Amboss Rheumatology and Immunology

Autoantibodies in rheumatic diseases Antibody diagnostics play a vital role in the differential diagnosis of rheumatic diseases. Many of these autoantibodiescan be differentiated into antibodies against nuclear antigens (ANAs) and antibodies against cytoplasmic antigens (ANCAs). Although both of these antibodies are detectable in numerous autoimmune diseases, elevated ANAs are typical for connective tissue diseases and elevated ANCAs for vasculitis. Diagnosis of individual conditions can be further supported by detecting disease-specific ANAs or ANCAs, such as anti-dsDNA in systemic lupus erythematosus or c-ANCA in Wegener granulomatosis.

Antinuclear antibodies (ANAs) Brief descriptionANAs are comprised of numerous antibodies against specific nuclear antigens.In addition, ANAs include autoantibodies against DNA and histones. AssessmentElevated ANA levels are observed in various autoimmune diseases, especially in the diseases listed below.An increase is typically observed in connective tissue diseases, but may also be found in, e.g., rheumatoid arthritis(RA), autoimmune hepatitis, and vasculitides.In general, elevated ANA levels are considered nonspecific; exact diagnosis requires determination of individual antibodies. Systemic lupus erythematosus(SLE)Anti-dsDNA (in ∼ 70% of cases) Anti-Sm (Smith)Anti-histone (in drug-induced SLE)Anti-Ro/SSAAnti-La/SSBAnti-U1 RNP (ribonucleoprotein) Antiphospholipid antibodies (anti-cardiolipin most common type)Anti-C1q antibodies (correlates with disease activity) Systemic sclerosis(scleroderma)Anti-Scl-70 (anti-topoisomerase antibody I: seen in 30-70%of casesAnticentromere (ACA) Anti-RNA polymerase IIISjögren syndromeAnti-Ro/SSAAnti-La/SSB60-80% of patients positive for one or both antibodiesRheumatoid factor (RF); present in > 50% of patientsAnti-CCPSalivary gland antibodies Polymyositis and dermatomyositisAnti-Jo1Anti-Mi2RFMixed connective tissue diseaseAnti-U1-RNPRF Antineutrophil cytoplasmic antibodies (ANCAs) Description: ANCAs are comprised of antibodies against specific cytoplasmic antigens AssessmentAn increase is observed in various autoimmune diseases, especially vasculitidesAtypical fluorescence patterns of p-ANCA (perinuclear ANCA) also play an important role in the diagnosis of primary sclerosing cholangitis (PSC). c-ANCA(Proteinase-3 antibody)Granulomatosis with polyangiitis (Wegener granulomatosis) 90% of patients are c-ANCA positive.Rarely in microscopic polyangiitis, Churg-Strauss syndromep-ANCA(Myeloperoxidase antibody)Microscopic polyangiitis: ∼ 70% of patients are ANCA positive (mostly p-ANCA).Churg-Strauss syndrome: ∼ 50% of patients are ANCA positive (both c-ANCA and p-ANCA).Rarely: polyarteritis nodosa, granulomatosis with polyangiitisatypical p-ANCAPSCUlcerative colitisRarely: primary biliary cirrhosis, Crohn's disease

Connective tissue diseases Connective tissue is an important biological tissue composed of an extracellular matrix that binds, anchors, and supports organs. There are various types of connective tissue, all of which consist of varying combinations of fibers, cells, and intercellular substance. Over 200 conditions, which may be inherited or autoimmune, affect connective tissue, and they are collectively known as connective tissue diseases (CTDs). Inherited CTDs are caused by mutations that affect one of the two fibers (collagen and fibrin). Autoimmune CTDs have no clear etiology, but the incidence is higher in women and among genetically predisposed individuals. As the name suggests, in autoimmune CTDs, the immune system develops antibodies against components of connective tissue. Individual conditions can affect a vast range of bodily structures (including cartilage, blood vessels, bone, tendons, and organs) and thus present with a wide array of clinical findings.

Autoimmune connective tissue diseases Systemic lupus erythematosus Rheumatoid arthritis Inflammatory myopathies (e.g., polymyositis, dermatomyositis) Systemic sclerosis Sjögren's syndrome Mixed connective tissue disease (Sharp's syndrome) Inherited connective tissue diseases Ehlers-Danlos syndrome Marfan syndrome Osteogenesis imperfecta Alport syndrome Loeys-Dietz syndrome [1]Autosomal dominant inheritanceFeatures shared with Marfan syndrome: marfanoid habitus, increased risk of ascending aortic aneurysms and aortic dissectionDistinct features: hypertelorism, bifid uvula, cleft palate, easy bruising and keloids, arterial tortuosity (winding course of arteries) Autoimmune CTDsInherited CTDsGeneral features Fever, weight loss, fatigue Fatigue, weakness Musculoskeletal symptoms Polyarthritis, myositis Joint hypermobility, curved spine, brittle bones, bone deformities, growth abnormalities (short or tall stature) Skin manifestations Erythema, Raynaud's phenomenon Hyperextensive, fragile skin Organ manifestations Heart: pericarditisLungs: scarring (pulmonary fibrosis), pleurisyKidneys: nephritis (e.g., glomerulonephritis)CNS: depressive moods Heart: valve weakness/prolapseLungs: weakness, difficulty breathing, tendency to develop emphysemaBlood vessels: aneurysms, ruptures Eye abnormalities Connective tissue disorders This table lists the most important connective tissue disorders and some examples of their clinical features. For more information on Marfan syndrome, Ehlers-Danlos syndrome, and osteogenesis imperfecta, see the respective learning cards. The ATP7A gene is defective in Menkes disease, whereas the ATP7B gene is defective in Wilson's disease! Ehlers-Danlos syndrome and Menkes disease are both associated with reduced lysyl oxidase activity, resulting in defective collagen cross-linking and fibril synthesis.

Inflammatory myopathies Inflammatory myopathies (IM) are systemic muscle wasting diseases characterized by progressive weakness due to chronic inflammation of skeletal muscles. IMs are classified according to clinicopathological features and include polymyositis (PM), dermatomyositis (DM), and inclusion-body myositis (IBM). Patients with IM typically complain of muscle weakness with difficulties reaching overhead, climbing the stairs, and/or standing up. Advanced disease may present with dysphagia and aspiration because of oropharyngeal muscle involvement, or even respiratory failure if breathing muscles are affected. While IMs share many features, there are also some important differences between them: In contrast to PM and IBM, DM also affects the skin, resulting in lesions such as Gottron papules, heliotrope rash, and the shawl sign. Furthermore, DM is often associated with neoplasms (e.g., lung, ovary, lymphoma, GI). Unlike DM and PM, IBM mainly manifests in the elderly and progresses over years. Diagnosis of suspected IM is supported by laboratory tests, which show elevated muscle enzymes (e.g., creatine kinase, aldolase), as well as characteristic electromyogram(EMG) and biopsy findings. Treatment consists of immunosuppression with glucocorticoids or in some cases, with immunosuppressants such as methotrexate or azathioprine.

Definition Polymyositis (PM): inflammatory myopathy affecting the proximal skeletal muscles Dermatomyositis (DM): inflammatory myopathy that presents similarly to polymyositis, with the addition of skin involvement Inclusion body myositis (IBM): inflammatory myopathy affecting both the proximal and distal skeletal muscles Epidemiology IncidencePM and DM: 2/100,000 per yearIn the US, PM disproportionately affects the black population. SexPM and DM: ♀ > ♂ (2:1)IBM: ♂ > ♀ (2:1) Peak incidencePM: 30-60 yearsDM5-15 years (juvenile dermatomyositis)40-60 years (adult dermatomyositis)IBM: > 50 years Etiology Unknown origin, but most forms of IM seem to involve an autoimmune reaction that leads to muscle inflammation, particularly in genetically susceptible individuals; viral infections, malignancies, or connective-tissue disorders may play a role Polymyositis (PM): cell-mediated cytotoxicity against unidentified skeletal muscle antigens, chiefly affecting the endomysium Dermatomyositis (DM): idiopathic or paraneoplastic antibody-mediated vasculopathy, associated with malignancies(non-Hodgkin lymphoma; lung, stomach, colorectal, or ovarian cancer ) Clinical features General features of both PM and DM Proximal muscle weakness affecting both sides of the body (progresses within weeks to months)The pelvic and shoulder girdle muscles are most commonly affected. Other muscles, e.g., the neck flexors, may also be affected. Leads to difficulties combing hair, standing up, and climbing stairsDysphagia is present in approx. 30% of patients because of esophageal muscle involvement. Muscle tenderness in approx. 33% of cases Cutaneous manifestations of DM Gottron papulesProminent erythematous papules, symmetrically distributed on the extensor surface of the handsMost often affects the MCP and interphalangeal joints Heliotrope rash: erythematous rash on the upper eyelids, sometimes accompanied by edema Midfacial erythema Photosensitive poikiloderma: Shawl sign: erythema of the upper back, posterior neck, and shouldersV sign: erythema of the upper chest and neckHolster sign: erythema of the lateral thighs Juvenile DM Subcutaneous calcification (dystrophic calcinosis)Abdominal pain, hematemesis, melena Lipodystrophy Inclusion body myositis (IBM) Progresses slowly over years Selective and asymmetric muscle involvement of both proximal and distal muscle groupsQuadriceps muscle weakness: knees lack support → frequent fallingFinger flexors: difficulties gripping, e.g., shopping bags or a briefcase Diagnostics Diagnostic criteria Diagnosis of PM and DM is based on clinical presentation, laboratory results, and pathology findings. PM is diagnosed if the following criteria are fulfilled: Proximal muscle involvementPositive laboratory findingsElectromyogram (EMG) suggestive of inflammatory myopathyTypical biopsy findings DM is diagnosed if additional cutaneous manifestations are present. If two or more of the criteria are fulfilled, PM or DM is considered a possible diagnosis. Laboratory tests ↑ Muscle enzymes↑ CK and ↑ aldolaseAdditional elevated enzymes: myoglobin, LDH, AST, ALT Inflammatory markers: ↑ ESR, ↑ CRP, leukocytosis, γ-globulin in protein electrophoresis AntibodiesAntinuclear antibody (ANA) Myositis-specific antibodies (MSAs) Anti-Jo-1 antibodies (∼ 5% DM, 30% PM): especially in patients with interstitial lung disease; responds poorly to treatmentAnti-Mi-2 antibodies (∼ 10% of cases): more favorable prognosisAnti-signal recognition particle antibodies (anti-SRP): associated with a severe treatment-resistant necrotizing myopathy; typically in patients with PM [12] Other procedures Electromyography: abnormal in 90% of cases Imaging: An MRI may be helpful in identifying inflammation and a potential biopsy site, although it is not always recommended. Muscle biopsyMuscle fiber necrosis, degeneration, and regenerationPM: Cell-mediated inflammatory infiltrates that predominantly involve cytotoxic CD8+ T cells in the intrafascicular (within muscle fascicles) and endomysial (within the endothelial cell wall of endomysial capillaries) regionImmunohistochemistry: Overexpression of MHC-I on the sarcolemmaDM: Antibody-mediated inflammatory infiltrates that predominantly involve CD4+ T cells, plasmacytoid dendritic cells, and B lymphocytes in the perifascicular and perimysial region that lead to perifascicular atrophy Skin biopsy (for suspected DM) All patients diagnosed with DM should be tested for possible malignancies! Inflammatory myopathiesDermatomyositisPeak incidence: 5-10 years and ∼ 50 years♀ > ♂Proximal and symmetrical muscle weakness (esp. pelvic and shoulder girdle)Weakness progresses within weeks to monthsSkin is involved (i.e., heliotrope rash, Gottron's papules)Associated with malignancies ESR CK ↑ ↑↑Autoantibody-mediatedPerimysial and perivascular inflammationMuscle atrophy PolymyositisPeak incidence: > 20 years♀ > ♂Proximal and symmetrical muscle weakness (esp. pelvic and shoulder girdle)Weakness progresses within weeks to monthsNo skin involvement ESR CK ↑ ↑↑Intrafascicular infiltration of CD8+ T cellsEndomysial inflammation No muscle atrophy Inclusion body myositis Peak incidence: > 50 years ♂ > ♀ Proximal and distal, asymmetrical muscle involvement Weakness progresses slowly over years No skin involvement ESR CK ↑ ↔︎ OR Slightly ↑ Endomysial inflammation Intramuscular vacuolesresembling inclusion bodiesof aggregated proteins Polymyalgia rheumaticaElderly women Fatigue and malaiseOften rapid-onset: symmetric pain on shoulder, pelvic girdle, and neck (proximal muscles) Morning stiffness (> 45 min)Associated with giant cell arteritis ESR↑↑ CK NormalNot helpful in establishing diagnosis FibromyalgiaPeak incidence: 20-50 yearsTender points over multiple areas of the body with no signs of inflammationChronic fatigue, sleep disturbancesMorning stiffnessNormalNormalNot helpful in establishing diagnosis Hypothyroid myopathyMuscle stiffnessProximal muscle weakness affecting both sides of the bodyExercise intoleranceFurther symptoms of hypothyroidism ESR Normal CK ↑ Not helpful in establishing diagnosis Corticosteroid-induced myopathyInsidious-onset proximal muscle weakness of upper and lower limbsHistory of glucocorticoid intakePossible other side effects of glucocorticoid therapy ESR Normal CK ↑ Not helpful in establishing diagnosis Statin-associated myopathyHistory of statin intakeFatigueMuscle pain and weakness ESR Normal CK ↑Not helpful in establishing diagnosis SLE: does not present with proximal muscle weakness Acute myopathy: results from a viral or bacterial infection (patients shows symptoms of infection) ALS: distal muscle weakness with asymmetric onset Myasthenia gravis: presents with normal muscle enzymes, anti-acetylcholine receptor antibodies, and facial paralysis Muscular dystrophy: inflammatory infiltrate limited to affected muscle Treatment Drug of choice: corticosteroids (e.g., prednisolone) Alternative treatment: indicated in patients who do not tolerate or do not respond to corticosteroidsImmunosuppressants: e.g., methotrexate and cyclosporin IV immunoglobulins Plasmapheresis Complications Respiratory failure Myocarditis Esophageal disease Dystrophic calcinosis (common in juvenile dermatomyositis): Calcium deposits may be subcutaneous, intracutaneous, or intramuscular.

Chloroquine and hydroxychloroquine Chloroquine and hydroxychloroquine are drugs derived from the quinoline molecule. Both are used as antimalarial blood schizonticides, and hydroxychloroquine is also frequently used as an antirheumatic. Their mechanism of action is not entirely understood. However, despite their varying therapeutic dosage and toxicity, both drugs have similar clinical indications and side effects. One of their most serious side effects is retinal toxicity, referred to as 4AQ retinopathy or chloroquine retinopathy, which must be screened for in all cases of long-term use.

Effects Widely-accepted mechanisms of action Anti-malarial action: the drugs accumulate in the parasite's food vacuole → inhibit polymerization of heme into hemozoin and form the heme-chloroquine complex, which is highly toxic to the schizont → lyse membranes and kill the parasiteAnti-rheumatoid action: these drugs interfere with "antigen processing" in macrophages and other antigen-presenting cells → decrease the formation of peptide-MHC protein complexes → down-regulate the immune response against autoantigenic peptides Side effects Visual disturbances: in cases of long-term use, regular ophthalmological exams are recommended Irreversible retinopathy: key fundoscopic feature is Bull's eye maculopathy Reversible corneal opacityBlurred visionPhotophobia Gastrointestinal: e.g., nausea with cramps (most common), anorexia, vomiting Neurologic: e.g., sensorineural deafness, tinnitus, cranial nerve palsies, and myasthenia-like muscle weakness Dermatologic: e.g., photosensitivity, pruritus, alopecia, bleaching of hair Indications Treatment and prophylaxis of malaria due to Plasmodium malariae, P. ovale, or susceptible strains of P. falciparum (not P. vivax) (see also antimalarial medication) Used in mild courses of the following rheumatic diseases: Rheumatoid arthritis (basic therapy)Systemic and discoid lupus erythematosus (without organ involvement) Porphyria cutanea tarda (in low doses)

Osteoarthritis Osteoarthritis (OA) is a disabling joint disease characterized by a noninflammatory degeneration of the joint complex (articular cartilage, subchondral bone, and synovium) that occurs with old age or from overuse. It mainly affects the weight-bearing and high-use joints, such as the hip, knee, hands, and vertebrae. Despite the widespread view that OA is a condition caused exclusively by degenerative "wear and tear" of the joints, newer research indicates a significant heterogeneity of causation, including pre-existing peculiarities of joint anatomy, genetics, local inflammation, mechanical forces, and biochemical processes that are affected by proinflammatory mediators and proteases. Major risk factors include advanced age, obesity, previous injuries, and asymmetrically stressed joints. In early-stage osteoarthritis, patients may complain of reduced range of motion, joint-stiffness, and pain that is aggravated with heavy use. As the disease advances, nagging pain may also occur during the night or at rest. Diagnosis is predominantly based on clinical and radiological findings. Classic radiographic features of OA do not necessarily correlate with clinical symptoms and appearance. If lifestyle changes (moderate exercise, weight loss) and physical therapy fail to improve symptoms, nonsteroidal anti-inflammatory drugs (NSAIDs) in particular, are used for the management of active osteoarthritis. If medical interventions fail to improve the patient's quality of life, surgical procedures such as joint replacement may become necessary.

Epidemiology Most common joint disorder in the USA, affecting more than 20 million adults Incidence: increases with age Sex: ♀ > ♂, especially in patients older than 50 years Incidence rates in specific joints: knee > hip > hand Modifiable risk factorsObesityExcessive joint loading or overuseNonmodifiable risk factorsAge (> 55 years)Familial historyHistory of joint injury or traumaAnatomic factors causing asymmetrical joint stress Hemophilic hemarthroses and deposition diseases that stiffen cartilage Gender (see "Epidemiology" above) Classification Idiopathic OANo identifiable, underlying causeGenetic factors of causation have been implicated, but not definitively proven. Secondary OA HemochromatosisWilson diseaseEhlers-Danlos syndromeDiabetesAvascular necrosisCongenital disorders of jointsAlkaptonuriaJoint trauma Pathophysiology Joint damage/stress → cartilage damage → decreased proteoglycans levels → cartilage becomes friable and inelastic and starts to degrade → loss of joint space and bony surface → subchondral bone becomes thickened and sclerotic. Clinical features Early clinical findingsPain on exertion, which is relieved with restPain in both complete flexion and extensionCrepitus on joint movementJoint stiffness and restricted range of motionRadiating or referred pain (e.g., coxarthrosis may lead to knee pain) Late clinical findingsConstant pain (including at night)Morning joint stiffness usually lasting < 30 minutesMore severely restricted range of motion Subtypes and variants Heberden's nodes: Pain and nodular thickening on the dorsal sides of the distal interphalangeal joints (DIP), ♀ > ♂ Bouchard's nodes: Pain and nodular thickening on the dorsal sides of the proximal interphalangeal joints (PIP), ♀ > ♂. Hallux rigidus: Arthrosis of the first metatarsophalangeal joint (between the first metatarsal and the first proximalphalanx), characterized by hypertrophy of the sesamoid bones. Osteoarthritis of the hip and knee In contrast to osteoarthritis, rheumatoid arthritis does not affect the DIP joints. Diagnostics Osteoarthritis is usually diagnosed on the basis of clinical and radiographic evidence of joint degeneration. Radiological signs of osteoarthritis Irregular joint space narrowing Subchondral sclerosis Osteophytes (also: bone spurs) Subchondral cysts The patient's history and clinical diagnosis are essential for the assessment and treatment of osteoarthritis! Radiographic signs often do not correlate with the patient's perception and clinical findings! Treatment General Weight lossRegular exerciseShoe inserts (e.g., buffer insoles) in, e.g., valgus deformity of the kneeTargeted muscle growth, physiotherapy, and medical training therapyTopical and heat therapy PharmacotherapyPeripheral analgesicsAcetaminophenNSAIDs: e.g., ibuprofenIn combination with PPIs in patients with gastrointestinal risk (e.g., together with glucocorticoids)Opioid analgesics: e.g., tramadol Interventional therapyIn severe courses: intraarticular glucocorticoid injections (not a long-term treatment!) Surgical therapy: if conservative and interventional measures fail Endoprosthesis (joint replacement)In case of failure of endoprosthesis or in select OA subtypes (e.g., Heberden's OA): arthrodesis (operative ankylosis) Pharmacotherapy should be used as acute and symptomatic therapy only; long-term NSAID therapy should be avoided due to its many side effects!

Juvenile idiopathic arthritis Juvenile idiopathic arthritis (JIA, formerly called juvenile rheumatoid arthritis) is a broad term for childhood rheumatic diseases that begin before the age of 16 and involve joint inflammation lasting more than six weeks. It is classified into various types based on the pattern of joint involvement, the presence of extra-articular manifestations (e.g., uveitis, rashes, nail changes, lymphadenopathy, hepatosplenomegaly), laboratory findings, and disease prognosis. Oligoarticular JIA, which is the most common type, presents with asymmetric involvement of up to four joints (with the knee joint most often affected). Nearly half of all cases of oligoarthritic JIA are associated with anterior uveitis, which may be diagnosed by slit-lamp examination. Laboratory tests such as ESR, rheumatoid factor (RF), antinuclear antibodies (ANA), and the HLA-B27 antigen test are used to classify and determine the prognosis of JIA. Treatment of JIA is similar to that of adult rheumatoid arthritis and involves the use of NSAIDs, intra-articular steroid injections, and disease-modifyingantirheumatic drugs (DMARDs) such as methotrexate. Systemic glucocorticoid therapy should be avoided because of the risk of growth impairment.

Epidemiology Prevalence: 1/1000 children Sex: ♀ > ♂ Age of onset: < 16 years Etiology Idiopathic Immunological predisposition (different HLA association) Possibly triggered by a viral or bacterial infection Exposure to antibiotics during childhood may increase the risk of JIA. Pathophysiology Autoimmune and/or autoinflammatory disease → chronic synovial inflammation with infiltration of plasma cells, B lymphocytes, and T lymphocytes → joint capsule hyperplasia → growth of fibrovascular connective tissue (pannus) → invasion of the articular surface → loss of joint function Clinical features Arthritic symptoms: red, swollen joints, early morning stiffness, limited or painful joint movement Synovial thickening Fever and other extra-articular manifestations (e.g., uveitis, rashes, nail changes, lymphadenopathy, hepatosplenomegaly) may be present depending on the type of JIA (see "Subtypes and variants" below). Certain children may present with nonspecific features such as excessive crying, lethargy, decreased scholastic performance, and/or growing pains. Oligoarticular JIA Most common form (accounts for 50% of all JIA cases) 2-4 years♀ > ♂ (3:1)Arthritis involving ≤ 4 joints within 6 months of disease onsetAsymmetrical patternLarge, weight-bearingjoints (knee and ankle) are usually affected. Chronic anterior uveitis* Oligoarticular JIA has the highest risk of developing (up to 25%)Bilateral is common↑ ESRRF negativeANA positive (∼ 70% of cases)NSAIDsPossibly intra-articularsteroidinjectionsPossibly methotrexateMostly good Seronegative polyarticular JIA30% of cases1-4 years and 6-12 years(bimodal incidence) ♀ > ♂Arthritis involving more than ≥ 5 joints within 6 months of disease onsetSymmetrical or asymmetrical Chronic anterior uveitis* ↑ ESRRF negativeANA positive (∼ 40% of cases)Standard therapy with methotrexateand NSAIDsVariable clinical course and a high risk of functional limitationSeropositive polyarticular JIA< 10% of cases9-12 years♀ > ♂ (10:1)Symmetrical Cervical spine and temporomandibular joint are also affected.Rheumatoid noduleson the extensor surface of elbowsand the Achilles tendon (∼ 30% of cases).↑ ESRRF positive Persistent disease with periodic exacerbation and a high risk of progressive jointdestruction Systemic JIA(Still's disease)< 10% of cases2-4 years♀ = ♂Arthritis involving ≥ 1 joint ANDintermittent feverthat lasts for at least two weeks with fever spikes occuring on at least 3 consecutive days AND≥ 1 extra-articularmanifestationPolyarthritis Transient, migratory, salmon-pink rash Generalized lymphadenopathySplenomegalyand/or hepatomegalySerositis (peritonitis, pleuritis, and/or pericarditis)↑ ESR↑ Acute phase reactants(e.g., CRP, ferritin)Anemia, leukocytosis, and thrombocytosisRF negative The affected joints are often stiff in the mornings or after longer periods of inactivity (e.g., sitting). Mobility improves with movement and is less impaired later in the day! Diagnostics A prerequisite for the diagnosis of all forms of JIA is that arthritic symptoms begin before the age of 16 and last ≥ 6 weeks! Blood tests are used to classify JIA, to assess the prognosis, and to rule out other similar conditions (see "Subtypes and variants" above). Rheumatoid factor (RF) is absent in most cases of JIA except seropositive polyarticular JIA.↑ ESR is usually seen with all forms of JIA.↑ Acute phase reactants (e.g., CRP, ferritin) and leukocytosis are usually associated with systemic JIA.↑ ANA (antinuclear antigen) levels may be seen with oligoarticular, polyarticular, and psoriatic JIA.Anti-CCP antibodies indicate a poor prognosis. CBC: Anemia, thrombocytosis, and/or leukocytosis are seen in the case of systemic JIA. Imaging (e.g., X-ray, ultrasound) of the affected joint Regular ophthalmological screening using slit lamp examination for anterior uveitis Anterior uveitis that occurs with JIA may be asymptomatic (especially in the case of chronic anterior uveitis). However, untreated anterior uveitis is associated with a high risk of developing glaucoma, cataracts, and optic nerve damage. Therefore, early detection via slit lamp examination and swift initiation of treatment are of paramount importance! Differential diagnoses The differential diagnosis of JIA includes other causes of nonsuppurative arthritis in children: Acute lymphocytic leukemia Reactive arthritis Acute rheumatic fever Treatment Most drugs that are used to treat adult rheumatoid arthritis may be used to treat JIA as well (see "Therapy" in rheumatoid arthritis). However, certain forms of therapy (e.g., systemic glucocorticoid therapy) should, as a rule, be avoided in children. Definitive therapyFirst-lineNSAIDs Local intra-articular steroids (e.g., triamcinolone) are indicated in the case of active arthritis.Second-lineDisease-modifying antirheumatic drugs (DMARDs) Therapy with DMARDs should be started as early as possible in the case of high disease activity. The DMARD of choice is determined on an individual basis with methotrexate being used in most cases. Biologic agents (e.g., etanercept, adalimumab, anakinra, tocilizumab) are indicated if the response to DMARDsis poor. Systemic glucocorticoid therapy (oral, IV) Rarely used in children because of the risk of catabolic side effects (osteoporosis, growth impairment) A short course of systemic glucocorticoid therapy may be prescribed in the following situations: Severe systemic involvement (e.g., severe serositis; see Still's disease)As bridge therapy to control severe arthritic symptoms while DMARDs are being initiated if adequate symptomatic relief is not obtained with NSAIDs.Acute anterior uveitisMacrophage activation syndrome Supportive therapyPhysiotherapy: to prevent joint deformitiesSurgery, splints, and/or orthotics: to correct limb length discrepancy and/or joint deformities Complications Joint destruction → joint subluxation, joint deformities (e.g., swan-neck, boutonniere deformities) Limb length discrepancy Growth retardation Chronic anterior uveitis → blindness Pericarditis, pleuritis Prognosis The clinical course and prognosis are highly variable (see "Subtypes and variants" above) . However, most cases (∼ 95%) resolve by puberty. Factors associated with a poor prognosisEarly onsetProlonged active systemic diseaseHip and/or wrist involvementPolyarthritisSymmetrical diseasePresence of RFPresence of anti-CCP antibodies Early disease onset is associated with a greater degree of growth impairment and deformity!

Fibromyalgia Fibromyalgia (FM) is a neurosensory disorder characterized by chronic musculocutaneous pain. The etiology and pathogenesis of this condition are not fully understood, but, notably, there is no identifiable inflammation that causes the musculocutaneous symptoms. Patients typically present with functional symptoms (e.g., fatigue, unrefreshing sleep, morning stiffness) and often have a history of psychiatric disorders (e.g., depression, generalized anxiety disorder). Physical examination reveals characteristic tender points over multiple areas of the body with no signs of inflammation(i.e., no notable swelling, deformity, or erythema). Findings from laboratory tests are normal. Although this disorder is benign, it causes patients significant psychological strain and discomfort. Treatment focuses on lifestyle changes and multidisciplinary pain management.

Epidemiology Prevalence: 2-3% [1] Sex: ♀ > ♂ (2:1) [2] Peak incidence: 20-50 years (risk of occurrence increases with age) Etiology The pathophysiology of FM is not fully understood, but its etiology is likely multifactorial. The interaction of the following factors may play a role: Genetic predisposition Environmental triggers (e.g., physical or psychosocial stress) Dysregulation of the neuroendocrine and autonomic nervous systems Clinical features Common symptoms Chronic, widespread pain, primarily at points where muscles and tendons attach to bone (tender points) Headache Fatigue Morning stiffness Unrefreshing sleep Cognitive dysfunction (known as fibro fog) Paresthesias Further symptoms of autonomic dysfunction: digestive problems, weight fluctuation, palpitations, sexual dysfunction, night sweats Common associations The following disorders can manifest with symptoms that sometimes resemble those seen in FM, and these conditions may occur alongside FM. Functional somatic syndromes (e.g., chronic fatigue syndrome , irritable bowel syndrome, tension or migraine headaches, chronic pelvic and bladder syndromes) Psychiatric disorders (depression, generalized anxiety disorder) Sleep disorders (e.g., sleep movement disorders such as restless leg syndrome) Inflammatory rheumatic diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis) Diagnostics FM is a clinical diagnosis. The 2010 American College of Rheumatology (ACR) criteria take into account: Symptom duration of at least 3 monthsPatient self-reporting using the fibromyalgia score : Widespread pain or tenderness in up to 19 different regions of the body (widespread pain index; WPI)Presence and severity of symptoms such as fatigue, sleep disturbance, depression, headache, and cognitive impairment (symptom severity scale)Traditionally, a tender-point examination was performed based on the 1990 ACR diagnostic criteria : Symptom duration of at least 3 monthsTender points: ≥ 11 of 18 FM-associated localized areas of painPain-affected areas: all four quadrants of the body Laboratory values and imaging findings are normal (helpful for excluding other causes or comorbidities). A combined assessment of the number, duration, and severity of cognitive and somatic symptoms provides the most accurate diagnosis. Differential diagnoses Myofascial pain syndrome: a chronic pain syndrome caused by muscle tension, injury, or repetitive motion and characterized by the presence of trigger points in muscles and/or fascia (small tender knots) [14]Clinical features Pain is mostly confined to one anatomical region: fewer tender points compared to FM (≤ 11 of 18) Leads to weakness and limited range of motionJump sign (myofascial pain syndrome): A physical examination finding characterized by an involuntary, sudden jerk or wince in response to stimulation of a tender area or trigger point (not seen in FM).Fatigue, headache, and sleep disturbances are less frequent compared to FMTreatment: physical therapy, massage, stretching, ice packs, NSAIDs Other differentials Polymyalgia rheumaticaHypothyroid myopathyComplex regional pain syndromeSleep apneaRheumatoid arthritisSystemic lupus erythematosusMalignancy See also differential diagnoses of myopathies. Treatment Initial approach Patient education: Explain that the condition, though painful, is benign, and recommend coping strategies such as relaxation exercises. Lifestyle changes: dietary recommendations, sleep hygiene, regular physical activity MedicationInitially monotherapy: low-dose tricyclic antidepressants (TCA, e.g., amitriptyline), selective serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine), or anticonvulsants (e.g., pregabalin, gabapentin)Avoid narcotic medications (e.g., opioids) Consider comorbidities (e.g., sleep disorders) in treatment planning Nonresponders Multidisciplinary management (e.g., with rheumatology, psychiatry) and adequate pain managementPsychological interventions (e.g., cognitive-behavioral therapy)Physiotherapy (e.g., stretching, hydrotherapy, and heat application) Combination therapy with the drugs mentioned above

Rheumatoid arthritis Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder characterized by joint pain, swelling, and synovial destruction. RA predominantly affects middle-aged women. The condition can also cause various extra-articularmanifestations such as rheumatoid nodules and pulmonary fibrosis. Diagnosis is mainly based on clinical features (e.g., morning stiffness, symmetrical joint swelling) and laboratory tests (e.g., anti-CCP). X-ray findings (e.g., soft tissue swelling or joint space narrowing) occur late in the disease and are therefore not typically used for diagnosis. Early intervention with disease-modifying antirheumatic drugs (DMARDs) plays a decisive role in successful treatment. RA is not curable, but early effective treatment may help offset severe complications (e.g., permanent damage to the affected joints).

Epidemiology Prevalence: ∼ 1% of the population Sex: ♀ > ♂ (3:1) Peak incidence: 50-75 years Etiology Chronic inflammatory autoimmune disorder of unknown etiology Hypotheses suggest the etiology is multifactorial, with the following factors playing a role: Genetic disposition: RA appears to be associated with specific HLA types (HLA-DR4, HLA-DR1). [3]. Environmental triggers (e.g., infection, tobacco)Hormonal factors Pathophysiology 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 hyperplasiaPannus formation along the synovial tissue → produce proteinases → destroy cartilage extracellular matrix Patients with positive rheumatoid factor (RF) are more likely to develop extra-articular manifestations of rheumatoid arthritis. [6] Clinical features Articular manifestations PolyarthralgiaSymmetrical pain and swelling of affected joints (also at rest). Frequently affected joints [9]Metacarpophalangeal joints (MCPJs)Proximal interphalangeal joints (PIPJs)Wrist jointsKnee jointsJoints of the axial skeleton are usually spared except for the cervical spine (see RA of the cervical spine) Morning stiffness > 30 min; often improves with activity Joint deformities"Rheumatoid hand" is characteristic, and can include the following deformities: Deepening of the interosseous spaces of the dorsum of hand Swan neck deformity: PIP hyperextension and DIP flexion Boutonniere deformity: PIP flexion and DIP hyperextension.Hitchhiker thumb deformity (Z deformity of the thumb): hyperextension of the interphalangeal joint with fixed flexion of the MCP jointUlnar deviation of the fingersHammer toeAtlanto-axial subluxation DIP joints are not typically affected in RA! Extra-articular manifestations Constitutional symptoms: low-grade fever, myalgia, malaise, night sweats Skin: rheumatoid nodules (common); non-tender, firm, subcutaneous swellings (2 mm-5 cm) Lungs: fibrosis, nodules, pleuritis, and pleural effusions Eye: keratoconjunctivitis sicca, scleritis, and episcleritis Endocrine and exocrine glands: secondary Sjögren syndrome Hematological: anemia of chronic disease Other musculoskeletalTenosynovitis and bursitisCarpal tunnel syndrome (entrapment neuropathy) Typical nocturnal paresthesia of volar hand and fingers I-IIIAtrophy of thenar muscles → difficulty making a fist; inability to oppose the thumbTarsal tunnel syndrome Heart: pericarditis and myocarditis; higher risk of myocardial infarction, stroke, and CHF Vascular: peripheral vasculitis manifesting as livedo reticularis, Raynaud phenomenon, purpura, necrosing fingertips or peripheral neuropathy Subtypes and variants RA of the cervical spine [9] RA normally spares the thoracic and lumbar spine. In some cases, it initially affects the cervical spine, causing early-morning neck pain at rest. Complication: atlanto-axial subluxation Life-threatening complication!SymptomsPain and stiffness of the neckNeurological deficits, e.g., cervical radiculopathy with peripheral paresthesiasDeformity, e.g., stiffness and scoliosisIn some cases, symptoms of high spinal cord compression (see also spinal cord injury) Slowly progressive spastic quadriparesisHyperreflexia or positive Babinski reflexRespiratory insufficiencyDiagnosisExtension and flexion x-rays of the cervical spineMRITreatment: surgery if instability or myelopathy are present Felty syndrome [9] Definition: Felty syndrome is a severe subtype of seropositive RA . Clinical featuresClinical triad consisting of arthritis, splenomegaly, and neutropenia (leads to ↑ risk of recurrent bacterial infections)Other symptoms: skin ulcers of the lower limbs (indicating vasculitis), hepatomegaly, fever, and chest pain(indicating pleuritis or pericarditis)Associated with increased risk of developing non-Hodgkin lymphoma DiagnosisLeukopenia with selective neutropenia↑↑ RF↑↑ ACPA TreatmentDMARD: methotrexateAlternative: cyclophosphamidePrompt and aggressive antibiotic treatment for suspected infections Consider splenectomy to treat leukopenia and improve the disease course. If a patient has arthritis, splenomegaly, and neutropenia, consider Felty syndrome. Other subtypes Juvenile idiopathic arthritis Caplan syndrome-Pneumoconiosis with intrapulmonary nodules in combination with rheumatoid arthritis. Diagnostics The diagnosis of RA is based on diagnostic criteria that include laboratory testing. Imaging may support the diagnosis, but radiological joint findings are no longer included in the criteria, as they often become evident only in late stages of disease. ACR criteria for RA (ACR/EULAR classification criteria (2010) [21] Rheumatoid arthritis = score of ≥ 6 points + confirmed presence of synovitis in at least one typical joint without an alternative, more probable diagnosis (e.g., trauma or degenerative joint conditions)For every column, the highest score is taken into account. PointsJoint involvement (pain/swelling)SerologyAcute phase reactantsDuration of symptoms*0≤ 1 large joints**Negative RF and ACPANormal CRP and ESR< 6 weeks12-10 large joints↑ CRP or ESR≥ 6 weeks21-3 small jointsLow positive RF or ACPA34-10 small jointsHigh positive RF or ACPA (> three times higher than normal)5> 10 joints (at least one small joint) *In the most chronically affected joint **Large joints = shoulders, elbows, hips, knees, and anklesSmall joints = metacarpophalangeal joints (MCP) and proximal interphalangeal joints (PIP) I-V; metatarsophalangeal joints (MTP) II-V, thumb interphalangeal joints, and wrists. The carpometacarpal joints (1st CMC), metatarsophalangeal joints (1st MTP), and distal interphalangeal joints (DIP) of hand and feet are not included here. Laboratory tests Non‑specific parameters↑ Inflammatory markers: CRP, ESR correlate with inflammatory activity. ↑ Ferritin as an acute phase proteinPossibly leukocytosis, thrombocytosisAnemia of chronic disease Serology (specific parameters)ACPA (e.g., anti-CCP ) Specificity > 90% Rheumatoid factor (RF)IgM autoantibodies against the Fc region of IgGLow specificity Antinuclear antibodies (ANA): elevated in 30% of cases Synovial fluid analysisSynovial fluid is collected by joint aspiration.Findings Cloudy yellow appearanceSterile specimen with leukocytosis (WBC: 5,000-50,000/μL)↑ Neutrophils, granulocytes, and ragocytes ↑ Proteins, ↓ viscosityPossibly rheumatoid factor Imaging Conventional x-ray Dorso-palmar x-ray of both handsRadiological findingsEarly: soft tissue swelling, demineralization (juxta‑articular)Late: joint space narrowing, erosions of cartilage and bone, demineralization (generalized) Even if radiographic findings are normal, RA is still possible! MRI: (with or without contrast), especially if cervical spine involvement is suspected or in early stages Ultrasound: joint effusion, formation of pannus Further diagnostic measures: contrast-enhanced ultrasound, scintigraphy Before undergoing general anesthesia, airway and neck assessment is crucial in patients with rheumatoid arthritis. Atlanto-axial subluxation may be present, which increases the risk for spinal cord injury. Preoperative flexion-extension radiographs can help to evaluate the position of the cervical vertebra atlas (C1) with regard to the axis (C2). Pathology Synovial pannus formation and bone invasion: proliferative granulation tissue with mononuclear inflammatory cells Angiogenesis Synovial lining hyperplasia with mononuclear cell infiltrate Perivascular inflammatory infiltrates Fibrin deposition on synovial surfaces Characteristic histology of rheumatoid nodules: central fibrinoid necrosis with histiocytes and surrounding epithelioid cells Other differential diagnoses: Osteoarthritis(most common) Psoriatic arthritis Gout Pseudogout Autoimmune-related arthritis (e.g., sarcoidosis, SLE, rheumatic fever, mixed connective tissue disease, polymyalgia rheumatica) Arthritis associated with Inflammatory bowel disease Vasculitides Hemochromatosis Viral arthritis (e.g., parvovirus B19, hepatitis viruses) Lyme arthritis Reactive arthritis (post-urethritis, post-enteritis) Fibromyalgia

Psoriasis Psoriasis is a common chronic inflammatory skin disorder affecting individuals with an underlying genetic predisposition. The disease manifests following exposure to various triggers (e.g., infection, medication). The typical lesions are sharply demarcated, erythematous, scaly, pruritic plaques, which occur most often on the extensor surfaces of the knees and elbows, but may also affect the scalp and back. Other common clinical findings include involvement of the nails (e.g., pitting or discoloration) or joints, which generally manifests with arthritis of the fingers and lower spine. As psoriasis presents with several subtypes, the size, location, and severity of the lesions vary. The diagnosis is based primarily on clinical findings, but may also be confirmed with tests (e.g., Auspitz sign) or biopsy. Mild psoriasis is treated with topical agents such as steroids, whereas moderate to severe disease requires systemic therapy (e.g., PUVA, biologics).

Epidemiology Prevalence: ∼ 2% of the white population Age of onset: 20-40 years Etiology Genetic predisposition: most likely determined via polygenic inheritance Trigger factors InfectiousInfections of the upper respiratory tract caused by β-hemolytic streptococci Staphylococcal infectionsHIVMechanical irritationDrugs (e.g., beta-blockers, chloroquine, lithium, interferon) Pathophysiology Increased proliferation of keratinocytes Acanthosis: thickening of the epidermisParakeratosis: retention of nucleated keratinocytes in the stratum corneum T cells secrete cytokines, which mediate an inflammatory response. Clinical features Course: relapsing, with symptom-free intervals Well-demarcated, erythematous lesions, and silvery-white scaling plaquesInitially, a few single lesions typically appear, which then often become confluent.Mainly on scalp, back, elbows, and knees (extensor surfaces), but any other site may be involvedPruritus in ∼ 80% of cases (typically mild, but may also be severe) Involvement of nails (in ∼ 50% of cases)Nail pitting: small, round depressions in the nailOil drop sign (or salmon spot): well-circumscribed, yellow-reddish discoloration of the nailBrittle nails: nail dystrophy with crumbling of the nailOnycholysis: partial and mostly distal separation of the nail plate Subtypes and variants Psoriatic arthritis Definition: inflammation of joints (primarily on hands, feet, spine) that may occur with psoriasis Epidemiology: 5-30% of psoriasis patients affected Clinical featuresPsoriasis and psoriatic arthritis may occur independently or together There are several types of psoriatic arthritis: Oligoarthritis (most common, accounting for 70% of cases): typically with involvement of both the distal and proximal interphalangeal joints Spinal involvement (up to 40% of cases) Other rheumatological features EnthesitisTenosynovitisDactylitis: inflammation and swelling of fingers or toes ("sausage digit")Arthritis mutilans: destruction of the IP joints and resorption of the phalanges; causes the soft tissue of the fingers to collapse ("telescoping fingers" or "opera glass hand") DiagnosisThere is no specific test for diagnosing psoriatic arthritisThe ClASsification Criteria for Psoriatic ARthritis (CASPAR) is helpful for diagnosing psoriatic arthritis (≥ 3 out of the 5 following points required). Evidence of psoriasis Psoriatic nail dystrophyNegative rheumatoid factor (RF)DactylitisRadiologic signsImaging studies: joint destruction, ankylosisFingers: pencil-in-cup deformity Spine: syndesmophytes, and in particular asymmetric paravertebral ossification Treatment Mild disease: NSAIDsModerate to severe disease: disease-modifying antirheumatic drugs (DMARDs) Physical therapy If first-degree relatives of patients with psoriasis have joint problems, psoriatic arthritis should be considered! Cutaneous variants Plaque psoriasis: most common variant characterized by symmetrically distributed, thick, scaly, erythematous lesions Guttate psoriasis: lesions the size of drops of water; may develop into psoriasis; occurs mainly in children and adolescents after streptococcal infection Erythrodermic psoriasis: generalized erythematous lesion with diffuse scaling; may lead to severe illness with feverand dehydration Inverse psoriasis: mainly affects skin folds and flexural creases of large joints (flexural psoriasis) Diagnostics Koebner phenomenon: Physical stimuli or skin injury (e.g., trauma, scratching, irritating clothing) lead to skin lesions typical of the underlying condition appearing on previously healthy skin ("isomorphic response"). Auspitz sign: small pinpoint bleeding when scales are scraped off Skin biopsy: rarely needed, but may be performed to rule out other diseasesParakeratosis: retention of nuclei in the stratum corneum of the epidermisMunro microabscesses: accumulation of neutrophils in the stratum corneum surrounded by parakeratosisAcanthosis: epidermal hyperplasia of the stratum spinosumSpongiotic dermatitis: epidermal intracellular edema widening the intracellular space between keratinocytes. Epidermal infiltration by lymphocytes is common.Chronic fluid accumulation leads to the formation of intraepidermal vesicles. Laboratory testsIn case of psoriatic arthritis: ↑ ESR and CRPRheumatoid factor (RF) negativeAnti-CCP antibodies present in 10-15% of patients PsoriasisClearly demarcated, erythematous plaques with silvery scaling, pruritusScalpExtensor surfaces of joints (knees, elbows)BackAtopic dermatitisPoorly demarcated, eczema, white scales, severe xerosis and pruritusExtensor surfaces of extremities (e.g., shins)Flexural creases (antecubital, popliteal)Seborrheic dermatitisClearly demarcated, erythematous plaques, greasy-looking yellow scales"Cradle cap" in infantsFacial involvement (hairline, periocular, nasolabial folds)TrunkPityriasis rubra pilaris Disseminated, plaques with orange-pink scales, hyperkeratosis, erythrodermaTypically palms and soles Islands of unaffected skin (sparing)Follicular keratosis Erythroderma Erythema, scaling 2-6 days following onset, lesions of underlying disease, pruritusGeneralized erythemaScaling initially in flexural creases Mild to moderate psoriasisModerate to severe psoriasisSevere psoriasisFirst-line: moisturizers and topical medicationsSteroids (triamcinolone, fluocinonide, clobetasol)Vitamin D derivatives (calcipotriene)Tar preparations (anthralin) Retinoids/vitamin A derivativesTopical medication as combination therapyAdd systemic agents as needed (methotrexate, retinoid, cyclosporine)PhototherapyTopical + systemic treatmentPhototherapyBiologicals (etanercept, adalimumab, infliximab) Systemic treatment is always required for psoriatic arthritis (immunosuppressants and NSAIDs)! Phototherapy Ultraviolet light is effective in treating dermatological conditions, as it has antiproliferative effects (slowing keratinization) and anti-inflammatory effects (inducing apoptosis of pathogenic T cells) on the skin. UVB therapyIndications: psoriasis, vitiligo, chronic pruritus, and atopic dermatitisIrradiation with narrowband UVBAccelerates photodamage (e.g., sunburn) and increases cancer risk PUVA therapy (psoralen + UVA) Indications: psoriasis, lichen planus, scleroderma, vitiligo, mycosis fungoidesTopical (bath, lotions) or oral administration of psoralen → increases photosensitivity of skin → UVA radiationIncreases risk of squamous cell carcinoma Complications Increased risk of other comorbidities Metabolic syndromeCardiovascular diseases (hypertension, coronary heart disease, myocardial infarction, stroke) Chronic kidney disease Prognosis Lifelong disease, usually benign Patients may experience remissions of varying lengths; acute episodes of exacerbation possible. Psoriasis is associated with depression and a decreased quality of life. Prevention Avoidance of nicotine and alcohol Regular physical activit

Giant cell arteritis Giant cell arteritis (GCA) is a type of autoimmune vasculitis that causes chronic inflammation of large and medium-sizedarteries, in particular the carotid arteries, its major branches, and the aorta. It is most common in white women over the age of 50, and approximately 50% of patients also have polymyalgia rheumatica. Patients usually present with constitutional symptoms (e.g., fever, weight loss, night sweats, fatigue, and malaise), new-onset headache, a tender, hardened temporal artery, jaw claudication, or amaurosis fugax. Laboratory tests typically show signs of inflammation(e.g., elevated erythrocyte sedimentation rate and CRP), and temporal artery biopsy should be performed to confirm the diagnosis. The classic histopathological findings are mononuclear infiltration of the vessel wall and formation of giant cells. If GCA is suspected, prompt administration of glucocorticoids is essential to reduce the risk of permanent vision loss and cerebral ischemia.

Epidemiology Sex: ♀ > ♂ Peak incidence: 70-79 years; rarely seen in patients < 50 years Most common among individuals of northern European descent Women of advanced age are particularly prone to the disease! Etiology Unknown; possible contributing factors include: Genetic predisposition (e.g., human leukocyte antigen HLA-DR4)Viral infections (e.g., parvovirus B19) Association with polymyalgia rheumatica (PMR): 40-50% of patients with giant cell arteritis also have PMR. Pathophysiology Giant cell arteritis is thought to be due to a cell-mediated immune response to endothelial injury. However, the initiating factors are not fully understood. InflammationActivation of dendritic cells in the adventitia of blood vessel walls → Dendritic cells recruit Th1 cells, CD8+ T cells, and monocytes.Monocytes differentiate to macrophages and giant cells, which produce cytokines (e.g., IL-6, TNF-α) that augment the inflammatory response. Local vascular damage: macrophages produce metalloproteinases → destruction of vessel wall structures (e.g., internal elastic lamina) Concentric intimal hyperplasia: macrophages and giant cells produce PDGF and VEGF → stimulate intimalproliferation → reduced blood flow and ischemia Clinical features Constitutional symptomsFever, weight loss, night sweatsSymptoms of anemia: fatigue and malaise Symptoms of arterial inflammation: extracranial branches of the common carotid, internal carotid, and external carotid arteries (the temporal artery is the most commonly affected vessel) New-onset headache (can be pulse-synchronous, throbbing, dull); typically located over the templesHardened and tender temporal artery Jaw claudication: jaw pain when chewing Vision loss Scintillating scotomaAmaurosis fugax or permanent loss of vision Diplopia Symptoms of polymyalgia rheumatica (if both diseases are present) About 50% of patients with giant cell arteritis also have polymyalgia rheumatica! Diagnostics ACR criteria (3 of the 5 criteria are required)Age at disease onset ≥ 50 yearsHeadachesAbnormalities of the temporal arteryElevated ESR (≥ 50 mm/h; see "Laboratory tests" below)Histopathological abnormalities in the temporal artery (see "Temporal artery biopsy" below) Laboratory tests ↑↑ ESR, specifically > 50 mm/h (However, a normal ESR does not rule out giant cell arteritis!)→ can lead to Rouleaux formation of RBCs↑ CRPMild thrombocytosisNormochromic anemiaNo autoantibodies Temporal artery biopsy (gold standard): mandatory in all patients Pathology Panarteritis of the large and medium-sized arteries Proliferation of the intima (and subsequent stenosis of the artery) Fragmentation of the internal elastic lamina Predominantly mononuclear infiltration of the vessel wall with formation of giant cells Differential diagnoses Polymyalgia rheumaticaGiant cell arteritis and polymyalgia rheumatica (PR) often occur simultaneously and share common features (e.g., elevated ESR, constitutional symptoms). PR causes shoulder girdle and pelvic stiffness and pain rather than ocular or cerebral findings. Other vasculitidesTakayasu arteritisPolyarteritis nodosaGranulomatosis with polyangiitisSystemic lupus erythematosusRheumatoid arthritis Other causes of monocular vision loss, e.g.: Carotid artery diseaseThromboembolismRetinal vein occlusion Treatment Ischemic organ damage (e.g., impaired vision): high dose of IV glucocorticoids or oral glucocorticoids Uncomplicated disease: medium dose of oral glucocorticoids After symptoms have resolved (usually after 2-4 weeks), slowly taper glucocorticoids to the lowest dose that is needed to control symptoms (The mean duration of treatment is 1-2 years). Low-dose aspirin to prevent ischemic complications Tocilizumab (antagonizes IL-6 receptor) may be used to reduce the required dose of steroids. Immediate administration of high-dose glucocorticoids is crucial to prevent permanent vision loss in patients with giant cellarteritis! Complications Permanent vision loss: ∼ 20-30% if giant cell arteritis is left untreated Cerebral ischemia (e.g., transient ischemic attack and stroke): < 2% of cases Aortic aneurysm and/or dissection: ∼ 10-20% of patients

Polymyalgia rheumatica Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease that mainly affects patients above the age of 50 years and occurs twice as often in women than in men. Patients typically present with new-onset pain in their shoulders, hips or neck, morning stiffness, and systemic symptoms (e.g., fatigue, malaise, B symptoms, and depressed mood). In addition to clinical presentation, the diagnosis is made based on laboratory studies, which usually show a highly elevated erythrocyte sedimentation rate (ESR), while creatine kinase and autoantibodies are negative. Bursitis and serositis in the joints of the shoulder and pelvic girdle on ultrasound may also help to confirm the diagnosis. The most important step in the management of PMR is to administer a low dose of oral glucocorticoids and taper them slowly until full remission is achieved. Patients with polymyalgia rheumatica should be routinely monitored for symptoms of giant cell arteritis because this type of vasculitis commonly develops during the course of disease.

Epidemiology Sex: ♀ > ♂ (2-3:1) Peak incidence: 70-79 years; rarely seen in patients < 50 years More common among individuals of northern European decent Most common inflammatory rheumatic disease in the elderly (second most common overall) Women of advanced age are particularly prone to the disease! Etiology Unknown; possible contributing factors are: Genetic predisposition (e.g., human leukocyte antigen HLA-DR4)Association with giant cell arteritis: 10-20% of patients with polymyalgia rheumatica also have GCA Clinical features Systemic symptomsConstitutional symptoms: fever, weight loss, night sweatsFatigue and malaiseDepressed moodSymptoms of anemia Musculoskeletal symptoms: new onset, symmetric painShoulder and pelvic girdle, neckWorse at nightMorning stiffness (> 45 min)Subjective weakness ∼ 10-20% of patients with polymyalgia rheumatica also develop typical symptoms of giant cell arteritis Diagnostics ↑↑ ESR, specifically > 50 mm/h ↑ CRP Leukocytosis Normochromic anemia Normal creatine kinase, negative rheumatoid factors and no autoantibodies Bursitis on ultrasound of affected joints Differential diagnoses Giant cell arteritisBoth diseases often coexist and share common findings (e.g., elevated ESR, B symptoms)May develop during the course of PMR (patients should be routinely evaluated for symptoms of GCA) Rheumatoid arthritis: positive rheumatoid factor and/or anti-CCP antibodies Polymyositis and dermatomyositis: ↑↑ serum creatine kinase (normal in PMR) Fibromyalgia: normal laboratory values Treatment Low-dose of oral glucocorticoids (alternative: IM glucocorticoids) If symptoms improve (usually within 2-4 weeks): slowly taper and eventually stop glucocorticoids No improvement after 2 weeks or relapse: increase dose

Sjogren syndrome Sjogren syndrome is a chronic inflammatory autoimmune disease that occurs mainly in middle-aged women. The cause of primary Sjogren syndrome is unknown, whereas secondary Sjogren syndrome is associated with underlying autoimmune diseases (e.g., rheumatoid arthritis). As the immune system mainly attacks lacrimal and salivary glands, patients typically present with xerophthalmia (dry eyes) and xerostomia (dry mouth), the combination of which is also known as sicca syndrome. The disease may also involve the skin, joints, internal organs, and nervous system. It is diagnosed via the detection of autoantibodies (anti-SSA/Ro, ANA) and salivary gland biopsy. Management focuses on supportive measures and, in more severe cases, immunosuppressants.

Epidemiology Sex: ♀ > ♂ (∼ 9:1) Age of onset: typically 40-60 years Etiology Primary Sjogren syndrome: idiopathic (association with HLA-DR52 estimated in 87% of cases) Secondary Sjogren syndromeAutoimmune connective tissue diseases: rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositisPrimary biliary cirrhosis (PBC) Clinical features Glandular symptoms Inflammation of the salivary glands: decreased production of saliva → xerostomia (dry mouth)DysphagiaIncreased formation of dental caries and tendency to oral infections Parotitis Inflammation of the lacrimal glands (chronic dacryoadenitis): decreased secretion of tears → xerophthalmia (dry eyes)→ keratoconjunctivitis siccaRedness, itching, burning of eyesSensation of sand or foreign body in the eyesBlurred vision Sicca syndrome: combination of dry mouth and dry eyes Nasal dryness → chronic rhinitis, nosebleeds Pharyngeal, tracheal, and bronchial dryness → persistent, dry cough Vaginal dryness → dyspareunia (painful intercourse) and increased risk of infections Extraglandular symptoms General symptoms: fatigue and arthralgias (∼ 70% of cases) Skin manifestations: xerosis ; Raynaud's phenomenon (∼ 15-30% of cases) Vasculitis (∼ 10% of cases) Palpable purpura of the legsRecurrent urticaria, skin ulcerationsGlomerulonephritis Neurological and psychiatric manifestationsDepressionVariety of focal and/or diffuse findings (e.g., impaired gross motor control, paresis, seizures, peripheral neuropathy) Gastrointestinal manifestations: e.g., dyspepsia, reflux esophagitis The classical presentation is a middle-aged woman with dry eyes and a dry mouth, accompanied by rheumatoid arthritis or systemic lupus erythematosus! Diagnostics Sjogren syndrome is diagnosed based on the typical clinical features and is confirmed via detection of specific antibodiesand a pathologically low tear production. Biopsy of the salivary gland is the most accurate test, but is not needed to establish the diagnosis. Laboratory tests Blood testsNonspecific findings: ↑ ESR, normocytic anemia, leukopenia, eosinophilia, hypergammaglobulinemiaImmunological findings (also found in antibody diagnosis of autoimmune diseases) Anti-Ro/SSA antibody and anti-La/SSB antibody (∼ 70% of cases): target ribonucleoprotein antigens (Ro/La) of epithelial cells, especially of the salivary glandsAntinuclear antibodies (ANAs; positive in up to 97% of cases)Rheumatoid factor (RF) Urinalysis: possible signs of glomerulonephritis or interstitial nephritis (e.g., proteinuria, red cell casts) Eye examinations Schirmer's test: shows decreased tear production < 5 mm of moisture on the filter paper after 5 minutes are indicative of Sjogren syndrome Slit lamp examinationRose Bengal stain : shows damaged epithelium of the cornea and conjunctivaReduced tear break-up time Biopsy Taken from the salivary gland or the inner mucosa of the lip Shows destruction of minor salivary glands (fibrosis, parenchymal atrophy) Sialadenitis with dense lymphocytic infiltrations Treatment Treat the underlying disease in secondary Sjogren syndrome. For dry mouthRegular dental careAdequate hydration and foods that stimulate salivary flow (e.g., dried fruit slices)In moderate/severe disease: artificial saliva, muscarinic agonists, and immunosuppression (e.g., hydroxychloroquine) For dry eyesAvoid dry environments (e.g., shield eyes from wind, keep air humid)Artificial tearsIn moderate disease: topical immunosuppression (e.g., cyclosporine), lubricants Treatment of extraglandular disease depends on the specific manifestation: arthralgia may be managed with NSAIDsor hydroxychloroquine, whereas neurological manifestations, for instance, often require aggressive immunosuppression. Complications Risk of developing associated conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis) Corneal scarring, ulcer, rupture, and infection Pregnancy: fetal loss, infant with neonatal lupus syndrome and associated complete heart block Increased risk of lymphomas (B-cell lymphoma, MALT lymphoma)!

Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that predominantly affects women of childbearing age. The exact cause is still unknown, but hormonal and immunological influences as well as genetic predisposition are considered likely etiological factors. The presentation of the disease is variable and may range from mild localized symptoms to life-threatening systemic disease. Typical findings include fever and fatigue, a malar rash(facial butterfly rash), myalgia, and arthritis. SLE may affect any organ, but damage to the kidneys (lupus nephritis) or the nervous system is associated with an especially poor prognosis. The diagnosis of SLE is based on clinical findings and is further supported by antibody tests, particularly for ANA and anti-dsDNA. Management consists of supportive measures, such as avoiding sun exposure, and medication adapted to disease severity. Long-term pharmacotherapy typically involves hydroxychloroquine, which has been shown to reduce flares and decrease mortality. For acute flares, glucocorticoids are given as induction therapy, with dose and treatment duration being adapted to the severity of the flares. In severe cases, additional immunosuppressants (e.g., mycophenolate, azathioprine) may be given.

Epidemiology Sex: ♀ >> ♂ (10:1) Peak incidence: women aged 20-40 years; no particular age of manifestation in men US prevalence: highest in African-American, Hispanic, and Asian populations Etiology The exact etiology is unknown, but several predisposing factors have been identified: Genetic predisposition: HLA-DR2 and HLA-DR3 are commonly present in individuals with SLEGenetic deficiency of classical pathway complement proteins (C1q, C2, C4) in approx. 10% [2] Hormonal factors: studies suggest that hyperestrogenic states (e.g., due to oral contraceptive use, postmenopausalhormonal therapy, endometriosis) are associated with an increased risk of SLE. [3] Environmental factors: UV light, stimulation of immune cells through infection with bacteria and viruses (in particular EBV, which causes disease flares following infection), medications (e.g., procainamide, hydralazine) Pathophysiology Hormonal and environmental factors as well as genetic predisposition (see "Etiology" above) → loss of self-tolerance →production of antibodies against perceived nuclear and cellular antigens → damage to tissue via type III hypersensitivityreaction and, to a lesser extent, type II hypersensitivity reaction Possible mechanisms for the development of autoantibodies [5]Deficiency of classical complement proteins (C1q, C4, C2) → failure of macrophages to phagocytose immune complexes and apoptotic cell material (i.e., plasma and nuclear antigens) → dysregulated, intolerant lymphocytes begin targeting normally protected intracellular antigens → autoantibody production (e.g., ANA, anti-ds DNA) Mechanism of tissue damageType III hypersensitivity → antibody-antigen complex formation in microvasculature → complement activation and inflammation → damage to skin, kidneys, joints, small vesselsType II hypersensitivity → IgG and IgM antibodies directed against antigens on cells (e.g., red blood cells) → cytopenia Clinical features The severity of SLE varies. While some individuals only experience mild symptoms, others suffer from severe symptoms and rapid disease progression. SLE is typically characterized by phases of remission and relapse. It can affect any organ. Most common symptoms (see also ACR criteria for SLE diagnosis below) Skin (> 70% of cases) Malar rash (butterfly rash) with sparing of the nasolabial foldsPhotosensitivityDiscoid rash Oral ulcersAlopecia (nonscarring) Periungual telangiectasia JointsArthritis and arthralgia (> 90% of cases)Mostly nonerosive polyarthritis (normal x-ray) Fever (> 50% of cases), fatigue (> 80% of cases), weight loss Other signs and symptoms Musculoskeletal: myalgia and lymphadenopathy Serositis: pleuritis and pericarditis; effusions and chest pain may occur Kidneys: nephritis with proteinuria (see lupus nephritis) Heart: involvement of the myocardium, pericardium, valves, and coronary arteries; Libman-Sacks endocarditis (LSE) Lungs: pneumonitis, interstitial lung disease, pulmonary hypertension Gastrointestinal: esophagitis, hepatitis, pancreatitis Vascular: Raynaud phenomenon, vasculitis, thromboembolism (see antiphospholipid syndrome) Neurologic: e.g., seizures, psychosis, personality changes, aseptic meningitis, polyneuropathy, myasthenia gravis Hematologic: hemolytic anemia, thrombocytopenia, leukopenia; for other features, see "Diagnosis" below. Eyes: keratoconjunctivitis sicca [8] SLE can cause LSE (Libman-Sacks endocarditis). Damage to the kidneys or nervous system is associated with a poor prognosis! Subtypes and variants Cutaneous lupus erythematosus Discoid lupus erythematosus (DLE) Accounts for 50-85% of cases of cutaneous lupus erythematosus Clinical featuresTypically affects face, neck, and head (triggered by exposure to UV light)Begins as erythematous raised scaling plaques with active inflammationHeals and leaves scar tissue with central atrophy DiagnosisLupus band test (immunoglobulin deposits found only in macroscopically affected skin)Often ANA and anti-Ro negative Prognosis: Patients with DLE have a 10-15% risk of developing SLE. Subacute cutaneous lupus erythematosus (SCLE) Accounts for approx. 10% of cases of SLE Clinical features Usually affects the neck, shoulders, and forearms, but spares the faceSmall erythematous lesions that develop into either annular or psoriasiform lesions Drug-induced lupus erythematosus (DILE) Description: lupus-like symptoms triggered by medication that resolve within days to months after discontinuation of the drug Common triggersSulfa drugsCertain non-sulfa drugs: hydralazine, methyldopa, isoniazid, procainamide, phenytoin, TNF-α inhibitors (e.g., etanercept)Risk factor: decreased acetyltransferase activity causing slow acetylation of the above-mentioned drugsEpidemiology♂ = ♀More common in older individuals (50-70 years) Symptoms FeverPolyarthritisSerositis (especially pleuritis and pericarditis)MyalgiaRash DiagnosisAnti-histone antibodies: Anti-histone antibodies are characteristic for DILE and manifest in approx. 95% of cases. They may also be present in SLE but are significantly less common.Elevated ANANo anti-dsDNA antibodies Prognosis: remission after discontinuation of offending drugs Drug-induced lupus erythematosus may manifest with a variety of the features also seen in idiopathic SLE, e.g., fever, arthritis, malar rash, and serositis. However, unlike idiopathic SLE, DILE typically does not affect the oral mucosa, CNS, or kidneys! Diagnostics Approach [16] Suspect SLE in patients with symptoms in more than two of the organ systems listed in the ACR criteria for SLE. Screening test: ANA titer (SLE is unlikely if the test is negative) ↑ ANA titer → confirm diagnosis with tests that are highly specific for SLEAnti-dsDNA antibody testing: autoantibody against double-stranded DNA (dsDNA)Positive in 70% of patients and highly specificLevels correlate with disease activityAssociated with lupus nephritisAnti-Sm antibody testingAutoantibody against Smith antigens (nonhistone nuclear proteins)Positive in only ∼ 30% of patients, but highly specific for SLE Tests listed in "Other laboratory tests" below may support the diagnosis. Anti-nuclear antibody (ANA) testing has the highest sensitivity (95%) but low specificity for SLE. Anti-dsDNA antibody and anti-Smith antibody testing are the most specific for SLE. Diagnostic criteria (according to the American College of Rheumatology, ACR) [17][1] Requirements: at least 4 of the 11 criteria must be met (specificity: 95%, sensitivity: 85%) DermatologicalMalar rash (butterfly rash): flat or raised fixed erythema over both malar eminences; tends to spare nasolabial foldsDiscoid rash: erythematous raised patches with adherent keratotic scaling and follicular pluggingPhotosensitivity: individuals with SLE develop a rash due to an overly sensitive reaction to lightOral or nasopharyngeal ulcers: usually painlessInternal organsNonerosive arthritis: involves at least two peripheral joints with swelling, tenderness, or effusion; rarely deforming (normal x-ray) Serositis: evidence of pleuritis and/or pericarditisPleuritis: history of pleuritic chest pain, pleuritic rub during auscultation, or pleural effusion ORPericarditis: evidence on ECG (e.g., diffuse ST elevations), a pericardial rub during auscultation, and/or pericardial effusionRenal disorderPersistent proteinuria (> 0.5 g/day) ORCellular casts (red cells, hemoglobin, granular, tubular, or mixed)Neurologic disorder: Seizures OR psychosis; both in the absence of offending drugs or known metabolic derangementsLaboratory testsHematologic disordersAutoimmune hemolytic anemia with reticulocytes ORThrombocytopenia < 100,000/mm3 in the absence of offending drugs ORLeukopenia < 4,000/mm3 on ≥ 2 occasions ORLymphopenia < 1,500/mm3 on ≥ 2 occasionsImmunological findingsPositive findings of Anti-dsDNA antibodies ORAnti-Sm antibodies ORAntiphospholipid antibodies on an abnormal serum level of IgG/IgM anticardiolipin antibodiesAntinuclear antibodies (ANA): on immunofluorescence or an equivalent assay in the absence of medications associated with drug-inducedlupus "SOAP BRAIN MD" is the acronym for the ACR diagnostic criteria for SLE:S = Serositis O = Oral ulcers A = Arthritis P = PhotosensitivityB = Blood disordersR = Renal involvementA = Antinuclear antibodiesI = Immunologic phenomenaN = Neurologic disorderM = Malar rashD = Discoid rash Other laboratory tests Complete blood count and differential: autoimmune hemolytic anemia, thrombocytopenia, leukopenia, lymphopenia ESR is frequently elevated, while CRP is often normal. ↓ C3 and C4 complement levels Urinalysis and urine microscopy: proteinuria and/or casts Additional antibody testsAntiphospholipid antibodies may be elevated.Anti-histone antibodies are elevated in drug-induced lupus erythematosus.Anti-Ro antibodies are elevated in the majority of cases of neonatal lupus erythematosus.For a list of additional antibodies that may be elevated in SLE, see section on antinuclear antibodies in antibody diagnosis of autoimmune diseases. Further diagnostics Lupus band test (LBT): direct immunofluorescence staining of immunoglobulin and complement component deposits (IgG, IgM, IgA und C3); found along the dermoepidermal junction in affected as well as unaffected skin Kidney biopsy: if lupus nephritis is suspected(proteinuria, red blood cell casts, or acanthocytes in urinary sediment) Imaging studies: assessment of organ or joint involvement (e.g., x-ray for joint symptoms, ultrasound to evaluate renal complications) Treatment General management Avoid exposure to UV light (sunlight) Smoking cessation Immunize patients before initiating immunosuppressants UV phototherapy and UV photochemotherapy (PUVA) are contraindicated! Complications Lupus nephritis (LN) Description: Most crucial prognostic factor in SLECan be nephritic and/or nephrotic (see also overview of glomerular diseases) Epidemiology: common (∼ 50% of individuals with SLE) Pathophysiology: mesangial and/or subendothelial deposition of immune complexes (e.g., anti-dsDNA antibodies, anti-Sm antibodies) → expansion and thickening of mesangium, capillary walls and/or glomerular basement membrane[23] Classification: classified according to different grades of severity (WHO classes I-VI) DiagnosisUrine tests: proteinuria, hematuria, cellular casts (red cells, hemoglobin, granular or tubular)Kidney biopsy: determination of severity of diseaseClassically, immune complex-mediated glomerulonephritisDiffuse proliferative glomerulonephritis (DPGN): characterized by increased glomerular cellularity in more than 50% of the glomeruli.Electron microscopy typically shows subendothelial deposits leading to capillary ("wire loop") thickening.Most commonly seen in SLE and IgA nephropathy, but also other inflammatory, autoimmune, or infectious diseases Treatment: Depending on the severity of the disease, prednisone, cytostatic drugs (mycophenolate, cyclophosphamide), and general measures to protect the kidneys (e.g., blood pressure control) may be necessary. Comorbid conditions Accelerated atherosclerosis and cardiovascular complications (e.g., myocardial infarction) Pulmonary hypertension Pancytopenia Osteopenia/osteoporosis Antiphospholipid syndrome ↑ Risk of thrombosis (particularly in individuals with antiphospholipid syndrome) → avoid treatment with estrogens Prognosis Mortality 10-year survival rate > 90% Mortality is highest in individuals > 45 years of age (65% of deaths) Causes of deathIn early disease High disease activity with renal or neurological complicationsInfections due to immunosuppressive therapyIn late disease: cardiovascular complications, end-stage renal disease , adverse effects of long-term medication Cardiovascular disease is the most common cause of death in SLE. Special patient groups SLE and pregnancy CharacteristicsFertility is not affected.Pregnancy may cause flares in disease activity.↑ Risk of preterm birth, hypertensive complications (preeclampsia), intrauterine growth restriction, fetal AV block, and miscarriage Risk assessment [26]Cardiac, lung, and kidney screening Maternal antibodies: anti-Ro/SSA and anti-La/SSB Anticardiolipin antibodies and lupus anticoagulant (see antiphospholipid syndrome) ManagementPregnancy planning and counseling Prednisolone , azathioprine; cyclosporin, tacrolimus , and hydroxychloroquine are considered safer drug options during preconception, pregnancy, and breastfeeding.Some immunosuppressive medications used to treat SLE (e.g. mycophenolate and cyclophosphamide) have severe teratogenic and other adverse fetal effects.Low-dose aspirin is recommended in all pregnant women from 12 weeks gestation Neonatal lupus syndromeAssociated with the transfer of maternal antibodies (anti-Ro/SSA and anti-La/SSB)Symptoms:Periorbital or diffuse rash (often presents in the first weeks after birth)CytopeniaHepatitis, elevated liver enzymesFirst- to third-degree congenital AV block

Henoch-Schonlein purpura Henoch-Schonlein purpura (HSP) is an acute immune complex-mediated small vessel vasculitis that most commonly occurs in children. It is often preceded by an upper respiratory tract infection and typically presents with a tetrad of symptoms: palpable purpura, arthritis/arthralgia, abdominal pain, and renal disease. However, in any individual patient, only some of the classic tetrad of symptoms may be present. HSP is a clinical diagnosis, but in particularly unclear or atypical cases a biopsy may be used to confirm the diagnosis. Because the disease course is usually self-limiting, treatment is generally supportive. Severe cases may require glucocorticoids, antihypertensive drugs, and possibly dialysis. HSP has an excellent prognosis, usually resolving within one month when not complicated by significant renal disease.

Epidemiology Sex: ♂ > ♀ More common in children90% of cases < 10 years oldPeak incidence: 6 years Etiology The exact pathogenesis is unknown and assumed to be multifactorial. Factors that likely play a role include: Preceding infection> 75% of cases preceded by viral or bacterial infection 1-3 weeks priorMost commonly an upper respiratory tract infection caused by group A streptococcusGI infections also possible; many other organisms have also been associated with HSPGenetic predispositionDrugs (e.g., some antibiotics and antiarrhythmics) and vaccinations (e.g., yellow fever, cholera) Pathophysiology Hypothesized pathophysiological mechanism: exposure to allergen/antigen (e.g., infection, drugs) → stimulation of IgAproduction → deposition of IgA immune complexes in vascular walls (e.g., in the skin, GI tract, joints, kidneys) → activation of complement → vascular inflammation and damage Clinical features History Symptom onset often 1-3 weeks after an infection, typically affecting the upper respiratory tract Manifestations Skin (∼ 100% of cases)Symmetrically distributed, raised, erythematous macules or urticarial lesions that coalesce into palpable purpura(non-blanching skin lesions)Most common sites: the lower extremities, buttocks, and other areas of pressure or constraint (e.g., from socks or clothing) Joints (∼ 75% of cases): arthritis/arthralgia, most common in the ankles and knees Gastrointestinal tract (∼ 60% of cases)Colicky abdominal pain (may be severe enough to mimic an acute abdomen)Bloody stools or melenaNausea/vomiting Kidneys (∼ 50% of cases): HSP nephritis with signs and symptoms of nephritic syndrome Other organsScrotum (e.g., scrotal swelling, pain, and tenderness)Central and peripheral nervous system (e.g., headaches, seizures, focal neurologic deficits, ataxia, intracerebral hemorrhage, central and peripheral neuropathy)Respiratory tract (e.g., mild interstitial changes, pulmonary hemorrhage) HSP is characterized by a tetrad of clinical findings: palpable purpura, arthritis/arthralgia, GI symptoms, and renal diseaseHSP is one of the important differential diagnoses to consider in cases of pediatric limp! Diagnostics HSP is a clinical diagnosis, laboratory tests are not essential to HSP diagnosis. However, they may be useful for excluding differential diagnoses in patients exhibiting only one or two of the HSP tetrad of symptoms, as is often the case in the first few days. Laboratory tests are also useful for monitoring the extent of renal involvement, which helps determine the prognosis. Definitive diagnosis in uncertain cases is made via biopsy. Laboratory tests Indications: useful in patients with an incomplete or unusual presentation Complete blood cell count with differential: ↑ Platelet count Coagulation profile: usually normal Serum antibodies and complement: ↑ IgA in serum Serum chemistry: ↑ Creatinine and/or BUN Urinalysis to assess possible renal disease Hematuria, often with RBC castsPossibly proteinuria ↑ Inflammatory markers The platelet count in HSP is normal or elevated, as opposed to other causes of purpura! Imaging Indication: performed in patients with marked abdominal symptoms or suspected complications Abdominal ultrasound/CT Biopsy Indications: reserved for patients with unusual skin presentations or severe renal involvement (e.g., persistent nephrotic syndrome) Skin: Leukocytoclastic vasculitis with IgA and C3 immune complex deposition (hallmark) in small vessels of the superficial dermis KidneyRenal involvement characterized by mesangial IgA deposition; C3 and fibrin are also frequently present.Crescent formation in more severe cases Differential diagnoses HSP is a unique cause of purpura without thrombocytopenia! Purpura Hypersensitivity vasculitis: no IgA deposition on biopsy Small vessel vasculitides : no IgA deposition on biopsy, affects adults and is associated with specific antibodies Coagulopathies: abnormal coagulation studies Immune thrombocytopenia; hemolytic uremic syndrome: low platelet count, non-palpable purpura Meningococcal septicemia; acute leukemia: low platelet count, abnormal coagulation studies Arthritis/Arthralgia Autoimmune diseases : no IgA deposition on biopsy and associated with specific antibodies Septic arthritis: arthritis typically in a single joint Reactive arthritis: no rash, abdominal pain, or renal symptoms Renal disease IgA nephropathy (Berger's disease) : no rash, joint, or GI symptom and primarily affects (young) adults Treatment Most cases of HSP are self-limiting and only require supportive care (e.g., pain management) with regular outpatient follow-up. Severe HSP requires hospitalization and intensive medical therapy. Mild disease Outpatient treatment Usually no treatment necessary NSAIDs for pain management, rest, and adequate hydration Severe disease Inpatient treatment Systemic glucocorticoids for severe abdominal pain not relieved by NSAIDs IV fluids to maintain hydration In case of severe renal disease: IV methylprednisolone pulse therapy [6] Complications RenalIn some cases, HSP nephritis may progress to nephrotic syndrome. Serious complication: rapid-progressive glomerulonephritis (RPGN) with crescent formation GastrointestinalSmall bowel infarction or perforationIntussusception

Kawasaki disease Kawasaki disease is an acute, necrotizing vasculitis of unknown etiology. The condition primarily affects children under the age of five and is more common among those of Asian descent. The disease is characterized by a high fever, desquamative rash, conjunctivitis, mucositis (e.g., "strawberry tongue"), cervical lymphadenopathy, as well as erythemaand edema of the distal extremities. However, coronary artery aneurysms are the most concerning possible manifestation as they can lead to myocardial infarction or arrhythmias. Kawasaki disease is a clinical diagnosis, further supported by findings such as elevated ESR or evidence of cardiac involvement on echocardiography. Treatment with IV immunoglobulins and high-dose aspirin is essential and should be initiated immediately after diagnosis.

Epidemiology Sex: ♂ > ♀ (1.5:1) Age: primarily children < 5 years Peak incidence: occurs mostly in late winter and spring Prevalence: approx. 20 per 100,000 children; highest rate in children of Asian and Pacific-Islander descent Mortality: approx. 1% Etiology The exact cause of Kawasaki disease remains uncertain. However, it is associated with infectious and genetic factors: the prevalence is higher in patients of Asian descent and in siblings of affected children. Clinical features Clinical diagnosis requires fever for at least 5 days and: ≥ 4 other specific symptoms, or< 4 specific symptoms if the coronary arteries are involved Specific symptomsErythema and edema of hands and feet, including the palms and soles (the first week)Possible desquamation of fingertips and toes (after 2-3 weeks)Polymorphous rash, originating on the trunkPainless bilateral "injected" conjunctivitis without exudateOropharyngeal mucositisErythema and swelling of the tongue (strawberry tongue)Cracked and red lipsCervical lymphadenopathy (mostly unilateral) Nonspecific symptoms may precede the onset of Kawasaki disease (e.g., diarrhea, fatigue, abdominal pain) Always consider Kawasaki disease in small children with a rash and high fever unresponsive to antibiotics! Think of "CRASH and BURN" to remember the clinical features of Kawasaki disease: C = Conjunctivitis, R = Rash, A = Adenopathy, S = Strawberry tongue, H = Hands and feet, BURN = fever ≥ 5 days. Diagnostics Kawasaki disease is a clinical diagnosis (see "Clinical features" above) which is supported by the following diagnostic findings: Laboratory findings↑ ESR and CRPLeukocytosisThrombocytosis Echocardiography: for evaluating coronary artery aneurysmsMinimal evaluation: should be performed at diagnosis, at 2 weeks, and at 6-8 weeks after onset Treatment IV immunoglobulin (IVIG)high single-dose to reduce the risk of coronary artery aneurysmsmost effective if given within the first 10 days following disease onset High-dose oral aspirin IV glucocorticoids: may be considered in addition to standard treatment in high-risk patients, as they lower the risk of coronary involvement; also in cases of treatment-refractory disease To avoid the risk of Reye syndrome, children should not be treated with aspirin, especially if a viral infection is suspected. Kawasaki disease is an exception to this rule! Complications Coronary artery aneurysm: the risk of aneurysms is highest during the 2nd-3rd week after symptom onset Myocardial infarction Myocarditis Arrhythmias

Gout and hyperuricemia Gout is a common inflammatory arthropathy characterized by painful and swollen joints resulting from precipitating uric acid crystals. Decreased renal excretion and/or increased production of uric acid leads to hyperuricemia, which is commonly asymptomatic, but also predisposes to gout. Acute gout attacks typically manifest with a severely painful big toe (podagra) and occur most often in men following triggers such as alcohol consumption. Diagnosis is based on clinical presentation and synovial fluid analysis, which reveals negatively birefringent monosodium urate crystals. Acute attacks are treated with nonsteroidal anti-inflammatory drugs (e.g., naproxen or indomethacin), while management of chronic gout includes lifestyle modifications and possibly allopurinol to control hyperuricemia.

Epidemiology Sex: ♂ > ♀ (3:1) Age of onset: 30-60 years Prevalence: ∼ 8 million people in the US Higher incidence in African Americans Etiology Gout Deposition of urate crystals into joints Hyperuricemia predisposes to gout Associations: Diabetes mellitusHypertensionHypercholesterolemia, hypertriglyceridemiaAnemia Acute gouty arthritis is not always associated with elevated serum uric acid levels; it can also occur when serum uric acid is normal! Hyperuricemia Uric acid is an end-product of purine metabolism that is renally excreted. Insufficient excretion or increased production of purines leads to hyperuricemia, possibly triggering a gout attack. May be primary or secondary. Primary hyperuricemia Idiopathic extracellular supersaturation of uric acid No history of comorbidities or medications that affect uric acid formation or excretion Primary hyperuricemia is aggravated by poor dietary habits! Secondary hyperuricemia Decreased uric acid excretion (most common)Medications (e.g., pyrazinamide, aspirin, loop diuretics, thiazides, niacin)Chronic renal insufficiency; lead nephropathy Ketoacidosis (e.g., due to starvation, diabetes mellitus) and lactic acidosis Increased uric acid productionHigh cell turnover (e.g., tumor lysis syndrome, hemolytic anemia , psoriasis, myeloproliferative neoplasms, chemotherapy, or radiation)Enzyme defects (e.g., Lesch-Nyhan syndrome, phosphoribosyl pyrophosphate synthetase overactivity, von Gierke disease)High-protein diet Obesity Combined decreased excretion and overproduction: high alcohol consumption Pathophysiology Uric acid has poor water solubility, even under physiological conditions. Factors that trigger urate crystal deposition include: ↑ Uric acid levelsAcidosisLow temperature (e.g., cool peripheral joints) Crystalline arthritis: supersaturation of uric acid in extracellular fluid → intraarticular uric crystal precipitation (coated by IgGs) → phagocytized by polymorphonuclear cells → release of inflammatory mediators and enzymes → local jointinflammation Chronic effects: repeated attacks → aggregations of urate crystals and giant cells (tophi) → deformities and arthritis Clinical features Asymptomatic stage Hyperuricemia with no symptoms May last up to 20 years or even longer Acute gouty arthritis Triggers: anything that leads to hyperuricemia (see "Etiology" above) Arthritis: usually monoarticular during first attacksAcute severe pain with overlying erythema, decreased range of motion, swelling, and warmth; possible feverMore likely to occur at night, typically waking the patientSymptoms peak after 12-24 hours; regression may take days to weeks. The recovering joint may present with desquamation of the overlying skin. Locations: Peripheral small joints in the lower extremities are especially affected. Podagra: metatarsophalangeal joint (MTPJ) inflammation of the big toe is the most common site)Gonagra: inflammation of the kneeChiragra: inflammation of finger joints, esp. metacarpophalangeal joint of the thumb Others: ankle and tarsus, other toe joints, wrist, elbow Intercritical stage Asymptomatic May also last up to several years Chronic gouty arthritis No longer common Progressive joint destruction Tophi formation Multiple painless hard nodules with possible joint deformities Bone tophi: urate crystal deposition in bones (e.g., elbows, knees, extensor surfaces of forearms)Soft tissue tophi: urate crystal deposition in the pinna of the external ear, subcutis, tendon sheaths, or synovial bursas Renal manifestations with uric acid nephrolithiasis and uric acid nephropathy Diagnostics ArthrocentesisIndications New-onset acute gout attack If past suspected gout attacks were not confirmed via polarized light microscopy Polarized light microscopy findings: needle-shaped, negatively birefringent monosodium urate crystals Synovial fluid: WBC > 2000/μL with > 50% neutrophils Laboratory tests↑ Serum uric acid levels Typical in acute attacks: ↑ WBC and ↑ ESRTesting for ↑ renal uric acid may be indicated in some cases (see extra information for more details). Imaging Ultrasound"Double-contour" sign representing hyperechoic monosodium urate crystals covering hyperechoic bone contourTophus (a mixture of hyperechoic and hypoechoic structures) MRIExcellent measure to detect tophi formationMethod of choice to detect spinal involvementCT: can detect bone erosions as well as tophiX-rayAcute gout attack: not useful, as early changes cannot be detected Chronic gout: radiopaque soft tissue , punched-out lytic bone lesions with spiky periosteal appositions Differential diagnoses See differential diagnoses of inflammatory arthritis. Pseudogout (CPPD) Short description: paroxysmal joint inflammation due to calcium pyrophosphate crystal deposition (calcium pyrophosphate dihydrate) EpidemiologySex: ♂ = ♀Age of onset: adults > 50 years of age EtiologyMostly idiopathic (primary form)Secondary form: joint trauma, familial chondrocalcinosis, hyperparathyroidism, hemochromatosis, gout, hypophosphatemia Clinical presentationOften asymptomatic Acute (pseudogout attack): monoarthritis (rarely oligoarthritis), mostly affecting the knees and other large joints(e.g., hips, wrists, and ankles)May become chronic (can affect multiple joints) Osteoarthritis with CPPD (most common form of symptomatic CPPD): progressive joint degeneration with episodes of acute inflammatory arthritis typical of pseudogout attacks DiagnosisArthrocentesis should be performed, especially in acute cases. Polarized light microscopy: detection of rhomboid-shaped, positively birefringent CPPD crystalsSynovial fluid findings: 10,000-50,000 WBCs/μL with > 90% neutrophilsX-ray findings: cartilage calcification of the affected joint (chondrocalcinosis) Fibrocartilage (meniscus, annulus fibrosus of intervertebral disc) and hyaline cartilage (joint cartilage) may be affected.Test for hypercalcemia (esp. hyperparathyroidism).Serum uric acid levels are normal. TreatmentAsymptomatic cases do not require treatment unless there is an underlying condition (e.g., hyperparathyroidism). Symptomatic treatment (similar to gout) Best initial treatment: NSAIDsAlternatives: colchicine or intra-articular corticosteroidsArthroscopic lavage may also be consideredPossible joint replacement Treatment Acute gout attack NSAIDs (e.g., indomethacin, naproxen, ibuprofen)Indications: patients who cannot tolerate oral glucocorticoids or colchicineInitiate as soon as symptoms occur.Discontinue 2-3 days after symptoms resolve. The use of aspirin in acute gout attacks is contraindicated as it inhibits uric acid excretion, thereby delaying the cessation of symptoms. Colchicine: inhibition of microtubule polymerization → inhibits phagocytosis of urate crystals, leukocyte activation and migration, and cell chemotaxis. Indications: patients who cannot tolerate NSAIDs (e.g., patients with chronic kidney disease or gastrointestinal ulcers) or oral glucocorticoidsProphylaxis: prevents flares of acute or recurrent gouty attacks in patients beginning uricosuric agents (e.g., probenecid) or xanthine oxidase inhibitors (e.g., allopurinol) Side effects: diarrhea, nephrotoxicity, and myelosuppression Oral glucocorticoids (e.g., prednisolone)Indications: no response or contraindications to NSAIDs and colchicineDose should be tapered gradually (over the course of 2 weeks) Intra-articular corticosteroidsIndications: particularly with single-joint involvementFewer systemic side effects compared with oral corticosteroids Local ice therapy may help relieve pain. Rest the affected joint to avoid recurrence. Proton pump inhibitors should be given to patients being treated with both NSAIDs and glucocorticoids to avoid gastrointestinal ulcers. Chronic gout General measures Weight loss (if applicable) Purine-restricted diet (e.g., low-protein diet) Reduce alcohol consumption Sufficient/high fluid intake Close management of diabetes and blood pressure Consuming dairy products, vitamin C, and coffee can lower levels of uric acids and therefore prevent gout. Medical therapy Indications: Recurrent gout (e.g., more than 2 gout attacks per year)Uric acid nephropathyTophi developmentSerum uric acid > 9 mg/dL General approach: Delay initiation of urate-lowering medication until ∼ 2 weeks after an acute attack has resolvedDespite their therapeutic effect, urate-lowering medications may trigger or prolong an acute gout attack. Urate-lowering drugs should be combined with colchicine during the initiation of therapy for prevention of an acute exacerbation. First-line treatment: xanthine oxidaseinhibitors (allopurinol) Mechanism of actionReversible inhibitor of xanthine oxidase → Hypoxanthine and xanthine will not be degraded into uric acid. Allergic skin reaction Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome Standard medication for chronic goutand/or hyperuricemia (> 9 mg/dL) Hyperuricemia prophylaxis (e.g., tumor lysis syndrome) ContraindicationsAcute gout attack Previous hypersensitivity In kidney disease: dose adjustment (febuxostat is an alternative for patients with kidney disease) Interaction Increased bone marrow toxicity if given together with a purine analog (e.g., 6-mercaptopurine and azathioprine) Decreased action if given together with thiazides, probenecid, and benzbromarone Second-line treatment: uricosuric medications (benzbromarone, probenecid, lesinurad) Inhibition of uric acidreabsorption along renal tubules → increased renal elimination Urolithiasis (uric acid stones) Gastrointestinal symptoms Rash As an alternative to or in combination with allopurinol ContraindicationsAcute gout attack Kidney disease (e.g., nephrolithiasis, impaired renal function) Decreased action of allopurinol Third-line treatment: recombinant uricase(pegloticase) Catalyzes the breakdown of uric acid to allantoin Infusion reactions (multiple premedications are administered as a prophylactic measure, e.g., hydrocortisone and antihistamine) Patients who do not benefit from xanthine oxidase inhibitors or uricosuric medications Used if rapid relief is desired (e.g., to quickly reduce tophus or improve quality of life) ContraindicationsAcute gout attack G6PD deficiency No particular drug interactions The combination of allopurinol and azathioprine leads to increased bone marrow toxicity! During the first 2 weeks of an acute gout attack, treatment with urate-lowering drugs (e.g., allopurinol) should not be initiated or altered → can lead to urate crystal mobilization, which worsens the symptoms! Complications Nephrolithiasis: uric acid stones Uric acid nephropathyAcute uric acid nephropathy: possible in tumor lysis syndrome → tubular obstruction → acute renal failureChronic uric acid nephropathy: chronic tubulointerstitial nephropathy with monosodium urate crystal deposition in the stroma of the kidney → inflammatory process Clinical presentation HypertensionIn rare cases, progressive renal failure

Ankylosing spondylitis Ankylosing spondylitis (spondyloarthritis) is a chronic inflammatory disease of the axial skeleton that leads to partial or even complete fusion and rigidity of the spine. Males are disproportionately affected and upwards of 90% of patients are positive for the HLA-B27 genotype, which predisposes to the disease. The most characteristic early finding is pain and stiffness in the neck and lower back, caused by inflammation of the vertebral column and the sacroiliac joints. The paintypically improves with activity and is especially prominent at night. Other articular findings include tenderness to percussion and displacement of the sacroiliac joints (Mennell's sign), as well as limited spine mobility, which can progress to restrictive pulmonary disease. The most common extra-articular manifestation is acute, unilateral anterior uveitis. Diagnosis is primarily based on symptoms and x-ray of the sacroiliac joints, with HLA-B27 testing and MRI reserved for inconclusive cases. There is no curative treatment, but regular physiotherapy can slow progression of the disease. Additionally, NSAIDs and/or tumor necrosis factor-α inhibitors may improve symptoms. In severe cases, surgery may be considered to improve quality of life.

Epidemiology Sex: ♂ > ♀ (3:1) Age: 15-40 years Lifetime prevalence in the US: ∼0.5% Etiology Genetic predisposition: 90-95% of patients are HLA-B27 positive. Clinical features Articular symptoms Most common presenting symptoms: back and neck painGradual onset of dull pain that progresses slowlyMorning stiffness that improves with activityPain is independent of positioning, also appears at nightTenderness over the sacroiliac joints Limited mobility of the spine (especially reduced forward lumbar flexion) Inflammatory enthesitis (e.g., of the Achilles tendon, iliac crests, tibial tuberosities): painful on palpation Dactylitis Arthritis outside the spine: hip, shoulder, and knee joint Extra-articular manifestations Most common: acute, unilateral anterior uveitis (∼ 25% of cases) Gastrointestinal symptoms: associated with chronic inflammatory bowel disease (∼ 5-10% of cases, see also: colitis ulcerosa or Crohn's disease) Prostatitis Fatigue, weakness, fever, weight loss Restrictive pulmonary disease due to decreased mobility of the spine and thorax Rare Cardiac: aortic valve insufficiency, atrioventricular blocksKidney: IgA-nephropathy Diagnostics Diagnostic approach Physical examination, patient history, and pelvic x-ray: If results are conclusive, no additional testing is required! If inconclusive → HLA-B27 testing If still inconclusive → pelvic MRI Clinical tests Chest expansion measurement: in full expiration and inspiration Pathological difference: < 2 cmPhysiological difference: > 5 cm Spine mobility tests Examination of the hip[3]Mennell sign: tenderness to percussion and pain on displacement of the sacroiliac joints FABER test: FABER (Flexion, ABduction, and External Rotation) provokes pain in the ipsilateral hip Laboratory findings ↑ CRP and ESR Auto-antibodies (e.g., rheumatoid factor, antinuclear antibodies) are negative HLA-B27 positive in 90-95% of cases However, < 5% of HLA-B27 positive individuals have ankylosing spondylitis. Imaging X-ray Can help confirm a diagnosis or evaluate the severity of disease, but is not required for the diagnosis Changes are generally more evident in later disease Sacroiliac joints: signs of sacroiliitis, including ankylosis of sacroiliac joints SpineLoss of lordosis with increasing abnormal straightening of the spineSclerosis of the vertebral ligamentous apparatusSyndesmophytes resulting in a so-called 'bamboo spine' in anteroposterior radiograph in the later stages (see the table in "Differential diagnosis" below)Signs of spondyloarthritis, including ankylosis of intervertebral joints[4] Mild courses may only exhibit inflammatory changes in the sacroiliac joints on x-ray after a number of years. MRI More sensitive than CT scan for detecting sacroiliitis [5] Best method for early detection Differential diagnoses Disc prolapse Vertebral osteomyelitis Other spondyloarthritides (e.g., reactive arthritis, psoriasis arthritis, arthritis associated with inflammatory bowel disease) Diffuse idiopathic skeletal hyperostosis (DISH; also called Forestier's disease or hyperostotic spondylosis) Definition: degenerative disease of the vertebral column (especially the thoracic and lumbar spine), which is characterized by calcification and ossification of spinal ligaments and enthesesEpidemiologyNot related to HLA-B27[8]Mostly affects menCommon in patients with diabetesClinical presentationLimited mobilityMild or even no pain at allDiagnosis: X-ray of the spine Formation of osteophytes (see table below)No sacroiliitisTreatment: symptomatic Osteophytes of the spine Syndesmophytes OsteophytesDefinitionOssification or calcification of the annulus fibrosus or a spinal ligamentLipping of vertebral bodies Radiographic featuresSymmetrical, vertical growth, directly from vertebral body to vertebral bodyFull manifestation: "bamboo spine" Horizontal growth EtiologyInflammatory spine disease (e.g., ankylosing spondylitis)Degenerative spine disease (e.g., diffuse idiopathic skeletal hyperostosis) Syndesmophytes grow vertically, as opposed to osteophytes, which grow horizontally! Treatment Physical therapyConsistent and rigorous physical therapyIndependent exercises Medical therapyFirst choice: NSAIDs (e.g., indomethacin)Additional options Tumor necrosis factor-α inhibitors (e.g., etanercept) [12]In case of peripheral arthritis: DMARDs (especially sulfasalazine)In severe cases: temporary, intra-articular glucocorticoids Surgery: in severe cases to improve quality of lifeIndication: Severe deformity of the spinal columnInstability of the spineNeurologic deficitsProcedures: OsteotomyJoint replacementSpinal fusion Physical therapy is the most important treatment modality! Complications Complete fusion of the spine → severely limited mobility Increased risk of osteoporosis → pathological fractures Restricted chest expansion and spine mobility → breathing difficulties

Systemic sclerosis Systemic sclerosis (SSc) is a chronic disease caused by abnormal growth of connective tissue, which leads to diffuse thickening and hardening of the skin and often the inner organs. SSc is categorized into limited SSc and diffuse SSc. The more common, limited form of SSc begins with sclerosis of the fingers, hands, and face, which then progresses to the center of the body. Limited SSc is often associated with symptoms of CREST syndrome (calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) and may be followed by internal organ involvement as the disease progresses. Diffuse SSc is less common, but more aggressive, with early organ system involvement that may be life-threatening if damage to the heart, lungs, or kidneys occurs. Treatment is symptomatic and based on the extent of skin and organ system involvement. In the case of diffuse inflammation of the skin and/or organs, immunosuppressive drugs (e.g., methotrexate) should be administered. The prognosis varies depending on which organs are involved, with pulmonary arterial hypertension, interstitial lung disease, and cardiac disease significantly increasing the mortality rate.

Epidemiology ♀ > ♂ (3:1) Higher incidence in African Americans Peak incidence: 30-50 years Pathophysiology The pathophysiology of SSc is not completely understood Autoimmunologic component (see "Diagnostics")Inflammatory synthesis of extracellular matrix: fibroblast proliferation and increased synthesis of normal collagenNoninflammatory vasculopathy: underlying mechanism for many of the more severe disease features such as CAD, pulmonary artery hypertension, and renal crisis Clinical features Common symptoms Cutaneous findingsThickening and hardening of the skin (skin appears smooth and shiny)Depigmentation of the skin with sparing of perifollicular pigmentation (salt-and-pepper appearance) Sclerodactyly Red-blue discoloration of the fingersEdema and fibrosis with waxy appearance of the skin and limited range of motionAtrophy and necrotic spotsLesions on the proximal nail foldMultiple, painful ischemic digital ulcersFaceLoss of expression (mask-like facies)Shortened frenulumMicrostomia accompanied with characteristic perioral wrinkles Vascular diseaseRaynaud's phenomenonThromboembolism Fatigue, weakness Joint stiffness/pain Limited cutaneous systemic sclerosis In 90% of cases, Raynaud's phenomenon precedes the onset of other symptoms. Skin manifestations are usually restricted to the hands, fingers, and face. Extracutaneous organ involvement may occur. Often manifests as CREST syndromeC → Calcinosis cutis (small white calcium deposits on the pressure points of the extremities such as the elbows, knees, and fingertips)R → Raynaud's phenomenonE → Esophageal hypomotility (esophageal dysmotility, gastroesophageal reflux, heartburn, dysphagia, which is caused by smooth muscle atrophy and fibrosis)S → Sclerodactyly T → Telangiectasia Diffuse cutaneous systemic sclerosis Raynaud's phenomenon often coincides with or follows the onset of other symptoms. Skin manifestations typically spread proximally from the trunk to the elbow. Extracutaneous organ manifestations are commonArthralgia and myalgia → can result in contracturesGastrointestinal tractEsophageal dysmotility → dysphagia and refluxSmall bowel dysmotility → bloating, gas, constipation, and cramping Pulmonary disease: pulmonary hypertension and interstitial lung disease, increased risk of lung cancer Cardiac disease: fibrosis, myocarditis, pericarditisRenal disease: abnormal collagen deposition → thickening of renal arteriolar walls → decreased renal blood flow → reduced kidney functionScleroderma renal crisis:Occurs in 10-15% of cases of diffuse SSc Life-threatening complication with, e.g.: Oliguric renal failure(Malignant) hypertensionEncephalopathyMicroangiopathic hemolytic anemia Diagnostics Auto-antibodies: Antinuclear antibodies (ANA) present in about 90% of casesLimited SSc: anticentromere antibodies (ACA) Diffuse SScAnti-Scl-70 (anti-topoisomerase I antibody) Anti-RNA polymerase III See Antibody diagnosis of autoimmune diseases Serum protein electrophoresis: ↑ γ-globulins Complete blood count and differential Chest x-ray: detects possible pulmonary involvement Other tests may be indicated based on organ-specific symptoms (e.g., signs of renal crisis). Differential diagnoses Mixed connective tissue disease (MCTD, Sharp's syndrome) Definition: overlapping symptoms of systemic sclerosis, systemic lupus erythematosus (SLE), and polymyositis Clinical presentationMyositisArthritisAcrosclerosisRaynaud's phenomenonPulmonary hypertensionThe course is usually milder than that of other connective tissue diseases (CTD), but may progress into another CTD. Diagnosis: Most patients are positive for ANAs and anti-U1 RNP (see antibody diagnosis of autoimmune disease). Treatment Treatment focuses on organ-specific, symptomatic therapy. In the case of diffuse cutaneous disease or severe organ involvement, immunosuppressive therapy is indicated. General measuresPhysical therapy, massagePrevent dry skin Warm oil and paraffin bathsAvoid soapPhototherapy Immunosuppressive therapy: e.g., methotrexate Organ-specific therapy: e.g., PPIs in cases of gastroesophageal reflux disease

Antiphospholipid syndrome Antiphospholipid syndrome (APS) is an autoimmune disease that increases the risk of thrombosis as a result of procoagulatory antibodies. The condition may be idiopathic or acquired secondary to an underlying disease, such as systemic lupus erythematosus. Circulating antibodies deactivate anticoagulatory proteins and activate platelets, thereby inducing a hypercoagulable state. Typical clinical manifestations include recurring venous and arterial thrombotic eventssuch as deep vein thromboses, strokes, or transient ischemic attacks. A severe complication of APS in women are recurrent miscarriages of healthy fetuses. The condition should be suspected in patients with a history of thrombosis or miscarriages. It is confirmed by detecting serum antiphospholipid antibodies (e.g., lupus anticoagulant, cardiolipinantibodies). Acute thrombotic events are treated with low-molecular-weight heparin and high-dose glucocorticoids to eliminate antibodies. In mild cases, long-term management involves prophylaxis with low dose aspirin; for patients at high risk of thrombotic events, warfarin is the drug of cho

Etiology Primary: associated with genetic marker HLA-DR7 SecondarySystemic lupus erythematosusRheumatoid arthritisNeoplasmsHIV, hepatitis A/B/CBacterial infections (e.g., syphilis, Lyme disease, tuberculosis) Pathophysiology Formation of procoagulatory antiphospholipid antibodies Antibodies form complexes with anticoagulant proteins, thereby inactivating them (e.g., protein C and S, antithrombin III)Antibodies activate platelets and vascular endothelium Induction of a hypercoagulable state → ↑ risk of thrombosis and embolism Clinical features APS usually presents with recurring thrombotic events that may affect any organ. VenousDeep vein thrombosis Pulmonary embolismLivedo reticularis Ulceration (see chronic venous insufficiency) ArterialStroke, transient ischemic attacksOcclusion of organ arteries (e.g., myocardial infarction)Occlusion of distal extremity arteries (ischemia and gangrene) Pregnancy-related: recurrent miscarriages and premature births Capillaries: splinter hemorrhages Diagnostics History ofArterial or venous thrombosisRecurrent miscarriages (≥ 1) Serology for antiphospholipid antibodiesLupus anticoagulant (LA): leads to a prolonged aPTT Mixing study Dilute Russell viper venom test Anticardiolipin antibodies (aCL) (IgG and IgM): patients with APS often test false positive for syphilis (positive VDRL or RPR), as the antigen used in syphilis tests is cardiolipin.Anti-β2-glycoprotein antibodies Thrombocytopenia Hemolysis, leukocytopenia Treatment Acute managementSC low molecular weight heparin (LMWH) or IV unfractionated heparinIn severe cases: high-dose glucocorticoids, plasmapheresis, and/or immunoglobulins Secondary prophylaxis Low risk: low-dose aspirinHigh risk, no desire to become pregnant: long-term treatment with oral warfarinWish to have children, prevention of miscarriage: LMWH + aspirin

Immunosuppressants Immunosuppressants use heterogeneous mechanisms of action to suppress the body's cell-mediated and humoral immune response. They may be used as transplant rejection prophylaxis or to treat autoimmune disorders such as lupus, psoriasis, and rheumatoid arthritis. Commonly used immunosuppressants include cyclosporine A, tacrolimus, glucocorticoids, methotrexate, and biological agents (like rituximab). A common side effect of immunosuppressants is an increased susceptibility to infection and malignancy. Glucocorticoids are discussed in detail in another learning card.

Immunosuppressant classCommon drugsMechanism of actionSuppression of cell-mediated immune responseSuppression of humoral immune responseMain clinical usesGlucocorticoidsPrednisolone, hydrocortisone, dexamethasone Inhibition of intracellular NF-κB → Multiple inflammatory and immune mediators are inhibited.Acute effect (occurs within minutes) → While the mechanism is not entirely clear, a membrane stabilizing effect is hypothesized. Long-term effects (in hours) → direct influence on gene expression✓✓Transplant rejectionprophylaxisTo suppress various allergic, inflammatory, and autoimmune reactionsCalcineurin inhibitors (calcineurin =calcium- and calmodulin-dependentserine-threonine phosphatase) Cyclosporine AImmunosuppression: binds cyclophilin → inhibition of calcineurin → inhibition of NFAT activation→↓ IL-2 transcription → ↓ activation of T cellsCytostatic action: binding to multidrug resistance glycoprotein P-170 ✓-Transplant rejectionprophylaxis (in combination with other immunosuppressants)PsoriasisRheumatoid arthritisTacrolimus (also FK-506 or fujimycin)Binding to FK506 binding protein (FKBP) → inhibition of calcineurin → inhibition of NFAT activation → ↓ IL-2 transcription → ↓ activation of T cells✓-Transplant rejectionprophylaxisPimecrolimusAtopic dermatitis(topical use) mTOR inhibitors Sirolimus (also known as rapamycin)Binds to FKBP → inhibition of mTOR kinase→ inhibition of the IL-2-mediated cell cycle → prevents response to IL-2 → blocks T-cell activation andB-cell differentiation → ↓ IgM, IgG, and IgA production✓(✓)Renal transplantrejection prophylaxisAs a synergistic immunosuppressant with cyclosporineAlso used in drug-eluting stents.EverolimusRejection prophylaxis in liver and renal transplant (in combination with other immunosuppressants)Purine analogAzathioprine(mercaptopurine)Purine analog (antimetaboliteprecursor of 6-mercaptopurine) → blocks nucleotidesynthesis → inhibits proliferation of lymphocytesCytostatic effect at a high dosage via inhibition of cell proliferationImmunosuppressive effect at a low dosage with significant inhibition of lymphocyteproliferation✓(✓)Prophylaxis against renal transplantrejectionAutoimmune disease treatment (e.g., rheumatoid arthritis, Crohn disease, glomerulonephritis)To wean patients off long-term steroidtherapySteroid-refractorydiseaseProtein drugs Antibodies Specific binding to relevant structure in the immune cascade (detailed explanation below)✓✓See biological agentsfor immunotherapybelow.Other biological proteins IMDH/IMPDH inhibitors Mycophenolate mofetil Inhibition of inosine monophosphate dehydrogenase → selective inhibition of lymphocyteproliferation✓✓Lupus nephritisUsed in combination with cyclosporin or tacrolimus as transplant rejectionprophylaxisOther cytostatic and antiproliferative agentsMethotrexateFolic acid antagonist(antimetabolite) : inhibition of dihydrofolate reductase(DHFR) → ↓ pyrimidine and purine nucleotide synthesis → ↓ DNA synthesis✓✓Treatment of severe psoriasis and rheumatoid arthritisIn neoplastic diseaseslike gestational choriocarcinoma, chorioadenoma, and hydatidiform moleCyclophosphamideAlkylating agent: alkylation of DNA/RNA → cross-linking and strand breaks → impaired DNA synthesis(✓)✓Autoimmune disease therapy (e.g., SLE, autoimmune hemolytic anemias) Biological agents used in immunotherapy Biological agents are recombinant proteins that intervene in immunological processes. Used in autoimmune diseases and malignancies Although complex and costly, they can significantly improve the success of treatment in some cases. Antibody TypeTargetIndicationInfliximabChimericTNF-α inhibitionRefractory-therapy for chronic inflammatory systemic diseases Rheumatoid arthritisCrohn disease, ulcerative colitisAnkylosing spondylitisPsoriatic arthritisAdalimumabHumanizedEtanerceptFusion protein GolimumabHumanizedCertolizumabHumanizedRituximabChimericCD20Rheumatoid arthritisITPCLL, B-cell non-Hodgkin lymphoma (NHL)Symptomatic Waldenstrom macroglobulinemiaCetuximabChimericEpidermal growth factor receptor(EGFR inhibitor)Colorectal cancerHead and neck cancerAlemtuzumabHumanizedCD52Chronic lymphoid leukemia (CLL)Escalation therapy of multiple sclerosis (see subsection "Disease-modifying therapy", under Treatment section of multiple sclerosis)NatalizumabHumanizedAlpha-4 integrinEscalation therapy of multiple sclerosis (see subsection "Disease-modifying therapy", under Treatment section of multiple sclerosis)Crohn diseaseOmalizumabHumanizedIgESevere allergic asthma (stage V)AbciximabChimericAntagonist of GP IIb/IIIa receptorsAntiplatelet agent, especially in patients undergoing percutaneous coronary interventionMuromonab-CD3Mouse antibodyCD3 from T cellsSteroid-resistant acute rejection post-transplantationBasiliximabChimericAlpha chain (CD25 antigen) of the IL-2 receptor of T cellsEscalation therapy of multiple sclerosisFormerly used for the prevention of kidney rejection post-transplantation (in combination with cyclosporine and glucocorticoids) DaclizumabHumanizedTrastuzumabHumanizedHER2/neuHER2/neu-positive breast cancerStomach cancer with overexpression of HER2/neuBevacizumabHumanizedVEGFNeovascular age-related macular degeneration (off-label use in the US)Colorectal cancer, renal cell carcinomaEculizumabHumanizedComplement protein C5Paroxysmal nocturnal hemoglobinuriaUstekinumabHumanIL-12, IL-23 Psoriasis, psoriatic arthritis, Crohn diseaseTocilizumabHumanizedIL-6 receptor Giant cell arteritis, juvenile idiopathic arthritis, rheumatoid arthritis. Side effects Calcineurin inhibitors Cyclosporine A Nephrotoxic Neurotoxic Gingival hyperplasia Tremors Hypertension Hypertrichosis and hirsutism Hyperkalemia Nausea and diarrhea Diabetogenic effect (particularly after organ transplantation). This can lead to: HyperuricemiaHyperlipidemiaElevated liver enzymes Increase in malignancies and infectious diseases Tacrolimus Nephrotoxic: monitor for oliguria Neurotoxic Nausea and diarrhea Hypertension Hair loss Headache Insomnia Hyperglycemia Abdominal discomfort Hyperkalemia Hypophosphatemia Hypomagnesemia Many side effects of tacrolimus are similar to cyclosporine A, but tacrolimus does not cause gingival hyperplasia or hypertrichosis! Tacrolimus and cyclosporine A should not be combined because together they could have nephro- and neurotoxic effects! Purine analog (Azathioprine/Mercaptopurine) Pancytopenia (leukopenia, macrocytic anemia, thrombocytopenia) Increased by interaction with allopurinol Acute pancreatitis Hepatotoxicity Malignancies: e.g., cervical cancer, lymphoma, squamous cell carcinoma, melanoma (rare) Nausea, vomiting, and dose-related diarrhea Allopurinol causes toxic accumulation of azathioprine! In cases in which concomitant treatment is unavoidable, a dose reduction of azathioprine is necessary! mTOR inhibitors (Sirolimus, Everolimus) Infection (e.g., respiratory or urinary tract) Peripheral edema Hypertension Insulin resistance Pancytopenia Stomatitis Hyperlipidemia Mycophenolate mofetil Pancytopenia Infection (e.g., respiratory or urinary tract) Vomiting and diarrhea Peripheral edema Hyperglycemia ↑ Blood urea nitrogen Hypercholesterolemia Hypertension Back pain Cough Methotrexate Pancytopenia and/or macrocytic anemia Mucositis (particularly stomatitis, enteritis), susceptibility to infection Hepatotoxicity Nephrotoxicity Nausea and vomiting Diarrhea Pulmonary fibrosis and toxicity Hair loss Salvage therapy (leucovorin rescue therapy) The side effects of methotrexate can be reduced by administering salvage therapy. Salvage therapy involves the administration of folic acid and folinic acid (active folic acid = leucovorin = calcium folinate). Indications Methotrexate (MTX) intoxication (inadvertent overdosage or impaired elimination): administered every 6 hours until methotrexate level < 10 molProphylactic therapy: within 24-48 h of starting high dose MTX Biologics (e.g., daclizumab) General side effectsRash, dermatitisFlu-like symptoms LymphadenopathyInfections (e.g., nasopharyngitis)Gastrointestinal symptoms (e.g., diarrhea)Leukocytosis or leukopenia, thrombocytopenia, anemia↑ ALT, ASTDepressionFormation of anti-drug antibodies (especially for adalimumab and infliximab): can manifest with a decrease in clinical response (e.g., recurrence of symptoms), low drug levels, and/or allergic reactions. Rituximab and Natalizumab: Reactivation of a latent JC virus infection resulting in PML. Bevacizumab: Gastrointestinal perforationHemorrhages (e.g., GI bleeding)Wound healing complications Contraindications to anti-TNF-α treatment (infliximab, adalimumab, etanercept) PregnancyImmunosuppressed individuals Systemic or localized infectionsChronic infections (particularly tuberculosis; rule out latent tuberculosis before starting therapy )Multiple sclerosis Malignancy Moderate to severe heart failure (NYHA class III/IV) Both calcineurin inhibitors (cyclosporine and tacrolimus) are highly nephrotoxic. Perform testing for latent tuberculosis before initiating anti-TNF-α treatment!

Vasculitides Vasculitides are a heterogeneous group of autoimmune diseases, all characterized by inflammation of blood vessels (vasculitis) and subsequent ischemia and damage to the organs supplied by these vessels. Vasculitis may occur as a primary disease (idiopathic) or as a secondary response to an underlying disease (e.g., hepatitis B infection). Based on the size of the vessel affected, it can be classified into small-vessel, medium-vessel, or large-vessel vasculitis. While the inflammatory process may be confined to one organ, it may also involve several organ systems. Vasculitis should be considered in patients presenting with palpable purpura, pulmonary infiltrates, unexplained ischemic events, and multisystem disease. The detection of antineutrophil cytoplasmic antibodies (ANCA) in the blood is an important diagnostic marker; however, there are also ANCA-negative vasculitis syndromes. Immunosuppressive treatment is administered to stop vascular inflammation. Specific (e.g., antiviral drugs) or symptomatic (e.g., NSAID) management may be necessary. If the vasculitis is secondary to an underlying disease, treatment of the underlying disease should be initiated.

Overview EtiologyPrimary (idiopathic)Secondary (e.g., response to hepatitis B infection, hepatitis C infection) Large vessel vasculitis Giant cell arteritis (temporal arteritis) See giant cell arteritis for more information. Takayasu arteritis (aortic arch syndrome) Definition: granulomatous inflammation of the aorta and its major branches, resulting in stenosis of involved blood vessels and subsequent vascular symptoms EpidemiologyPeak incidence: 15-45 years of ageAsian heritage♀ > ♂ (3:1) Clinical featuresFever, malaise, arthralgia Vascular symptoms Decreased bilateral brachial and radial pulses → "pulseless disease"Syncope, angina pectorisImpaired visionMovement-induced muscular pain in one or more limbsRaynaud phenomenonBilateral carotid bruitsHypertension Skin manifestations Erythema nodosumUrticaria DiagnosticsLaboratory findings: ↑ ESRAngiography (gold standard): detects vascular stenosis Biopsy of affected vessel: granulomatous thickening of aortic arch; plasma cells and lymphocytes in media and adventitia; vascular fibrosis TreatmentCorticosteroids; if necessary, MTX or cyclophosphamide may be administeredSurgical intervention (e.g., bypass) may be required if critical stenosis of the aortic arch or its branches occurs.Antihypertensive treatment In Takayasu arteritis, I can't TAKA YA pulse (pulseless disease). Medium-sized vessel vasculitis Kawasaki disease (mucocutaneous lymph node syndrome) See Kawasaki disease for more information. Polyarteritis nodosa (PAN) [2][5] Definition: systemic vasculitis of the small and medium-sized vessels, which leads to tissue ischemia; most commonly involving skin, peripheral nerves, muscles, joints, gastrointestinal tract, and kidneys EpidemiologyPeak incidence: ∼ 45-65 yearsSex: ♂ > ♀Often associated with hepatitis B or C infection Clinical featuresNonspecific symptoms: fever, abdominal, muscle, and joint pain Renal involvement: hypertension, renal impairmentCoronary artery involvement; increased risk of myocardial infarctionSkin involvement: rash, ulcerations, nodulesNeurological involvement: polyneuropathy (mononeuritis multiplex), strokeGI involvement: abdominal pain, melena, nausea, vomiting Usually spares the lungs DiagnosticsBlood testsHepatitis B serologyHepatitis C serology↑↑ ESRAnemia, leukocytosisANCA-negativeUrine analysis: proteinuria, hematuriaMuscle biopsy: transmural inflammation of the arterial wall with leukocytic infiltration and fibrinoid necrosis Angiography: numerous small aneurysms and stenosis of small and medium-sized vessels of the involved organs(pulmonary arteries not usually affected) TreatmentImmunosuppression: corticosteroids, cyclophosphamideAntiviral therapy against HBV and HCV may be required. PAN should be considered in young adults presenting with stroke or myocardial infarction! The diagnosis may be confirmed with a biopsy of involved tissue.In PAN, the Pulmonary Artery is Not involved, PANmural inflammation of the arterial wall is present, and PAN is often associated with hePANitis B! Thromboangiitis obliterans An inflammatory, non-atherosclerotic, vaso-occlusive disease of both small and medium-sized vessels in the limbs that is associated with smoking. Classically presents with the triad of intermittent claudication, Raynaud's phenomenon, and migratory thrombophlebitis. ANCA-associated small vessel vasculitis Granulomatosis with polyangiitis (Wegener granulomatosis) Wegener granulomatosis is the 'C' disease: Curvy nose (saddle-nose deformity), Chronic sinusitis, Cough, Conjunctivitis and Corneal ulceration, Cardiac arrhythmias, nonCaseating granulomas on biopsy, cANCA, Corticosteroids and Cyclophosphamide as treatment. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) Definition: a multisystem disease characterized by necrotizing granulomatous vasculitis with eosinophilia, which most commonly involves the lungs and the skin but can also affect the renal, cardiovascular, gastrointestinal, central, and peripheral nervous systems. Etiology: unknown Clinical featuresSevere allergic asthma attacks (chief complaint)Allergic rhinitis/sinusitisSkin nodules, palpable purpuraPericarditisGastrointestinal involvement: bleeding, ischemia, perforation Pauci-immune glomerulonephritisCNS: impaired mental status, mononeuritis multiplex (loss of motor and sensory function) DiagnosticsPeripheral blood eosinophilia↑ IgE levelCirculating MPO-ANCA/pANCA (∼ 40% of cases)Biopsy (confirmatory test): tissue eosinophilia and necrotizing granuloma Treatment: immunosuppression with glucocorticoids; possible in combination with cyclophosphamide Churg-Strauss syndrome = pANCA and polyneuropathy (foot or wrist drop), allergic rhinitis/sinusitis/asthma, vasculitis, eosinophilia, and skin nodules Microscopic polyangiitis Definition: necrotizing vasculitis of small vessels, typically with renal, skin, and pulmonary involvement; however, multiple organ systems may be affected Clinical features: Renal: pauci-immune glomerulonephritis with hypertension Lungs: pulmonary vasculitis with hemoptysisSkin: palpable purpura, nodules, necrosis DiagnosticsBiopsy of involved organ: fibrinoid necrosis with infiltration of neutrophils; no granulomasLaboratory findings: MPO-ANCA/pANCA (∼ 70% of cases) Treatment: immunosuppression with corticosteroids and cyclophosphamide The presentation of microscopic polyangiitis is similar to that of Wegener granulomatosis, but it does not affect vessels in the upper and lower respiratory tract (no sinusitis or rhinitis), does not involve granuloma formation, and is associated with pANCA, not cANCA. Microscopic Polyangiitis has MyeloPeroxidase antibodies (i.e., p-ANCA). Non-ANCA-associated (leukocytoclastic) vasculitis of small vessels Henoch-Schonlein purpura (immunoglobulin A vasculitis) An acute immune complex-mediated small vessel vasculitis that most commonly occurs in children. It is often preceded by an upper respiratory tract infection and typically presents with a tetrad of symptoms: palpable purpura, arthritis/arthralgia, abdominal pain, and renal disease. Cryoglobulinemic vasculitis Definition: cryoglobulin-mediated vasculitis; characterized by temperature-dependent deposition of immune complexes in blood vessel walls and subsequent inflammation of involved vessels and surrounding tissue Etiology: type II and III cryoglobulinemia (mixed cryoglobulinemia)> 90% association with hepatitis C infectionFormation of hepatitis C IgG and IgM rheumatoid factor → immune complex formation with hepatitis C antigen→ complement activation and inflammation of blood vessels.Other underlying diseases: multiple myeloma, lymphoproliferative disorders, connective tissue diseases, autoimmune diseases (SLE), proliferative glomerulonephritis Clinical featuresNonspecific systemic symptoms: fatigue, malaise, myalgia, arthralgiaSkin lesions (nearly 100% of cases): palpable purpura, ulceration, necrosisVasomotor symptoms: Raynaud phenomenon, acrocyanosisPolyneuropathyHepatosplenomegalyGlomerulonephritis (severe cases or late complication) DiagnosticsLaboratory findings Cryoglobulinemia: cold-precipitable immune complexes (slow precipitation after 72 hours)↑ Rheumatoid factor (in almost all cases)Hypocomplementemia (90% of cases)Hepatitis C diagnosticsHepatitis C RNA and anti-hepatitis C antibodies↑ Liver transaminasesSkin or renal biopsy: Evaluate inflammatory vascular changes and renal damage; cryoglobulin deposits (IgG and IgAcomplexes) may be detected in glomeruli.Investigation of underlying cause: WBC, autoimmune antibodies, liver function testing, renal function testing, imaging (angiography, CT, chest x-ray) TreatmentTreatment of underlying diseases: hepatitis C infection (IFN-α, ribavirin)Immunosuppression: corticosteroids and/or cyclophosphamide are indicated in severe cases of organ involvement (renal, neurological). The triad of arthralgia, palpable purpura, and fatigue is seen in ∼ 30% of patients with mixed cryoglobulinemia. Cutaneous leukocytoclastic vasculitis (hypersensitivity vasculitis) Definition: necrotizing vasculitis of cutaneous small vessels Epidemiology: most common vasculitis seen in clinical practice Etiology: drug-induced (e.g., PTU, hydralazine, allopurinol, penicillins, sulfasalazine); infections Clinical features: Painful, palpable purpuraOther skin lesions may occur: subcutaneous nodules, chronic urticaria, ulcers, vesicles Diagnostics: Skin biopsyInvestigation of underlying causeSystemic vasculitis should be ruled out. Treatment: symptomatic; discontinue drug intake; immunosuppression may be required Behcet disease Definition: a systemic vasculitis that can affect arteries and veins of all sizes Epidemiology [10]Most common from the Mediterranean region to eastern Asia, with the highest prevalence observed in Turkey and Japan Peak incidence: 20-40 years EtiologyAutoimmune and infectious triggers (e.g., precipitating HSV or parvovirus infection) have been suggested. Strong HLA-B51 association Clinical features [11][12][13][10]Recurrent painful aphthous ulcers (usually last about 1-4 weeks).Recurrent genital ulcerationsOcular disease: uveitis (iridocyclitis, chorioretinitis), and/or retinal vasculitis Skin lesions: Erythema nodosumPapulopustular lesionsDermatographism: formation of urticaria after minor pressure is applied to the skin, likely mediated by local histamine release.Arthritis of knees, ankles, hands, and/or wrists Gastrointestinal disease: ileocecal ulceration Vasculopathy Superficial thrombophlebitisThrombosis of large veins (e.g., deep vein thrombosis, Budd-Chiari syndrome)Arterial thrombosisAneurysms (e.g., pulmonary artery aneurysms) Diagnostics [11][12][13]Positive pathergy skin test: erythematous papule or pustule 24-48 hours after a needle prick Nonspecific markers of inflammation may be present during flares (e.g., ↑ ESR, ↑ CRP).Autoantibodies (e.g., ANA, ANCA, rheumatoid factor) are usually absent. Diagnostic criteria (International Study Group criteria) Recurrent oral ulceration at least three times within a 12-month periodAND≥ 2 of the followingRecurrent genital ulcerationEye lesionsSkin lesionsPositive pathergy test Treatment [14][12]Oral ulcers and/or genital ulcers: topical corticosteroidsTopical lidocaine for pain reliefSkin lesions Papulopustular lesions: See "Treatment" of acne vulgaris.Erythema nodosum: colchicineArthritis: colchicineOcular disease and/or vasculopathy Systemic corticosteroidsImmunosuppressant therapy (e.g., azathioprine) PATHERGY: Positive pathergy test, Apthous mouth ulcers, Thrombosis (arterial and venous), Hemoptysis (pulmonary arteryaneurysm), Eye lesions (uveitis, retinal vasculitis), Genital ulcers, Young at presentation (3rd decade) Differential diagnosis of vasculitis Giant cell arteritis Elderly women, typically > 50 years Visual impairment → may result in blindness New-onset headache Tender temporal artery Jaw claudication Associated with polymyalgia rheumatica ↑↑ ESR Autoantibodies absent Halo sign around the vessel on duplex sonography Temporal artery biopsy (gold standard) shows granulomatous inflammation with giant cells and intima proliferation that results in stenosis. High-dose glucocorticoids to prevent permanent vision loss Takayasu arteritisAsian females, typically < 40 yearsDisparity in blood pressure between arms → "pulseless disease"Bruit over subclavian artery or abdominal aortaSyncope and angina pectoris↑ ESRAngiography shows stenosis of aortic arch and proximal great vessels (gold standard).Biopsy shows granulomatous inflammation of aorta and its major branches.GlucocorticoidsKawasaki syndromeChildren < 5 years"CRASH (Conjunctivitis, Rash, Adenopathy, Strawberry tongue, Hand-foot changes) and BURN" (5+ days of fever)↑ ESR, ↑ CRP, thrombocytosisEchocardiography may detect coronary arteryaneurysms. High-dose ASA and IVIGPolyarteritis nodosaPeak incidence: ∼ 45-65 years, ♂ > ♀Fever, malaiseAbdominal, muscle, and joint painRenal impairmentNeurologic dysfunction (e.g., polyneuropathy, stroke)Rash, ulcerations, nodulesAssociation with hepatitis B and CSpares the lungs!ANCA-negativeMuscle biopsy shows transmural inflammation of vessels.Glucocorticoids, cyclophosphamideThromboangiitis obliterans (Buerger disease)Men < 45 years Strong association with tobacco use!Intermittent claudication due to severe limb ischemia; acute necrosis of toes and fingers often requires amputationRaynaud phenomenonAngiography (confirmatory test): nonatherosclerotic segmental occlusion of arteriesSmoking cessationGranulomatosis with polyangiitis (Wegener)Nasopharyngeal involvement: chronic sinusitis/rhinitis, saddle nose deformityChronic otitis media and mastoiditisTreatment-resistant, pneumonia-like symptoms with cough, dyspnea, hemoptysisRapid progressive glomerulonephritisPR3-ANCA/cANCA-associatedBiopsy shows granulomatous, necrotizing inflammation of vessels, kidneys, and the lungs.Chest x-ray/CT: multiple bilateral cavitating nodular lesionsGlucocorticoids, cyclophosphamideEosinophilic granulomatosis with polyangiitis (Churg-Strauss)Severe allergic asthma, sinusitisSkin manifestations (e.g., tender nodules)Peripheral neuropathyGastrointestinal, cardiac, renal involvement possibleMPO-ANCA/p-ANCA-associatedPeripheral blood eosinophilia↑ IgEBiopsy (confirmatory test): tissue eosinophilia and necrotizing granulomasGlucocorticoids, cyclophosphamideMicroscopic polyangiitisHypertension and pauci-immune glomerulonephritisPalpable purpuraMPO-ANCA/p-ANCA-associatedSimilar to granulomatosis with polyangiitis but spares the nasopharynx!Biopsy shows inflammation; no granulomasGlucocorticoids, cyclophosphamidelmmunoglobulin Avasculitis (Henoch-Schönlein purpura)Children; 90% < 10 yearsPalpable purpura on lower limbsArthritis/arthralgiaIntestinal colicHematuria due to IgA nephropathyOften secondary to upper respiratory tract infections↑ IgA in serumBiopsy: leukocytoclastic vasculitis with IgA and C3 immune complex depositionSupportive care (e.g., NSAIDs) in mild casesGlucocorticoids and IV hydration in severe casesCryoglobulinemic vasculitisFatigueArthralgiaPalpable purpuraGlomerulonephritisThe majority of cases are secondary to hepatitis Cinfection.Cryoglobulinemia Glucocorticoids; cyclophosphamidein severe casesTreatment of hepatitis C infection (IFN-α, ribavirin)Cutaneous leukocytoclastic vasculitisPalpable purpuraDrug-induced, infectionsDiscontinue drug intakeBehcet diseaseMost common in Turkey, the Middle East, and JapanOral and genital ulcersUveitisErythema nodosumPositive pathergy skin testingGlucocorticoids

Glucocorticoids Glucocorticoids are a group of drugs with various anti-inflammatory and immunosuppressant as well as metabolic and endocrine effects. These drugs are structurally and pharmacologically similar to the endogenous hormone cortisol. Glucocorticoids have immediate effects that do not depend on DNA interaction (e.g., vasodilation). However, they exert their main anti-inflammatory and immunosuppressive actions by binding to glucocorticoid receptors, which, in turn, causes complex changes in gene transcription. These genomic effects only begin to manifest after several hours. Similarly, glucocorticoids bind to mineralocorticoid receptors, but for most glucocorticoid drugs, high doses are required for a significant mineralocorticoid effect. Systemic glucocorticoids are used for hormone replacement therapy (e.g., in Addison disease), for acute or chronic inflammatory diseases (e.g., rheumatoid arthritis), and for immunosuppression (e.g., after organ transplants). Local glucocorticoids are used to treat conditions like dermatoses, asthma, and anterior uveitis. Side effects include metabolic and endocrine disturbances, weight gain, skin reactions, hypertension, and psychiatric disorders. Contraindications for systemic glucocorticoids include systemic fungal infections and, in the case of dexamethasone, cerebral malaria. Status asthmaticus is a contraindication for inhalative glucocorticoids. Topical and ophthalmic glucocorticoids are usually contraindicated if there are pre-existing local infections.

Overview General Glucocorticoids are a type of corticosteroid These are hormones, based on cholesterol, originally derived from the adrenal cortex Synthetic derivatives of cortisol are used in a variety of conditions Routes of administration : Topical (e.g., eyes, skin, mucous membranes)Local injection (i.e., intraarticular)InhaledOralParenteral DrugRelative glucocorticoid potency Relative mineralocorticoid potency DurationCortisol or hydrocortisone11Short: 8-12 hoursCortisone0.80.8Short: 8-12 hoursTriamcinolone50Intermediate: 12-36 hoursMethylprednisolone50.5Intermediate: 12-36 hoursFludrocortisone15150Intermediate: 24-36 hoursPrednisolone orprednisone 40.8Intermediate: 12-36 hoursDexamethasone orbetamethasone300Long: 36-54 hours Other drugs for mainly local administration: beclomethasone ., budesonide , clobetasol, and fluticasone Do not confuse cortisol and cortisone! Effects Anti-inflammatory and immunosuppressiveAcute effects (within minutes) ↓ Vasodilation and ↓ capillary permeability↓ Leukocyte migration to inflammatory fociLong-term effects (within hours) : Glucocorticoids bind to cytoplasmic glucocorticoid receptors (GRs) → inhibition of neutrophil apoptosis and demargination (loss of neutrophil binding to adhesive endothelial integrin molecules)→ neutrophilic leukocytosis→ Promotion of apoptosis in eosinophils, monocytes, and lymphocytes → ↑ Inhibition of phospholipase A2, which decreases the production of arachidonic acid derivatives.→ ↑ Inhibition of transcription factors (e.g., NF-κB) → ↓ expression of pro-inflammatory genes→ Translocation to the cell nucleus and binding to glucocorticoid responsive elements (GREs) within the promoters of anti-inflammatory genes (e.g., interleukin-10) → ↑ expression of anti-inflammatory genes Mineralocorticoid properties: e.g., reduced sodium excretion, increased potassium excretion Antiproliferative: triggers cell apoptosis, and inhibits fibroblast proliferation Anabolic-androgenic effects with steroid abuse : increase in muscle mass and strength Both acute and long-term effects lead to inhibition of inflammatory processes and to immunosuppression! Side effects Systemic glucocorticoids Glucocorticoid toxicity depends on the dose that is administered over a certain period of time. Therefore even low doses can have toxic effects if administered long-term. If glucocorticoids are administered once or only briefly (e.g., for treatment of anaphylactic shock), there are usually no significant side effects even in high doses. SkinSkin atrophy: due to loss of dermal collagen Stretch marksPurpura Acne HypertrichosisIncreased risk of squamous and basal cell carcinomasCardiovascular systemHypertension Metabolism, electrolytes and endocrine systemWeight gain with truncal obesity, buffalo hump, and moon face (Cushingoid appearance)Proteolysis and lipolysis Hyperglycemia → glucocorticoid-induced diabetes Hypocalcemia → PTH activation → secondary osteoporosis CNS and psycheMood disorders Cognitive disorders Psychosis EyesCataractGlaucomaOtherAdrenocortical atrophyAcute adrenal insufficiency Avascular necrosis of boneOsteoporosis, osteopeniaChronic glucocorticoid use: RANKL-mediated activation of osteoclasts and apoptosis of osteoblasts lead to decreased bone formation and increased bone resorption Corticosteroid-induced myopathyAcute: generalized muscle weakness Chronic Classic form of steroid myopathyProgressive weakness of proximal limb muscles, myalgiaPeptic ulcers and gastrointestinal hemorrhage Growth inhibition in childrenImmunosuppression Specific to anabolic-androgenic steroid abuseEndocrine/reproductive Women: e.g., amenorrhea, hirsutism, breast atrophy, deep voiceMen: e.g., gynecomastia, small testes, low sperm densityCardiovascular: ↑ heart rate, ↑ blood pressureHematologic: ↑ LDL, ↓ HDL, ↑ hematocritNeuropsychiatric: e.g., aggressive behaviorTendon ruptures Hepatic damage Many of the side effects listed above are also features of iatrogenic Cushing's syndrome! Topical glucocorticoidsInhaled glucocorticoidsLocal effectsSkin manifestations as in systemic glucocorticoidsAllergic dermatitisOral candidiasisLung infectionsHoarseness Allergic dermatitis EyesAs in systemic glucocorticoidsOcular reactionsOther-Growth inhibitionOsteoporosisAdrenal suppression Local side-effects of inhaled glucocorticoids can be avoided by reducing the dose to the lowest effective amount, rinsing with mouthwash after each puff, improving the inhalation technique and compliance, and keeping vaccinations up to date! Indications Replacement therapyAdrenocortical insufficiency (Addison's disease)Congenital adrenal hyperplasia Systemic symptomatic treatmentAcuteAllergic reactions and anaphylactic shockAsthmaAntiemetic treatment (e.g., nausea due to cytostatic treatment) Toxic pulmonary edemaAcute exacerbation of autoimmune diseases (e.g., multiple sclerosis, psoriasis)Acute exacerbation of COPD Cerebral edema Long-termChronic, inflammatory diseases (e.g., asthma, chronic obstructive pulmonary disease, inflammatory bowel disease)Rheumatic diseases (e.g., sarcoidosis, Sjogren's syndrome) Graves' ophthalmopathy Local symptomatic treatment: anterior uveitis, dermatoses, tenosynovitis, and osteoarthritis or juvenile idiopathic arthritis ProphylacticOrgan transplant Preterm delivery Contraindications General: hypersensitivity SystemicSystemic fungal infectionsIntrathecal administrationCerebral malaria (dexamethasone)Concomitant live or live attenuated virus vaccination (if glucocorticoids are used in immunosuppressive doses)Idiopathic thrombocytopenic purpura (IM administration)Use in premature infants (formulations containing benzyl alcohol) TopicalDermatological: bacterial, viral or fungal infection of the mouth or throat (triamcinolone)Ophthalmic Systemic fungal infection (triamcinolone)Acute untreated purulent ocular infections (prednisolone)Fungal or mycobacterial ocular infections, viral conjunctivitis, or keratitis (prednisolone, dexamethasone) Inhalation: status asthmaticus or acute asthma episode requiring intensive measures (beclomethasone, budesonide) Guidelines & therapy recommendations Systemic administration Tapering to avoid toxicityShort-term administration (≤ 3 weeks): no tapering necessaryLong-term administration (> 3 weeks): tapering regimen based on patient age and condition and on duration/dose of prior glucocorticoid administration → e.g., tapering over 2 monthsPrincipally no IM application If the Cushing threshold is exceeded over a longer period of treatment, the glucocorticoid dose should be gradually decreased to minimize the risk of adrenocortical insufficiency! An intratendinous injection carries the risk of bacterial spread and iatrogenic bacterial arthritis!

Seronegative spondyloarthropathies Seronegative spondyloarthropathies include several chronic inflammatory arthritic diseases that affect the vertebral column. The most important diseases in this group are ankylosing spondylitis, reactive arthritis, and psoriatic arthritis. Common features include the absence of rheumatoid factor (RF) and a strong genetic association with HLA-B27. Spondyloarthropathies disproportionately affect men, with symptom onset generally occurring before the age of 45. The cardinal sign is slowly progressive pain in the lower back and sacroiliac joints (especially at night). Asymmetrical oligoarthritis and enthesopathy are also common. The diseases differ in the involvement of other organs, such as the eyes, the genitourinary tract (particularly in reactive arthritis) or the skin (particularly in psoriatic arthritis). Seronegative spondyloarthropathies usually respond well to NSAID therapy.

Types of seronegative spondyloarthropathies The different types of seronegative spondyloarthropathy do not necessarily represent distinct diseases, but may overlap significantly in etiology, pathology, clinical features, and treatment. Ankylosing spondylitis (most common) Reactive arthritis Psoriatic arthritis Undifferentiated spondyloarthropathy Spondyloarthritis associated with Crohn's disease and ulcerative colitis Common features of seronegative spondyloarthropathies Negative for rheumatoid factor Genetic association with HLA-B27 Generally more commonly affects men Age of onset: typically between 20-40 years of age Non-specific symptoms (fever, fatigue, weight loss) ArthritisInsidious, often unilateral onsetParticularly of the sacroiliac joints (especially for ankylosing spondylitis)Asymmetrical peripheral oligoarthritisStiffness and pain is worse in the morning (typically > 30 minutes) and improves with movementOften involves inflammatory enthesopathy (e.g., achillodynia)Usually responds well to NSAID therapy Extra-articular manifestatitons vary according to type, but involvement of the eye is common (e.g., iritis, iridocyclitis, uveitis) HLA-B27 associations Mnemonic: Conditions commonly associated with HLA-B27 are A-PAIR: Ankylosing spondylitis, Psoriasis, Acute anterior uveitis, Inflammatory bowel disease, Reactive arthritis Ankylosing spondylitis Psoriasis Acute anterior uveitis Inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) Reactive arthritis