Connective Tissue Diseases in Childhood PDF

Connective tissue diseases in childhood Pediatric department Lect. Ausra Snipaitiene Acc. prof. Rima Sileikiene 1. Arthritis and different forms of this syndrome Arthralgia Reactive arthritis Juvenile idiopathic arthritis (JIA) 2. Systhemic connective tissue diseases Systhemic lupus er...

Connective tissue diseases in childhood Pediatric department Lect. Ausra Snipaitiene Acc. prof. Rima Sileikiene 1. Arthritis and different forms of this syndrome Arthralgia Reactive arthritis Juvenile idiopathic arthritis (JIA) 2. Systhemic connective tissue diseases Systhemic lupus erythematosus (SLE) Dermatomyositis Scleroderma 3. Vasculitis IgA vasculitis (Henoch-Schönlein purpura) Kawasaki disease Polyartheriitis nodosa 4. Rheumatic fever Arthritis – inflammation of the joint Joint swelling Soft-tissue swelling Exudate accumulation in the joint Synovial hyperplasia And at least 2 of the following: Limited range of movement (pain? stiffness?) Pain or tenderness during joint movements Increased temperature of skin overlying joint (warm joint) NOTE: Peripheral joint inflammation can be determined more easily. Hip, spine, sacrum arthritis is less marked in signs of inflammation.  Septic (bacterial, viral) Arthritis Reactive – Juvenile secondary to extraarticular idiopathic infection arthritis - JIA Possible accompanying symptoms Loss of weight Weakness Systemic/nonspecific Fever Anaemia Muscule damage (atrophia, granuloma) Uveitis Other organ systems Serositis Skin, fingernalis changes Lymphadenopathy Arthralgia – pain with NO inflammation Fibromyalgia Hypermobility syndromes Osteochondropathy Idiopathic pain (growing pains, benign foot pain) Overuse syndrome Arthritis or arthralgia in other disease Systemic connective tissue diseases (systemic lupus erythematosus – SRV) Vasculitis Neoplastic disorders Haemophilia (hemarthrosis) Metabolic disorders (gout, heavy metal intoxication, obesity) Hemathological conditions (severe condition, not compatible with signs in the joints) Endocrine diseases (diabetes mellitus, hypo-, hyperthyroidism) Localized bone or cartilage tumours Diagnostic tests Nonspecific Immunological Radiological Total blood RF Ultrasound count (TBC) Anti-CCP Rx ESR ANA MRI CRP ANCA CT Protein Complement 3 fraction test and 4 (C3, C4) Cryoglobulins Reactive arthritis Aseptic acute inflammation of the joints soon after extraarticular infection with no pathogens in joint space Most common form of arthritis in childhood Peack incidence 8-14 years (80% ankles>hips) Uncommon: Large amount of fluid in the joint Crepitation Morning stiffness Muscule atrophy Contractures Lasts for 1-2 weeks General condition is satisfactory X-ray nothing special Treatment If proved – treat infection Chronic infections eradication, if recurrent reactive arthritis NSAIDs up to 6 weeks 2023-10-02 12 Juvenile idiopathic arthritis - JIA Criteria for the diagnosis: Onset before age of 16y Persisting 6 weeks or more Excluded other conditions associated with or mimicking arthritis  Systhemic Persistent - ILAR Fever, rash, no more than 4 joints serositis, ↑ clasification l/n, ↑ hepatis Oligo throughout the disease course and/or spleen 4 or less Other during first Extended - Affects a total of 6mo of the more than 4 disease joints after the first 6 months of disease Psoriatic Psoriasis in a JIA Poly RF- first degree 5 or more relative Enthesitis Poly RF+ related 5 or more  JIA epidemiology Most common rheumatic disease in childhood; Incidence in Europe 2-20/100 000, North America 16-150/100 000 ; EPOCA study: > 9000 children from 49 countries, 5 continents : Age at onset younger in South Europe; Lower economy associated with higher disease activity and joint damage; correlation with time when patient is refered to the pediatric rheumatologist. 1. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369:767–778. doi: 10.1016/S0140-6736(07)60363-8. 2. Consolaro, A., Giancane, G., Alongi, A., van Dijkhuizen, E. H. P., Aggarwal, A., Al-Mayouf, S. M., … Flato, B. (2019). Phenotypic variability and disparities in treatment and outcomes of childhood arthritis throughout the world: an observational cohort study. The Lancet Child & Adolescent Health. doi:10.1016/s2352-4642(19)30027-6 Consolaro A, et al. A multinational study of the epidemiology, treatment and outcome of childhood arthritis (epoca study): preliminary data from 6,940 patients. Pediatr Rheumatol Online J. 2014;12(Suppl 1):O8. Published 2014 Sep 17. doi:10.1186/1546-0096-12-S1-O8  Genetics Multiple factors are involved 13% of cases of JIA can be attributed to familial factors1 Closest relation is between HLA-B27 and the enthesitis-related arthritis (ERA) (or ankylosing spondylitis in adults) Other known relations: Polyarthritis with HLA-DR4 Systhemic form IL10-1082A and IL20-468T Also some associations with HLA-DR5 and HLA-DR8 1Prahalad S, et al. Quantification of the familial contribution to juvenile idiopathic arthritis. Arthritis Rheum 2010;62:2525–9 Ethiopathogenesis Disturbance in cellular and humoral immune responce Trigger disease: infection, drugs, trauma Pro-inflammatory Synovial Cartlige T lymph cytokines: TNFα, proliferation IL-1, IL-6 destruction Autoantibodies Ab react Immune B lymph production (eg. with own complex activation ANA) antigens formation Accumulation in tissues and destruction Oligoarthritis Symptoms Asymmetric arthritis, affected up to 4 joints, at the beginning larger joints, sometimes monoarthritis Frequency 1 type 2 type 25% 15-20% Age at onset (average) in years 2 10 Gender distribution F>M F8 Gender distribution F>M F>M Rheumatoid factor (RF) (-) (+) Antinuclear antibodies (ANA) 25% 75% Outcome Good, in 10% develops Reminds adult bone erosion, especialy rheumatoide arthritis, hip and 50% cases – destructive temporomandibuliar arthritis joint LIETUVOS SVEIKATOS MOKSLŲ UNIVERSITETAS | SKYRIAUS TEMA 23 Systemic JIA Symptoms Systemic manifestation (fever, rashes, visceral involvement, serositis, myalgia, blood changes) + later arthritis Frequency 20% Age at onset (average) 5 yrs Gender distribution F=M Rheumatoid factor (RF) (-) Antinuclear antibodies (-) (ANA) Outcome Systemic signs disappear, arthritis (usually symmetric or polyarthritis) progresses to chronic form, in 25% cases severe destructive arthritis Organ damage indicators Urine test Biochemical studies (creatinine, urea, liver enzymes, feritin) Blood culture ECG Ultrasound (serositis, hepatis, spleen) X-ray (chest, bones, joints) CT, MRI Genetic: link with HLA DR25, DR4, DR8, A2, B39, B27 LIETUVOS SVEIKATOS MOKSLŲ UNIVERSITETAS | SKYRIAUS TEMA 27 Differential diagnosis of systemic JIA Infections (sepsis, viral infections, typhus) Malignant disease (leukemia, limfoma, neuroblastoma) Rheumatic fever Systemic connective tissue disease (systemic lupus erythematosus, Kawasaki syndrome, polyartheriitis) Inflammatory bowel disease Autoinflammatory disorders (FMF, hyper-IgD syndrome, CAPS, TRAPS, PFAPA) Important NOTES: There is no one pathognomonic finding for JIA in children ANA are found only in 50% (considering all types of arthritis) Synovial biopsy does not reveal anything specific (only inflammation) X-ray changes in the beginning of the disease can not be found Diagnosis relies only on clinical criteria JIA is an exclusion diagnosis JIA treatment Cytostatic, BM transplantation Step-up approach Biological therapy Depends from JIA form DMARDs Any time can be added GCC NSAIDs and/or intraarticular injections JIA treatment Not systemic JIA Systemic JIA  Complications if JIA not treated Erosions Uveitis Chronic pain Anaemia Destruction Osteoporosis Glaucoma Movement Amyloidosis Jaw injury restrictions Contractures Cataract Delayed Muscle atrophy Worsened maturation Muscle weakness quality of life Impaired growth (low stature, Social distance different leg length) Systemic lupus erythematosus (SLE) Morbidity 1:2000 (adult and children) M:F 1:4 (up to 10y, 1:9 after 10y) 15-20% became ill till 18y age Disease peculiarities in children (juvenile SLE): High disease activity at onset Aggressive clinical course Systematization (rarely - isolated plaque form) Require aggressive treatment  SLE diagnostic criteria SLICC (Systemic Lupus International Collaborating Clinics) – diagnostic criteria To diagnose SLE: 4 possitive criteria from 17, at least 1 clinical and 1 immunological OR histologialy proven lupus nephritis. Clinical SLE criteria Acute cutaneous lupus Subacute cutaneous or discoid lupus Non-scaring alopecia Oral ulcers Joint involvement Serositis Renal injury Neuropsychiatric disorders Hemolytic anaemia Leukopenia or lymphopenia Thrombocytopenia Immunological SLE criteria ANA Anti-dsDNR Anti-Sm Antiphospholipid antibodies Low complement levels (C3 and/or C4) Positive direct Coombs reaction 2019 ACR/EULAR SLE clasification criteria „Butterfly“ rash SLE treatment Sunscreen SPF50 Steroids Synthetic disease modifying antirheumatic drugs (DMARDs): hydroxichloroquine, azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, cyclosporine Biological DMARDs – Rituximab Intravenous immunoglobulin (IVIG) Symptomatic treatment: NSAIDs, ACEi, antiepileptics, antidepressants, antipsichotics, calcium and vitamin D.  Juvenile dermatomyositis It is a primary autoimmune disease affecting proximal striated muscule with skin involvement It is the most common inflammatory myopathy of childhood Epidemiology 1.6-4 : 1 000 000 per year1 F:M 1.4-5 : 1 Onset most common between 5 and 10y, younger age related with worse prognosis Mortality about 3.1%, high rate of disability 6.5%2 1 Meyer A et al. Incidence and prevalence of inflammatory myopathies: a systematic review. Rheumatology (Oxford). 2015 Jan;54(1):50-63. 2 Martin, Neil et al. “Juvenile dermatomyositis: new insights and new treatment strategies.” Therapeutic advances in musculoskeletal disease vol. 4,1 (2012): 41-50. doi:10.1177/1759720X11424460  Diagnostic criteria for inflammatory muscle disease by Bohan A., Peter J.B. in 1975 (1) 1. Symmetrical, progressive muscule weakness 2. Characteristic triad of myositis electromyogram a) Short-term, small, low-amplitude polyphasic motor unit potentials b) Fibrillation potentials, even during sleep/rest c) Reccuring disorted high-frequency discharges 3. Enzyme elevation in blood serum: a) Creatine kinase (CK) b) Aldolase c) Lactate dehydrogenase (LDH) d) Transaminases (ALT/SGPT and AST/SGOT) Bohan A and Peter JB, N Engl J Med. 292:344-7, 1975  Diagnostic criteria for inflammatory muscle disease by Bohan A., Peter J.B. in 1975 (2) 4. Chronic inflammation of muscle in biopsy: a) Necrosis of muscle fibres types I and II b) Muscle cell degeneration and regeneration, different contents of fibre size with perifascicular atrophy 5. Rashes typical to dermatomyositis: a) Flaky, scaly rash over metacarpal, proximal interphalangeal joints (Gottron‘s papules) b) periorbital violaceous (heliotropic) erythema c) Flaky, scaly rash in face, neck, extensor surface of extremity particularly in the hands Bohan A and Peter JB, N Engl J Med. 292:344-7, 1975  Skin changes in JDM Schmieder, A., Komorowski, G. V, Peitsch, W. K, Goerdt, S., & Goebeler, M. (2009). Juvenile dermatomyositis in an 8-year-old boy. Dermatology Online Journal, 15(6). Retrieved from https://escholarship.org/uc/item/2w9993p3 Frequency of symptoms Rash 100 Weakness 100 Myalgia 73 Fever 65 Dysphagia 44 Nasal voice 43 Abdominal pain 37 Arthritis 35 Calcification 23 Frequency in % Scleroderma Most frequently – localized, divided : Morphea (appearance of circle and scatter may occur anywhere on the body) Linear (subcutaneous fascia fibrotic lesions affecting the lengh of extremities, can also affect joint) „En coup de sabre” (profound, deforming lesions of skin and deeper tissue in the face. If accompanied by one side face atrophy - Parry-Romberg syndrome) No systemic changes Autoantibodies and fibrosis of skin Lilac ring –circle indurated plaque En coup de sabre – sword strike Scatter depigmentations with central hypopigmentation, peripheral edema and halo zone Stages: Redness Swelling Induration Atrophy „Coup de sabre” Vasculitis An inflammation of the vessel wall causing internal organ damage: primary, secondary, associated with infection, drugs, connective tissue diseases, oncology. Incidence 12-53 per 100 000 children. Vasculitis clasification IgA vasculitis (Henoch-Schönlein) Henoch Schönlein purpura most often diagnosed in children (about 1,5 cases in 1000 school-age children) In 50% cases occur after respiratory tract infection Pathogenesis – IgA deposition in blood vessels IgA vasculitis clinical features Palpable purpura Arthritis Abdominal pain, bleeding from the gastrointestinal tract Nephritis Kawasaki disease First described in 1967 by pediatrician Tomisaku Fever + 4 out of 5 criteria Kawasaki Usually until 5y of age It is threatening disease with vascular aneurysm formation, especially in coronary arteries! CT of the coronary arteries Treatment of Kawasaki disease Immunoglobulin i/v 2 g/kg 1x Aspirin 80-100 mg/kg/d If necessary repeat i/v immunoglobulin 1 g/kg Trombolytics (heparin, fraxiparin) – during formation of aneurysm  Polyarteritis nodosa At least 3 of the 10 ACR criteria should be present when a radiographic or pathological diagnosis of vasculitis is made. Treatment: puls therapy i/v methylprednisolone Rheumatic fever It is a secondary disease caused by β hemolytic streptococcus Most often affects children at 5-18y of age Genetic predisposition (HLA DR4 ,HLA2 DR) Epidemiology Pathogenesis Streptococcal antigens cross-reacts with human tissue: Heart Skin Brain Smooth and striated muscle Clinical manifestations Revision of the Jones Criteria for the Diagnosis of Acute Rheumatic Fever in the Era of Doppler Echocardiography: A Scientific Statement From the American Heart Association. Circulation 2015;Apr 23 Szczygielska I, Hernik E, Kołodziejczyk B, Gazda A, Maślińska M, Gietka P. Rheumatic fever - new diagnostic criteria. Reumatologia. 2018;56(1):37-41. doi:10.5114/reum.2018.74748c Treatment of rheumatic fever attack Penicillin – 14 days Aspirin, NSAID’s Treatment of chorea: Haloperidol 0,5- 1mg/kg/day, up to 5mg/kg/day Valproatine acid 15-20mg/kg/d Carbamasepin phenobarbital 5-7mg/kg/day Treatment of carditis: Aspirin 80 -100 mg/kg Corticosteroids 1mg/kg Duration of treatment: up to 8-12 weeks  Important!!! The risk of chronic rheumatic heart disease is 1.6–2 times higher in female patients2 Younger paitients have higher risk for relapses1 AHA recommends that all the patients with suspected RF undergo Doppler echocardiographic examination after the Jones criteria have been verified, even if no clinical signs of carditis are present3 If echocardiography is doubtfull – repeat in the following weeks1 The diagnosis of subsequent episodes of the disease requires a confirmation of two major criteria or one major and two minor criteria or three minor criteria3 1. Szczygielska I et all. Rheumatic fever - new diagnostic criteria. Reumatologia. 2018;56(1):37-41. doi:10.5114/reum.2018.74748 Poland 2. Zühlke Lj et all. Group A Streptococcus, Acute Rheumatic Fever and Rheumatic Heart Disease: Epidemiology and Clinical Considerations. Curr Treat Options Cardiovasc Med. 2017 Feb;19(2):15. doi: 10.1007/s11936-017-0513-y. PMID: 28285457; PMCID: PMC5346434. South Africa 3. Gewitz M, Baltimore R, Tani L, et al. Revision of the Jones Criteria for the Diagnosis of Acute Rheumatic Fever in the Era of Doppler Echocardiography: A Scientific Statement From the American Heart Association. Circulation 2015; 131: 1806- 1818 If you have any questions or would like to discuss some pediatric rheumatology topics e-mail: [email protected] or [email protected] 2023-10-02 71