveatnotonlycontrollingtheday-todaysymptomsbutalsoinpreventingthedestructiveprocessofthedisease.
PatientstakingDMARDsorbiologicsorbothwillrequireregularbloodteststoassessfor
hematologic andhepatictoxicities. Patientswhoareabouttostartbiologicsmayneedtobe
tested for hepatitis B, hepatitis C, and/or tuberculosis infection as these medications can
worsenor activatetheseconditions.Allpatientson immunosuppressive drugshaveahigher
susceptibilityto infection,and the symptoms of infection may be masked by the drug. It is
common practice to stop thesemedicationswhen an infection is suspected and havea low
thresholdfortheinitiation of antibiotics.Finally, vaccinationsagainstinfluenza, pneumonia,
andzosterarefrequentlysuggestedtopatientstakingDMARDsandbiologicagentstopartly
counteracttheir higherriskof infections.Influenzaand pneumoniavaccinescanbegivento
patientswhoareconcomitantlytakingeitherDMARDsorbiologicagents,andthesepatients
willgenerateanimmuneresponsetothevaccine.
Spondyloarthropathy
Spondyloarthropathyisagroupofinflammatoryarthritidesthatincludethefollowingentities:
ankylosing spondylitis,PsA,enteropathicarthritis (thearthritis associatedwithinflammatory
bowel disease), reactive arthritis (an arthritis that follows an episode of dysentery or a
sexually transmitted disease), and SAPHO (synovitis, acne, pustulosis, hyperostosis, and
osteitis;thearthritisassociatedwithpustularacneandhidradenitissuppurativa).Theseentities
are tied together by the following features: a genetic association with HLA-B27, spine
involvement (a region usually not targeted in rheumatoid arthritis), and involvement of the
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