Outcome measures and classification criteria for the rheumatic diseases. A compilation of data from OMERACT (Outcome Measures for Arthritis Clinical Trials), ILAR (International League of Associations for Rheumatology), regional leagues and other groups

The International League of Associations for Rheumatology (ILAR) has been meeting with the World Health Organization (WHO) on a regular basis to discuss issues of mutual interest. Over the last few years these meetings have focused on the development of outcome measures in the rheumatic diseases, principally driven through OMERACT (Outcome Measures for Arthritis Clinical Trials). OMERACT has now held five meetings addressing a number of important areas in rheumatology, including clinical and imaging outcome measures, health economics and drug safety. The advantage of the WHO/ILAR Task Force Meeting has been to ratify these measures and allow them to be promulgated widely around the world. This paper summarizes discussions which took place at the Sixth Joint WHO/ILAR Task Force Meeting on Rheumatic Diseases which was held in Geneva on 16 January 2000. This meeting reviewed a number of outcome measures for rheumatic diseases that had been developed over the past few years under the aegis of OMERACT. The WHO/ILAR meeting formally endorsed these outcome measures and acknowledged them as the gold standard for outcome measures in these conditions. At the same meeting, a series of criteria for the classification of rheumatic diseases was also reviewed. These criteria have also been established through discussion by a number of different organizations, including ILAR, the American College of Rheumatology and EULAR (the European League of Associations for Rheumatology). These classification criteria have been put together by experts and have been adopted widely throughout the world. The meeting recommended that WHO/ILAR adopt these well‐recognized classification criteria and encourage their use in clinical and epidemiological studies. It should be noted that classification criteria should not be used as diagnostic criteria but for the purposes of classifying patients in studies. An understanding of this concept will help in the interpretation of many clinical studies. The outcome measures for rheumatoid arthritis clinical trials were developed at OMERACT 1 [1] and are very similar to those developed by the ACR [2]. The recommendations for the preliminary core set were: acute‐phase reactants disability joint pain/tenderness joint swelling pain patient global assessment physician global assessment radiographs for studies of 1 yr or longer. These outcome measures for future phase III clinical studies in hip, knee and hand osteoarthritis were developed at OMERACT 3 and were published in the Journal of Rheumatology [3]. The core set of outcome measures in osteoarthritis should be: pain physical function patient global assessment joint imaging (using standardized methods for taking and rating radiographs, or any demonstrably superior imaging technique) for studies of 1 yr or longer. Quality of life and/or utility measures are also strongly recommended, but further work should be carried out to assess the usefulness of biological markers, stiffness, measures of inflammation and other assessments such as performance‐based measures, time to surgery, flares or analgesic consumption before they are accepted as core measures. This core set of endpoints in ankylosing spondylitis clinical trials was developed at OMERACT 4 and published in the Journal of Rheumatology [4]. Defined core sets have been developed for use in four settings: disease‐controlling anti‐rheumatic therapy (DC‐ART), symptom‐modifying anti‐rheumatic drugs (SM‐ARD) and physical therapy, and for clinical record keeping. These are as follows: SM‐ARD and physical therapy physical function spinal stiffness patient global assessment spinal mobility and pain Clinical record keeping add acute‐phase reactants and peripheral joints/ entheses DC‐ART add fatigue hip radiograph spine radiograph. A core set of outcome measures and response criteria were developed during OMERACT 4 and published in the Journal of Rheumatology [5, 6]. The core outcome domains to be measured in both randomized clinical trials and longitudinal observation studies in systemic lupus erythematosus are: disease activity health‐related quality of life damage toxicity/adverse events. The core endpoints for osteoporosis trials were discussed at OMERACT 3 and subsequently published in the Journal of Rheumatology [7]. The outcome measures for osteoporosis trials were discussed according to two broad groupings of trials: randomized trials where prevention of rapid bone loss was the primary aim and randomized trials where prevention of fractures may be a feasible outcome because patients were already at high risk of osteoporotic fractures either on the basis of low bone mass or previous osteoporotic fracture. Two core outcome measures of clinical benefit were considered appropriate: (a) bone minimum density (measured at two sites: the lumbar spine and proximal femur); (b) biochemical markers which should include at least one resorption marker (which should be based on a urinary cross‐linked excretion) and at least one formation marker. Non‐core outcome measures of clinical benefit were considered to be: (a) fractures; (b) quality of life; (c) change in height (measured in a standardized manner). The core outcome measures of benefit were: (a) fracture; (b) hip and spine bone mineral density; (c) biochemical markers; (d) change in height. The non‐core outcome measures of benefit in these studies would include: (a) quality of life instrument; (b) back pain measure; (c) economic evaluation, including health service utilization such as hospitalization, cotherapy, etc.; (d) measure of incident falls. It was recommended that these studies should be of 3–5 yr duration. Low back pain and stiffness for more than 3 months not relieved by rest; Pain and stiffness of the thoracic region; Limited motion in lumbar spine; Limited chest expansion; Evidence or history of iritis or its sequelae. Requirements: either positive radiographs (bilateral SI) and one or more clinical criteria, or four out of five clinical criteria. (1) Presence of history of pain at dorsolumbar junction or in lumbar spine; (2) Limitation of motion in anterior flexion, lateral flexion and extension; (3) Limitation of chest expansion to 1 inch (2.5 cm) or less at the fourth intercostal space. Requirements: either positive radiographs (grade 3–4 bilateral sacroiliac) and one or more clinical criteria, or grade 3–4 unilateral or grade 2 bilateral SI with clinical criterion (2) or with clinical criteria (1) and (3). Inflammatory spinal pain or synovitis asymmetric predominantly in the lower limbs and one or more of the following: alternate buttock pain; sacroiliitis; enthesopathy; positive family history; psoriasis; inflammatory bowel disease; urethritis or cervicitis or acute diarrhoea occurring within 1 month before arthritis. Level 1, SM‐ARD/physical therapy: physical function; pain; spinal mobility; spinal stiffness; patient global assessment. Level 2, Clinical record keeping: acute‐phase reactants; peripheral joints/entheses. Level 3, DC‐ART: spine radiograph; hip radiograph; fatigue. Findings applicable only in the absence of other clinical explanations. aHistory of allergy, other than asthma or drug‐related, is included only in the tree classification criteria set and not in the traditional format criteria set, which requires four or more of the six other items listed here. aHistory of allergy, other than asthma or drug‐related, is included only in the tree classification criteria set and not in the traditional format criteria set, which requires four or more of the six other items listed here. History of widespread pain Definition: Pain is considered widespread when all of the following are present: pain in the left side of the body, pain in the right side of the body, pain above the waist, and pain below the waist. In addition, axial skeletal pain (cervical spine or anterior chest or thoracic spine or low back) must be present. In this definition, shoulder and buttock pain is considered as pain for each involved. ‘Low back’ pain is considered lower segment pain. Definition: Pain, on digital palpation, must be present in at least 11 of the following 18 tender point sites: occiput—bilateral, at the suboccipital muscle insertions; low cervical—bilateral, at the anterior aspects of the intertransverse spaces at C5–C7; trapezius—bilateral, at the midpoint of the upper border; supraspinatus—bilateral, at origins, above the scapula spine near the medial border; second rib—bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces; lateral epicondyle—bilateral, 2 cm distal to the epicondyles; gluteal—bilateral, in upper outer quadrants of buttocks in anterior fold of muscle; knee—bilateral, at the medial fat pad proximal to the joint line. Digital palpation should be performed with an approximate force of 4 kg. For a tender point to be considered ‘positive’ the subject must state that the palpation was painful. ‘Tender’ is not to be considered ‘painful’. For classification purposes, patients will be said to have fibromyalgia if both criteria are satisfied. Widespread pain must have been present for at least 3 months. The presence of a second clinical disorder does not exclude the diagnosis of fibromyalgia. For the purposes of classification, a patient shall be said to have giant cell (temporal) arteritis if at least three of these five criteria are present. The presence of any three or more criteria yields a sensitivity of 93.5% and a specificity of 91.2%. aUsed as a surrogate if artery biopsy is not available [criterion (2)] or if temporal artery abnormality is not present [criterion (5)]. aUsed as a surrogate if artery biopsy is not available [criterion (2)] or if temporal artery abnormality is not present [criterion (5)]. (a) The presence of characteristic urate crystals in the joint fluid, and/or (b) a tophus proved to contain urate crystals by chemical or polarized light microscopic means, and/or (c) the presence of six of the 12 clinical, laboratory, and X‐ray phenomena listed below: maximum inflammation in 1 day; more than one attack; monoarticular arthritis; redness; first metatarsophalangeal joint (MTP) pain or swelling; unilateral first MTP; unilateral tarsal; suspected tophus; hyperuricaemia; asymmetric swelling; subcortical cysts, no erosions; negative organisms on culture. For the purposes of classification, a patient shall be said to have Henoch–Schönlein purpura if at least two of these four criteria are present. The presence of any two or more criteria yields a sensitivity of 87.1% and a specificity of 87.7%. For the purposes of classification, a patient shall be said to have hypersensitivity vasculitis if at least three of these five criteria are present. The presence of any three or more criteria yields a sensitivity of 71.0% and a specificity of 83.9%. Fever lasting from 1 to 2 weeks and not responding to antibiotics Bilateral congestion of ocular conjunctivae Changes in lips and oral cavity: dryness, redness and fissuring of lips; protuberance of tongue papillae (strawberry tongue); diffuse reddening of oral and pharyngeal mucosa. Changes in peripheral extremities: reddening of palms and soles (initial stage); indurative oedema (initial stage); membranous desquamation from fingertips (convalescent stage). Polymorphous exanthema of body trunk without vesicles or crusts Acute non‐purulent swelling of cervical lymph nodes of 1.5 cm or more in diameter Carditis, especially myocarditis and pericarditis Diarrhoea Arthralgia or arthritis Proteinuria and increase of leucocytes in urine sediment Changes in blood tests: leucocytosis with shift to the left; slight decrease in erythrocyte and haemoglobin levels; increased erythrocyte sedimentation rate; positive C‐reactive protein; increased α2‐globulin; negative anti streptolysin‐O titre Changes occasionally observed: aseptic meningitis; mild jaundice or slight increase in serum transaminase Hand pain, aching, or stiffness and three or four of the following features: hard tissue enlargement of two or more of 10 selected joints; hard tissue enlargement of two or more distal interphalangeal joints; fewer than three swollen metacarpophalangeal (MCP) joints; deformity of at least one of 10 selected joints. The 10 selected joints are the second and third distal interphalangeal, the second and third proximal interphalangeal (PIP), and the first carpometacarpal joints of both hands. This classification method yields a sensitivity of 94% and a specificity of 87%. Hip pain and at least two of the following three features: erythrocyte sedimentation rate < 20 mm/h; radiographic femoral or acetabular osteophytes; radiographic joint space narrowing (superior, axial, and/or medial). This classification method yields a sensitivity of 89% and a specificity of 91%. Hip pain and Femoral and/or acetabular osteophytes on radiograph or Erythrocyte sedimentation rate ≤ 20 mm/h and Axial joint space narrowing on radiograph This classification method yields a sensitivity of 91% and a specificity of 89%. ESR, erythrocyte sedimentation rate (Westergren); RF, rheumatoid factor; SF OA, synovial fluid signs of osteoarthritis (clear, viscous, or white blood cell count<2000/mm3). aAn alternative for the clinical category would be four of six, which is 85% sensitive and 89% specific. ESR, erythrocyte sedimentation rate (Westergren); RF, rheumatoid factor; SF OA, synovial fluid signs of osteoarthritis (clear, viscous, or white blood cell count<2000/mm3). aAn alternative for the clinical category would be four of six, which is 85% sensitive and 89% specific. BUN, blood urea nitrogen; PMN, polymorphonuclear neutrophils. BUN, blood urea nitrogen; PMN, polymorphonuclear neutrophils. For classification purposes, a patient shall be said to have polyarteritis nodosa if at least three of these 10 criteria are present. The presence of any three or more criteria yields a sensitivity of 82.2% and a specificity of 86.6%. Shoulder pain and/or stiffness bilaterally Onset of illness of <2 weeks’ duration (refers to time taken for symptoms to reach their full‐blown picture) Initial erythrocyte sedimentation rate ≥40 mm/h Morning stiffness duration >1 h Age >65 yr Depression and/or loss of weight Upper arm tenderness bilaterally (1) Skin lesions: (a) heliotrope rash (red purple erythema on the upper palpebra); (b) Gottron's sign (red purple keratotic, atrophic erythema, or macules on the extensor surface of finger joints); (c) erythema on the extensor surface of extremity joints: slightly raised red purple erythema over elbows or knees. (2) Proximal muscle weakness (upper or lower extremity and trunk). (3) Elevated serum creatine kinase or aldolase level. (4) Muscle pain on grasping or spontaneous pain. (5) Myogenic changes on EMG (short duration, polyphasic motor unit potentials with spontaneous fibrillation potentials). (6) Positive anti‐Jo‐1 (histadyl tRNA synthetase) antibody. (7) Non‐destructive arthritis or arthralgias. (8) Systemic inflammatory signs (fever: more than 37°C at axilla, elevated serum C‐reactive protein level or accelerated erythrocyte sedimentation rate of more than 20 mm/h by the Westergren method). (9) Pathological findings compatible with inflammatory myositis (inflammatory infiltration of skeletal muscle with degeneration or necrosis of muscle fibres; active phagocytosis, central nuclei, or evidence of active regeneration may be seen). A patient is said to have dermatomyositis if at least one item from (1) and at least four items from (2) to (9) are present. The sensitivity is 94.1% (127/135), and the specificity of skin lesions against systemic lupus erythematosus and systemic sclerosis is 90.3% (214/237). A patient is said to have polymyositis if at least four items from (2) to (9) are present. The sensitivity is 98.9% (180/182) and the specificity of polymyositis and dermatomyositis against all control diseases combined is 95.2% (373/392). The numbers in parentheses indicate the number of patients correctly classified/the number tested. The numbers in parentheses indicate the number of patients correctly classified/the number tested. Major manifestations Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules Clinical findings: arthralgia; fever. Laboratory findings: elevated acute‐phase reactants erythrocyte sedimentation rate C‐reactive protein prolonged PR interval Supporting evidence of antecedent group A streptococcal infections Positive throat culture or rapid streptococcal antigen test Elevated or rising streptococcal antibody titre If supported by evidence of preceding group A streptococcal infection, the presence of two major manifestations or of one major and two minor manifestations indicates a high probability of acute rheumatic fever. For classification purposes, a patient shall be said to have rheumatoid arthritis if he/she has satisfied at least four of these seven criteria. Criteria (1)–(4) must have been present for at least 6 weeks. Patients with two clinical diagnoses are not excluded. Designation as classic, definite, or probable rheumatoid arthritis is not to be made. Ocular symptoms Definition: a positive response to at least one of the following three questions: (a) Have you had daily, persistent, troublesome dry eyes for more than 3 months? (b) Do you have a recurrent sensation of sand or gravel in the eyes? (c) Do you use tear substitutes more than three times a day? Oral symptoms Definition: a positive response to at least one of the following three questions: (a) Have you had a daily feeling of dry mouth for more than 3 months? (b) Have you had recurrent or persistently swollen salivary glands as an adult? (c) Do you frequently drink liquids to aid in swallowing dry foods? Ocular signs Definition: objective evidence of ocular involvement, determined on the basis of a positive result on at least one of the following two tests: (a) Schirmer‐1 test (≤5 mm in 5 min); (b) Rose Bengal score (≥4, according to the van Bijsterveld scoring system). Histopathological features Definition: focus score ≥1 on minor salivary gland biopsy (focus defined as an agglomeration of at least 50 mononuclear cells; focus score defined as the number of foci in 4 mm2 of glandular tissue). Salivary gland involvement Definition: objective evidence of salivary gland involvement, determined on the basis of a positive result on at least one of the following three tests: (a) Salivary scintigraphy; (b) Parotid sialography; (c) Unstimulated salivary flow (≤1.5 ml in 15 min). Autoantibodies Definition: presence of at least one of the following serum autoantibodies: (a) Antibodies to Ro/SS‐A or La/SS‐B antigens; (b) Antinuclear antibodies; (c) Rheumatoid factor. Exclusion criteria: pre‐existing lymphoma, acquired immunodeficiency syndrome, or Inflammatory spinal pain or synovitis asymmetric or predominantly in the lower limbs and one or more of the following: positive family history; psoriasis; inflammatory bowel disease; or acute diarrhoea within 1 month before arthritis; buttock pain right and left enthesopathy; The classification is based on 11 criteria. For the of patients in clinical a shall be said to have systemic lupus erythematosus if any four or more of the 11 criteria are or during any interval of Proximal is the major sensitivity was 91% and specificity was over digital of fingertips or loss of of the distal finger and further as minor criteria in the absence of proximal major or two or more minor criteria were in of systemic sclerosis but only in of the patients with systemic lupus or For the purposes of classification, a patient shall be said to have arteritis if at least three of these six criteria are present. The presence of any three or more criteria yields a sensitivity of and a specificity of For the purposes of classification, a patient shall be said to have if at least two of these four criteria are present. The presence of any two or more criteria yields a sensitivity of and a specificity of aUsed as a surrogate if biopsy are not aUsed as a surrogate if biopsy are not A for the development of classification criteria for in had been by a of and published in the Journal of Rheumatology in These classification criteria were at a meeting in in and published in the Journal of Rheumatology in Systemic Polyarthritis Polyarthritis arthritis arthritis no other category more than one category