Rheumatoid Arthritis
Current Care Guideline in Finnish «Nivelreuma»1
Please note that the guideline in Finnish, Nivelreuma «Nivelreuma»1, has been partially updated on Feb 18th, 2022. Therefore this English version is not currently up to date.
Summary
- A patient suspected of having rheumatoid arthritis (RA) should be referred without delay to a multi-disciplinary rheumatology clinic for confirmation of the diagnosis and treatment start.
- If left untreated or if treated with inferior drugs, patients with RA will experience disease progression and the RA will become a crippling disease. Effective treatment, on the other hand, can prevent disease progression for most patients.
- The goal of treatment of early RA is prompt and sustained disease remission, which allows the patient to recover and maintain his or her functional capacity and working ability.
- Treatment of active RA is started with combination pharmacotherapy: methotrexate, sulfasalazine, hydroxychloroquine and a low dose of glucocorticosteroid (usually prednisolone 5.0–7.5mg or an equivalent glucocorticosteroid in the morning for at least 6 months), if there are no contraindications. The efficacy of monotherapy is poorer than of combination therapy.
- Methotrexate is the anchor drug, onto which other antirheumatic drugs are added. If methotrexate is contraindicated, leflunomide or azathioprine may be used.
- A glucocorticosteroid should be injected intra-articularly into inflamed joints.
- If active RA does not respond to combination treatment, the disease should be treated with biologics.
- Since RA is associated with an increased risk of bone fractures, prevention of osteoporosis is important.
- The patient's risk for cardiovascular disease should be assessed as a part of overall disease assessment.
- Patient education aims to ensure the compliance of the patient with long-term treatment.
- Patients are encouraged to exercise and to maintain their muscle strength.
- The multi-disciplinary team at the rheumatology clinic follows the patient's condition and disease activity, and when the RA has been in stable remission for a given period of time, e.g., two years, it is recommended that the patient visits annually a physician with a good understanding of rheumatology. ̣
Goals
- The aim of these guidelines is to improve and harmonise the diagnosis and management of RA to ensure that the quality of life, the working capacity and the functional capacity of patients with RA are maintained.
Target groups
- These guidelines are targeted at health care professionals at all levels (e.g., general practice, occupational health service and specialised care), who care for patients with inflammatory rheumatic diseases.
Epidemiology
Incidence and prevalence
- The incidence and prevalence of RA depend on how RA is defined.
- RA begins as an immunological disturbance, and circulating biomarkers, e.g., rheumatoid factor (RF), anti-citrullinated peptides and other inflammatory mediators, are present in the serum of patients many years before the clinical onset of RA (pre-clinical RA) «Deane KD. Preclinical rheumatoid arthritis (autoan...»1. A high RF-titre (>100 IU/ml) raises the risk of RA 26-fold compared to the general population «Nielsen SF, Bojesen SE, Schnohr P ym. Elevated rhe...»2. 37% of female smokers with a high RF titre will develop RA within 10 years «Nielsen SF, Bojesen SE, Schnohr P ym. Elevated rhe...»2.
- Early clinical symptoms are non-specific. The annual incidence of early inflammatory arthritis (EIA) ranges from 115 to 271 cases per 100,000 adults «Hazes JM, Luime JJ. The epidemiology of early infl...»3.
- Most patients with undifferentiated arthritis do not have RA and their condition may resolve without treatment, but persisting arthritis must be followed-up and treated. Antirheumatic treatment may prevent the development of frank RA «Wevers-de Boer KV, Heimans L, Huizinga TW ym. Drug...»4.
- Patients with arthritis who have a high risk of developing RA should be identified and treated promptly. For risk assessment, the ACR-EULAR 2010 classification criteria may be helpful (interactive table in Finnish «http://www.terveysportti.fi/xmedia/hoi/hoi21010/Nivelreuman_luokittelukriteerit.html»1), «Rantalaiho, Pirilä, Kautiainen Puolakka. Miten tuo...»5, «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6, «Aletaha D, Neogi T, Silman AJ ym. 2010 Rheumatoid ...»7.
- The annual incidence of RA in Europe and North America per 100,000 adults is 48–68 among females and 20–32 among males, depending on the criteria used «Rossini M, Rossi E, Bernardi D ym. Prevalence and ...»8, «Humphreys JH, Verstappen SM, Hyrich KL ym. The inc...»9, «Englund M, Jöud A, Geborek P ym. Prevalence and in...»10. These figures are comparable to the ones in Finland, where the overall annual incidence is 45:100,000 (59 among females and 30 among males) «Puolakka K, Kautiainen H, Pohjolainen T ym. Rheuma...»11. Two-thirds of the patients who fall ill with RA in Finland are younger than 65 years «Puolakka K, Kautiainen H, Pohjolainen T ym. Rheuma...»11.
- The prevalence of RA is 0.20–0.9% «Rossini M, Rossi E, Bernardi D ym. Prevalence and ...»8, «Englund M, Jöud A, Geborek P ym. Prevalence and in...»10, «Aho K, Kaipiainen-Seppänen O, Heliövaara M ym. Epi...»12, «Pedersen JK, Svendsen AJ, Hørslev-Petersen K. Prev...»13, «Neovius M, Simard JF, Askling J ym. Nationwide pre...»14, «Biver E, Beague V, Verloop D ym. Low and stable pr...»15, «Widdifield J, Paterson JM, Bernatsky S ym. The ris...»16, «Gabriel SE, Michaud K. Epidemiological studies in ...»17. The variation of these figures is due to variations in the criteria used to define RA as well as to differences in geographical region and timing of the studies.
- The global prevalence has been estimated to be 0.24%, and it has remained unchanged from 1990 to 2010. Population growth and an increase in the average age of patients translate into a higher burden of RA «Cross M, Smith E, Hoy D ym. The global burden of r...»18.
- The prevalence of RA is 2–3 times higher for females than males. The female risk is particularly high after delivery of the first child: it is 2.3-fold up to 2 years post partum compared to third to fourth years post partum «Wallenius M, Skomsvoll JF, Irgens LM ym. Postpartu...»19.
Aetiology
- Both genetic and environmental factors affect the development of RA.
- It is assumed that genetic factors account for approximately 60% of the incidence of RA, the HLA-antigen for 11–37% «Kurkó J, Besenyei T, Laki J ym. Genetics of rheuma...»20. In addition to shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, also alleles HLA-DRB1*13 and DRB1*15 are reportedly associated with the risk of RA. Expression of the HLA-antigen and of non-HLA genes is dissimilar between patients positive and negative for anti-citrullinated peptides (CCP) «Kurkó J, Besenyei T, Laki J ym. Genetics of rheuma...»20.
- The likelihood of both of monozygotic twins to fall ill with RA is 12–15% and of dizygotic twins 3–4% «Aho K, Koskenvuo M, Tuominen J ym. Occurrence of r...»21, «Silman AJ, MacGregor AJ, Thomson W ym. Twin concor...»22. Concordance is 3.7 times higher among SE-positive monozygotic twins than among SE-negative monozygotic twins and 5 times higher among SE-homozygotes than SE-heterozygotes. CCP-positive twins with RA are more often SE-positive than CCP-positive twins with no RA. Thus, genetic factors, especially the SE-status, contribute substantially to the development of RA in CCP-positive individuals «Hensvold AH, Magnusson PK, Joshua V ym. Environmen...»23.
- Genetic susceptibility and environmental factors interact in the aetology of RA. Emergence of citrullinated proteins in SE-positive individuals is promoted by substances in tobacco smoke, increasing the risk of CCP-positive RA «Klareskog L, Stolt P, Lundberg K ym. A new model f...»24, «Padyukov L, Silva C, Stolt P ym. A gene-environmen...»25, «Huizinga TW, Amos CI, van der Helm-van Mil AH ym. ...»26. Thus far, tobacco smoking is the only known modifiable risk factor for RA.
Mortality
- Compared to the general population, life expectancy of patients with RA is reduced «Myllykangas-Luosujärvi R. Mortality and causes of ...»27, «Sihvonen S, Korpela M, Laippala P ym. Death rates ...»28, «Dadoun S, Zeboulon-Ktorza N, Combescure C ym. Mort...»29, «Ogdie A, Haynes K, Troxel AB ym. Risk of mortality...»30. Mortality is associated with the markers of disease severity, the presence of RF and the anti-CCP titre «Kuller LH, Mackey RH, Walitt BT ym. Determinants o...»31, «Listing J, Kekow J, Manger B ym. Mortality in rheu...»32. Early effective treatment, and the use of methotrexate and biologics are associated with lower mortality «Listing J, Kekow J, Manger B ym. Mortality in rheu...»32, «Wasko MC, Dasgupta A, Hubert H ym. Propensity-adju...»33, «van Tuyl LH, Boers M, Lems WF ym. Survival, comorb...»34, «Nakajima A, Saito K, Kojima T ym. No increased mor...»35. There are no differences between the different biologcs in this respect «Simard JF, Neovius M, Askling J ym. Mortality rate...»36.
- More than half of the premature deaths of patients with RA are due to cardiovascular disease «Myllykangas-Luosujärvi R. Mortality and causes of ...»27, «Sihvonen S, Korpela M, Laippala P ym. Death rates ...»28, «Humphreys JH, Warner A, Chipping J ym. Mortality t...»37. Risk calculators for the general population underestimate the cardiovascular risk of patients with RA «Kuller LH, Mackey RH, Walitt BT ym. Determinants o...»31, «Masuda H, Miyazaki T, Shimada K ym. Disease durati...»38.
- The overall mortality of patients diagnosed with RA in Finland since the year 2000 was not increased according to statistics extending, however, only to the year 2008 «Puolakka K, Kautiainen H, Pohjolainen T ym. No inc...»39. Nor was the cardiovascular mortality higher than for the general population «Kerola AM, Nieminen TVM, Virta LJ, Kautiainen H, K...»40.
Diagnostic goals
Importance of early diagnosis
- The goal is to establish the diagnosis as early as possible and to promptly start effective pharmacotherapy aiming at early remission.
- Antirheumatic treatment should be started without delay «Nivelreuman lääkehoidon varhainen aloitus parantaa ennustetta, jos lääkehoitona on perinteinen monoterapia. Pidempi oireiden kesto puoltaa yhdistelmälääkityksen käyttöä.»A.
- Early and sustained remission improves the prognosis of patients with RA «Varhainen remissio ennustaa pysyvää remissiota ja työkyvyn säilymistä. Pysyvä remissio ennustaa vähäisempää niveleroosioita, parempaa toimintakykyä ja pidempää eloonjääntiä.»A.
- The initial treatment regime of RA should induce remission preferably within 3 months, but at the latest within 6 months «Nivelreuman hoito on aloitettava lääkityksellä, joka mahdollistaa nopean remission.»A.
Signs and symptoms
- Joint inflammation is the sine qua non for a diagnosis of RA. Usually there is inflammation in several joints.
- The inflamed joint is typically swollen, stiff in the morning and painful on movement, but not necessarily painful at rest.
- Symptoms usually start in the small and medium-sized joints (MCP, PIP, wrists and MTP joints), although any joint may herald the disease.
- In typical cases, joint inflammation is symmetrical.
- Joint symptoms usually develop slowly and progress gradually, often in a relapsing-remitting
pattern. RA may cause inflammation in the cervical spine, but symptoms of the lower
back are not characteristic of RA.
- The more active the joint inflammation is, the longer is the duration of morning stiffness.
- Joint inspection and palpation are important. The inflamed joint is swollen and usually tender on palpation. Clinical examination of the joints requires experience.
- Joint erosions usually develop first in the MTP joints «Eroosiot ilmaantuvat ensin jalkateriin.»A. One of the therapeutic goals is to have the patient on antirheumatic pharmacotherapy before joint erosions and permanent damage develop.
- The erythrocyte sedimentation rate (ESR) and the concentraton of C-reactive protein (CRP) in the serum or plasma reflect disease activity acceptably well, but are not always increased. In long-standing chronic disease, ESR may be permanently high «Sokka T, Pincus T. Erythrocyte sedimentation rate,...»41.
- Approximately two thirds of patients with early RA are RF- or anti-CCP-positive «Möttönen T, Paimela L, Leirisalo-Repo M ym. Only h...»42. These findings are highly suggestive for RA, but are not a requirement for the diagnosis.
- If the patient has no joint inflammation, testing for RF and anti-CCP is usually not indicated.
- Joint inflammation of unknown aetiology requires synovial fluid analysis, if possible. The synovial fluid is analysed for cell count and differential count of white blood cells and crystals. If the joint aspirate is turbid, bacterial staining and culture are in order. In RA, synovial fluid is usually somewhat cloudy due to a high leukocyte count and its viscosity is reduced.
- If the leucocyte count of the synovial fluid is above 2,000 x 106/l, the finding is compatible with inflammation and suggests RA or some other form of arthritis (Table «Synovial fluid analysis: interpretation...»1).
Interpretation | Leucocyte count (x 106/l) |
---|---|
Non-inflammatory | < 2 000 |
Inflammatory | 2 000–60 000 |
Strongly inflammatory | > 60 000 |
Main diagnostic criteria
- There are several international criteria for the classification of RA, and the most recent one has been published by an American/European expert panel (ACR/EULAR2010; interactive table in Finnish «http://www.terveysportti.fi/xmedia/hoi/hoi21010/Nivelreuman_luokittelukriteerit.html»1). The criteria put special emphasis on the presentce of polyarthritis and of RF or anti-CCP present in high titres. Although the criteria are intended for disease classification, they aid clinical decision making.
Diagnostic levels
- A patient suspected of having RA should be referred without delay to a unit specialised in rheumatology where the services of a multidisciplinary team are available to confirm the diagnosis and start treatment.
- The note of referral should include information on the patient's history, signs, symptoms and clinical examination, and the numerical values of the ESR, CRP, RF and anti-CCP.
- Oral glucocorticosteroids may mask symptoms and compromise the diagnosis. Non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular glucocorticosteroid injections may be used to alleviate the sympotoms of the patient «Luosujärvi Riitta. Niveltensisäinen kortisonihoito...»43.
- If RA or some other chronic rheumatic joint diseases are not suspected and the diagnosis is, e.g., gout, reactive arthritis or erosive osteoarthritis, patients can often be treated outside rheumatology units.
- Local health care arrangements may slightly differ from the current recommendations. See tables «Evaluation of patient with arthritis...»2 and «Special features to consider in differential diagnostics....»3.
Clinical picture | Evaluation | |
---|---|---|
A | All patients with arthritis | |
Laboratory tests |
|
|
History (*see point D) |
|
|
B | Monoarthritis (gout, pseudogout, bacterial arthritis, reactive arthritis) |
|
C | Chronic/primarily arthritis primarily of the small joints (rheumatoid arthritis?) |
|
D | Patients who have history positive for (*)-marked items in point A and sudden arthritis in a young individual (infection related arthritis, reactive arthritis) |
|
E | Possible tick bite or erythema migrans, EM (history / current) |
|
Skin eruptions (pox) |
|
|
F | Fever and tonsillitis prior to arthritis (rheumatic fever?) |
|
Heart murmur, migrating polyarthritis, long PQ in ECG, pericarditis (rheumatic fever?) |
|
Diagnosis | Special features |
---|---|
Osteoarthritis | Pain that is worse after activity or towards the end of the day Bony growths (‘spurs') 'around joints' (e.g. fingers: DIP, PIP joints) Limited range of movement or stiffness that abates |
Spondyloarthropathy / Arthritis | Runs in family HLA-B27-associated in 60–80% of patients Low extremities, Enthesitis Usually oligo-monoarthritis Dactylitis (see Aikakauskirja Duodecim «http://www.terveysportti.fi/xmedia/duo/duo95528.pdf»2 and figures «Daktyliitti»1, «Daktyliitti»2 (in Finnish)) |
Polymyalgia rheumatica | Pain and stiffness in buttocks, hips, thighs, upper arms and shoulders Patient may have synovitis in knees, wrists Patient cannot squat or lift up arms Stiffness after rest or long periods of inactivity Consider possiblility of giant cell arteritis |
Virus arthritis | Sudden onset Usually poly- or oligoarthritis Usually dermatitis Usually in the fall |
Gout | Sudden onset of arthritis, usually at night Usually monoarthritis Signs of inflammation: pain, swelling and redness Most often MTP1 affected Risk factors: metabolic syndrome, diuretics Also elderly women with osteoarthritis might have gout |
Septic arthritis | Systemic symptoms usual Sudden monoarthritis usual Oligoarthritis rare but possible |
Lyme borreliosis | Erythema migrans, EM may be absent May start with arthralgias and myalgias, later monoarthritis (usually knee) or oligoarthritis Effusion more prominent than pain Dactylitis or tendinitis possible |
Psoriasis | Family history DIP joint involvement typical but rare Usually oligoarthritis but polyarthritis and spondyloarthritis possible Skin involvement Nail involvement Dactylitis, e.g., sausage toe or sausage finger |
Imaging
- Imaging supports clinical examination by identifying joint inflammation and permanent damage.
Radiography
- Radiography should be performed in radiology units that provide high quality images by appropriate techniques «Laasonen L. Tavanomainen röntgentutkimus perifeeri...»44.
- Radiographs are taken of the hands and feet as part of the diagnostic work-up of RA and other peripheral inflammatory joint diseases. A chest radiograph should be taken for differential diagnostic purposes and also before immunosuppressive pharmacotherapy is initiated.
- Serial radiographs of the hand and feet may be taken judiciously over time to document
disease follow-up.
- The progression of joint damage is usually fastest during the first two years of RA «van der Heijde DM. Joint erosions and patients wit...»45, but progression may vary from patient to patient in accordance with disease activity «Graudal NA, Jurik AG, de Carvalho A ym. Radiograph...»46.
- RA does not affect the spine, except the cervical part. In patients with severe and long-lasting RA, spinal subluxation may occur, best identified on flexion/extension lateral radiographs. In severe rheumatic spinal disease, in particular if the patient has atlanto-axial subluxation (AAS), there is a risk of spinal cord damage of the cervical spine, if the neck is moved into extreme positions. This needs to be taken into account prior to general anaesthesia (flexion/extension radiographs of the cervical spine should be taken preoperatively). Cervical subluxations (e.g., AAS) are most reliably identified in lateral radiographs taken during flexion of the neck. These lateral images are the most important images of the rheumatoid cervical spine.
Sonography
- Sonography is the most important clinical tool for rheumatologists. Sonography is
a reliable method for detecting swelling indicating arthritis. Increased blood flow
by power Doppler indicates active inflammation. In the hands of an experienced examiner,
sonography is a reliable method «Ultraäänitutkimus ilmeisesti lisää niveltulehduksen toteamisvarmuutta useilla nivelalueilla, mutta sen luotettavuus on riippuvainen tutkijasta.»B.
- Sonography is a suitable method for planning and guiding intra-articular joint injections.
MRI
- Of all modern imaging techniques, MRI provides the best anatomical images of the joints and the periarticular soft tissue «Magneettikuvaus on paras kuvantamismenetelmä nivelreuman aiheuttamien muutosten toteamisessa.»A.
- Contrast agents aid in the detection of active synovitis and enable earlier detection of erosions than conventional radiographs.
- MRI is not usually needed for diagnostic or monitoring purposes. Unequivocal indications
for MRI are differential diagnostic problems.
- In severe disease of the cervical spine, MRI should be performed. Subluxations are identified by plain extension/flexion radiographs of the cervical spine. If displacement of the cervical vertebrae are seen, the effect of these anatomical changes are to be taken into account when the MRI images are interpreted to document any compression of the neural structures and spinal cord.
Treatment of RA
Early treatment of RA
- Remission, defined as the absence of symptoms, is the target of treatment «Sokka T. Näkökulma. T2T-manifesti tähtää nivelreum...»47 and aims at recovery and maintenance of working ability and functional capacity of the patient «Rantalaiho V, Puolakka K, Korpela M ym. Long-term ...»48, «Puolakka K, Kautiainen H, Möttönen T ym. Early sup...»49.
- Remission entails the absence of symptoms and signs of joint inflammation. Early and sustained remission significantly improves the prognosis of RA «Varhainen remissio ennustaa pysyvää remissiota ja työkyvyn säilymistä. Pysyvä remissio ennustaa vähäisempää niveleroosioita, parempaa toimintakykyä ja pidempää eloonjääntiä.»A.
- Antirheumatic treatment is to be started without delay «Nivelreuman lääkehoidon varhainen aloitus parantaa ennustetta, jos lääkehoitona on perinteinen monoterapia. Pidempi oireiden kesto puoltaa yhdistelmälääkityksen käyttöä.»A. The initial treatment regime of RA should lead to remission preferably within 3 months, but at the latest within 6 months «Nivelreuman hoito on aloitettava lääkityksellä, joka mahdollistaa nopean remission.»A.
- It is recommended that the initial treatment consists of a combination of methotrexate, sulfasalazine and hydroxychloroquine (RACo-combination treatment), together with a small dose of glucocorticosteroid (usually prednisolone 5.0–7.5mg or an equivalent glucocorticosteroid daily) and intra-articular injections of a glucocorticosteroid into affected joints. In the NEO-RACo study, 90% of patients on the RACo combination met DAS28-remission criteria at 6 months «Nivelreuman hoito on aloitettava lääkityksellä, joka mahdollistaa nopean remission.»A. See DAS28-calculator «http://www.terveysportti.fi/dtk/ltk/avaa?p_artikkeli=pgr00042&p_haku=laskuri»3 (in Finnish, only for subscribers).
- Oral glucocorticosteroid treatment is given for a period of at least of 6 months, if there are no contraindications «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6, «Möttönen T, Hannonen P, Leirisalo-Repo M ym. Compa...»50.
- Methotrexate is the anchor drug of the disease-modifying antirheumatic drugs (DMARD), onto which other antirheumatic drugs are added. Methotrexate can be administered orally, although bioavailability is higher when it is administered subcutaneously or intramuscularly «Metotreksaatin hyötyosuus on parempi ihon alle tai lihakseen annosteltuna.»A. Bioavailability of oral methotrexate is not enhanced by increasing the daily dose above 15mg «Bingham SJ, Buch MH, Lindsay S ym. Parenteral meth...»51.
- If methotrexate or combination therapy are contraindicated, treatment may be started with leflunomide, sulfasalazine or azathioprine. However, monotherapy is less effective than combination therapy in achieving remission «Nivelreuman hoito on aloitettava lääkityksellä, joka mahdollistaa nopean remission.»A. Hesitant pharmacotherapy of RA only delays the time to remission.
- Inflamed joints should be treated locally with intra-articular glucocorticosteroid injections.
- Persisting disease despite active antirheumatic treatment (combination treatment including the maximal tolerated dose of methotrexate) should be treated with biologics.
- The rheumatology unit ensures that the patient understands 1) the importance of treatment and initiates treatment, 2) that possible adverse events do not preclude effective drug treatment and that 3) the goal of treatment is to achieve remission within the first few months of treatment.
- This working group recommends that the rheumatology unit ensures sustained remission for up to two years. Following this, the patient should have annual follow-up visits at a physician with a good understanding of rheumatology.
- An active attitude by the rheumatologist is essential for a good outcome «Aktiivinen ote nivelreumapotilaan hoitoon parantaa merkitsevästi hoitotulosta.»A.
- If renal failure «The effect of age and renal function on the effica...»52 or interstitial lung disease develop during methotrexate treatment, the rheumatology unit should be consulted regarding continuation of treatment. Methotrexate and leflunomide may not be used before conception, during pregnancy or during lactation. The male partner does not need to interrupt the use of methotrexate before conceiving a child «Malm H. Isän kautta välittyvä teratogeneesi - aihe...»53.
Rehabilitation
- Physical exercise as a form of rehabilitation has the strongest impact on the patient's functional capacity.
- Rehabilitation, as well as pharmacotherapy, aims at enhancing the patient's functional capacity, working ability and overall wellbeing.
- Pharmacotherapy and rehabilitation complement each other: the need for rehabilitation is often minimized, if active pharmacotherapy restores the patient's functional capacity.
- WHO's ICF-classification (International Classification of Functioning, Disability and Health) «http://www.who.int/classifications/icf/en/»4 provides a framework for rehabilitation measures which may be applied to the patient herself or himself as well as to the physical or social environment of the patient.
Medical rehabilitation
- An essential part of the treatment of RA is to provide advice and guidance on physical
exercise regimens for patients «Vliet Vlieland TP, van den Ende CH. Nonpharmacolog...»54 (See Current Care Guideline on exercise «Liikunta (ylläpito lopetettu)»2 in Finnish):
- at least 2.5 hours of aerobic exercise weekly
- muscle strengthening exercises at least twice weekly.
- Dynamic exercise (aerobic endurance or muscle-strengthening exercise) increases endurance and muscle strength of the patients without harmful effects on disease activity or radiographic joint damage «Dynaaminen harjoittelu (aerobinen kestävyysliikunta- tai lihasvoimaharjoittelu) lisää nivelreumaa sairastavien henkilöiden kestävyyskuntoa ja lihasvoimaa ilman haitallisia vaikutuksia sairauden aktiivisuuteen, kipuun tai röntgenologiseen nivelvaurioon.»A. Physical exercise apparently decreases the enhanced cardiovascular risks associated with RA «Liikuntaharjoittelu ilmeisesti vähentää nivelreumaan liittyvää suurentunutta kardiovaskulaaririskiä.»B.
- Occupational therapy focusing on educating patients on using their joints sparingly improves the patients' functional capacity «Toimintaterapia parantaa nivelreumapotilaiden toimintakykyä.»B. Custom-made foot orthoses may alleviate pain in the forefoot and sole «Yksilölliset tukipohjalliset saattavat helpottaa nivelreumapotilaiden jalkaterä- ja jalkapohjakipua.»C.
- Personalized physiotherapy or inpatient rehabilitation may be indicated for severely disabled patients. Severely disabled patients younger than 65 years with certain criteria are entitled to physical rehabilitation provided by «http://www.kela.fi/web/en/terms-of-use»5 (SII; Kela in Finnish). In addition, the SII arranges discretionary rehabilitation regardless of patient age.
- Inpatient rehabilitation arranged in rehabilitation centres (later referred to as specialised units) may be useful for supporting self-rehabilitation programmes, for improving compliance and for maintaining the functional capacity of patients with multiple problems.
- There is only little evidence on the effectiveness of inpatient rehabilitation at specialised units. There is a lack of well-performed studies and the available evidence that comes closest to inhouse rehabilitation in RA is based on studies comparing the effectiveness of multidisciplinary treatment carried out at inpatient wards with outpatient and daycare hospital units. If the principles of multidisciplinary care are applied, health benefit from outpatient and inpatient care is equal but is produced at a lower cost in outpatient units «van den Hout WB, Tijhuis GJ, Hazes JM ym. Cost eff...»55. Inpatient medical rehabilitation provided by the SII did not have a positive effect on the work capacity of RA patients receiving remission-targeted treatment in the RACo study «Puolakka K, Kautiainen H, Möttönen T ym. Cost of F...»56.
- Hydrotherapy (aquatic exercise) may have analgetic effects «Vesivoimistelulla saattaa olla lievä kipua lievittävä vaikutus.»C and can be recommended especially for patients with damage in the weight-bearing joints «Vliet Vlieland TP, van den Ende CH. Nonpharmacolog...»54.
- Heat and cold therapy has not been proven to have long-lasting effects on RA symptoms, functional capacity or on the need for analgetic medication «Lämpö- ja kylmähoidoilla ei ole osoitettua pidempikestoista tehoa oireisiin, toimintakykyyn eikä kipulääkityksen tarpeeseen nivelreumassa.»B. Laser therapy «Laserhoito saattaa helpottaa käsiniveloireita.»C and ultrasound applied under water «Ultraääni saattaa helpottaa käsiniveloireita nivelreumassa.»C might relieve symptoms in the joints of the hands. The effect of transcutaneous electrical nerve stimulation (TENS) on pain is controversial «Tutkimustulokset transkutaanisen sähköisen hermostimulaation (TENS) vaikutuksesta kipuun nivelreumassa ovat ristiriitaisia.»B.
Vocational rehabilitation
- The goal of vocational rehabilitation is to support the employment of disabled subjects by developing their professional skills and working environment.
- The patient's potential to retain his or her working capacity has to be assessed no later than after 90 weekdays of sickness allowance. This assessment is documented on a statement by the occupational health care physician. If the patient does not have the benefit of occupational health care services, the consultation of the employment office (TE-services) or the SII must be sought to assess the patient's possibilities for vocational rehabilitation. In addition, a multidisciplinary rehabilitation meeting arranged at a rheumatology or rehabilitation clinic may be helpful.
- Referral to vocational rehabilitation requires a plan for rehabilitation, i.e., a statement made by the treating physician. For continuously employed patients, the pension insurance company takes on the responsibility for the rehabilitation costs, otherwise the SII is the payor.
- Vocational rehabilitation is most beneficial when the subjects is threatened by disability or when work disability has been only temporary «Ammatillinen kuntoutus turvaa työkykyä todennäköisimmin silloin, kun kyseessä on työkyvyttömyyden uhka tai työkyvyttömyys on ollut tilapäistä.»B.
Ongoing rheumatoid arthritis treatment
- There is no curative treatment for RA. Pharmacotherapy is usually continued for years or decades, because RA symptoms tend to relpse on discontinuation of treatment. For patients who have remained asymptomatic for years, medication can be decreased but close observation must be maintained.
- 10–15% of patients with RA achieve sustained remission where no medication is needed «Nivelreumapotilaista 10–15 % voi päästä pitkäaikaiseen lääkkeettömään remissioon.»A.
- The patient with RA should visit annually a physician who has a good understanding of treatment of RA.
- If the medication has been reduced and the RA relapses, the pharmacotherapy to which
the patient previously responded is re-introduced or dosages increased.
- Subcutaneous or oral methotrexate may be re-introduced, even if it was discontinued after previous use, since discontinuation is often due to an ineffective dose or mild adverse events.
- If there are no contraindications, the RACo-combination is introduced: methotrexate, sulfasalazine, hydroxychloroquine and a low-dose glucocorticosteroid (usually prednisolone 5.0–7.5mg daily or equivalent).
- Leflunomide may be also used.
- If the response to methotrexate-based combination treatment poor or absent, the RA is treated with biologics.
- In long-lasting disease, triple combination therapy gives comparable results to treatment with biologics in patients who have responded inadequately to methotrexate monotherapy «Pidempäänkin kestäneessä nivelreumassa perinteinen yhdistelmähoito on biologisen lääkityksen veroinen potilailla, jotka eivät ole saaneet riittävää vastetta metotreksaatille.»A.
Pharmacotherapy of rheumatoid arthritis
Conventional synthetic disease modifying drugs (csDMARDs)
- Methotrexate is the anchor drug of the disease-modifying antirheumatic drugs (DMARD), onto which other antirheumatic drugs may be added. Methorexate may be used as monotherapy and as a part of combination therapy together with other DMARDs, e.g., sulfasalazine, hydroxychloroquine and glucocorticosteroids.
- For more information on csDMARDs, refer to tables (table «Methotrexate (MTX), special aspects...»4, «Sulfasalazine (SSZ), special aspects...»5, «Hydroxychloroquine (HCQ), special aspects...»6, «Leflunomide, special aspects...»7, «Cyclosporine, special aspects...»8, «Intramuscular gold (natriumaurothiomalate), special aspects...»9, «Azathioprine, special aspects...»10, «Azathioprine, special aspects...»11, «Cyclophosphamide, special aspects...»12, «Pennicillamine, special aspects...»13). See also Finnish Society for Rheumatology website «http://www.reumatologinenyhdistys.fi/ohjeet_etu_laakitys.html»6.
- Some patients may benefit from less common csDMARDs.
Dose | First dose 10–15mg sc or po Second dose of MTX is the maintenance dose a week later «Bykerk VP, Akhavan P, Hazlewood GS ym. Canadian Rh...»115 Recommended maintenance dose in the beginning of treatment is 20–25mg once a week. Later on, maintenance dose will be tailored for each individual, balanced between side effects and benefits. |
Side effects | Usual: GI-tract, nausea, dizziness, hair loss, stomatitis, elevated liver enzymes, increased red cell volume Rare: Interstitial lung disease, cytopenias |
Interactions | Trimetoprim, probenecid |
Contraindications | Pregnancy and breast feeding No need to interrupt MTX when planning fathering «Malm H. Isän kautta välittyvä teratogeneesi - aihe...»53 |
With caution | Compromized kidney function (creatinine clearance < 60ml/min) «The effect of age and renal function on the effica...»52, liver diseases, lung fibrosis |
Beneficial combination with | Hydroxychloroquine + sulfasalazine, bDMARDs, cyclosporine |
Other aspects | "Anchor" drug Bioavailability best sc or im vs po Folic acid (5mg/week e.g. following day) improves tolerability and safety If the serum aminotransferase increases to a level x 3 above the reference value, examinations are needed. If no other reasons except MTX, establish highest dose that the patient tolerates. |
Dose | Begin 500mg × 2, after 1–2 weeks increase to 1 g × 2. |
Side effects | Usual: GI-tract, mild CNS symptoms, oligospermia that resolves after discontinuation of SSZ, decreased sperm motility Rare: Severe skin reaction Severe cytopenias |
Interactions | May decrease absorption of digoxin |
Contraindications | Hypersensitivity to sulfonamids and salicylates |
Beneficial combination with | Methotrexate + hydroxychloroquine Intramuscular gold (=natriumaurothiomalate) |
Other aspects | Part of triple combination Can be used during pregnancy and breast feeding Folic acid is recommended during pregnancy. |
Dose | About 5mg/kg/day |
Side effects | Usual: GI-tract, mild CNS symptoms, nightmares, solar sensitivity Rare: Retinopathy, myopathy, kardiomyopathy |
Interactions | - |
Contraindications | Maculopathy of the eye |
Beneficial combination with | Intramuscular gold (=natriumaurothiomalate) Methotrexate and sulfasalazine |
Other aspects | Part of triple combination Can be used during pregnancy and breast feeding A baseline examination by an ophthalmologist and after 5 years of use «Marmor MF, Kellner U, Lai TY ym. Revised recommend...»114 |
Dose | 20mg x 1/day (if issues of tolerability, 20mg every other day) |
Side effects | Diarrhea, reversible hair loss, dermatitis, headache |
Interactions | Rifampicin (increases concentration) |
Contraindications | Liver disease, pregnancy |
Other aspects | If aminotransferase levelös increase 2–3 times above normal, careful follow-up
is indicated. If levels remain high, discontinue leflunomide and consider cholestyramine
to wash out leflunomide. Pay special attention to young women, as leflunomide may delay plans for pregnancy due to long withdrawal time of leflunomide |
Dose | Initial dose 2.5–3mg/kg/day, not >4mg/kg/day |
Side effects | Usual:
Increased hair growth, tremor, decreased kidney function, increased blood pressure, gingival overgrowth, GI-tract, paresthesia |
Interactions | Following drugs increase cyclosporin concentration:
Erythromycin, doxycycline, some antifungal drugs, calcium blockers, propaphenon, H2-blockers, metoclopramide, oral contraceptives and St. John’s wort (Hypericum perforatum) Following drugs decrease cyclosporin concentration: Barbiturates, carbamazepine, phenytoin, metamizole, rifampicin, nafcillin, trimethoprim (i.v.), sulfoamides (i.v.) |
Contraindications | Malignancy, uncontrolled hypertension, compromized kidney function, immunodeficiency, pregnancy, breast feeding |
Beneficial combination with | Methotrexate |
Other aspects | If aminotransferase levelös increase 2–3 times above normal, careful follow-up
is indicated. If levels remain high, discontinue leflunomide and consider cholestyramine
to wash out leflunomide. Pay special attention to young women, as leflunomide may delay plans for pregnancy due to long withdrawal time of leflunomide |
Dose | Intramuscular: after 10mg dose, 50mg weekly until a cumulative dose of 13mg/kg
Maintenance dose 50mg every 1–4 weeks |
Side effects | Usual:
Skin reactions, stomatitis, proteinuria Rare: Cytopenias, interstitial lung disease Polyneuropatia |
Interactions | |
Contraindications | Cytopenias, kidney or liver disease, pregnancy (3rd semester allowed) |
Beneficial combination with | Methotrexate Hydroxychloroquine |
Other aspects | Proteinuria indicates membranous glomerulonefritis and treatment needs to be discontinued. |
Dose | First week 50mg/day, thereafter 2–2.5mg/kg/day divided in 2–3 doses |
Side effects | Usual: GI-tract, nausea, elevated aminotransferases Rare: Severe cytopenias |
Interactions | Allopurinol (life-threatening interaction) |
Contraindications | Pregnancy and breast feeding (relative contraindication) |
Beneficial combination with | |
Other aspects | Constantly elevated aminotransferases |
Dose | 1–2 g/day, divided in two doses |
Side effects | Usual: Nausea, diarrhea, stomach pain, infections, cytopenias Rare: Increased aminotransferases, decreased kidney function |
Interactions | Rifampicin, rifamycin |
Contraindications | Pregnancy and breast feeding |
Beneficial combination with | |
Other aspects | Live vaccines not recommended
Risk of skin cancer is increased |
Dose | 1.5–2.5mg/kg/day, divided in 2–3 doses, po |
Side effects | Usual: GI-tract, cytopenias, infections, infertility Rare: Secondary malignancy |
Interactions | |
Contraindications | Susceptibility to infections, pregnancy, breast feeding |
Beneficial combination with | |
Other aspects | May be needed in systemic manifestations |
Dose | Initial dose 125mg × 1/day; increase by 125mg / 4 weeks until 500–600mg/day |
Side effects | Usual: Skin reactions, stomatitis, taste disturbance, proteinuria Rare: Cytopenias, myasthenia gravis, polymyositis, SLE, Goodpasture's syndrome, pemphigus |
Interactions | |
Contraindications | Decreased kidney function Pregnancy, breast feeding |
Beneficial combination with | - |
Other aspects | Needs special permit from Finnish Medicines Agency (Fimea) Proteinuria indicates membranous glomerulonephritis and treatment needs to be discontinued. Due to difficult dosage and side effects (especially dysgeusia) is rarely used nowadays |
Biologic disease modifying drugs (bDMARDs)
- If csDMARDs in combination are ineffective, biologics may be introduced «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6. Biologics are also called biologicals and biological products.
- Before a patient Is started on a biologic, infections are to be excluded (e.g., tuberculosis «http://www.reumatologinenyhdistys.fi/files/tuberkuloosireaktivaatio.pdf»7). A chest X-ray is taken and a dental exam is made. Hepatitis screening is performed, if appropriate. In addition, adequate protection against diseases with appropriate vaccinations need to be guaranteed, including pneumococcal vaccine «http://www.reumatologinenyhdistys.fi/ohjeet_rokote.html»8.
- A biologic DMARD in combination with methotrexate is more effective than the biologic alone «Biologinen lääke yhdistettynä metotreksaattiin on nivelreuman hoidossa tehokkaampi kuin yksin käytettynä.»A, «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6. Some studies suggest that tocilizumab and abatacept may be effective also as monotherapy «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6, «Gabay C, Hasler P, Kyburz D ym. Biological agents ...»57.
- TNF-α blockers maintain their efficacy to a higher degree when combined with methotrexate than when used alone.
- The following bDMARDs are used to treat RA:
- TNF-α blockers (adalimumab, etanercept, infliximab, golimumab and certolizumab pegol)
- interleukin 1 inhibitors (anakinra)
- interleukin 6 inhibitors (tocilizumab)
- B-cell blockers (rituximab)
- T-cell co-stimulation inhibitors (abatacept) (table «bDMARDs...»14)
- Biologics are effective and safe in the treatment of RA «Biologinen lääke yhdistettynä metotreksaattiin on nivelreuman hoidossa tehokkaampi kuin yksin käytettynä.»A, «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6. Biologics have the same effectivity, with the exception of anakinra, whose effect is weaker.
- Combination of two biologics is not recommended unless in exceptional circumstances and after careful consideration.
- The use of biologics varies markedly among different countries «Sokka T, Kautiainen H, Pincus T ym. Disparities in...»58. In low-income countries, the high expense of biologics precludes their use «Putrik P, Ramiro S, Kvien TK ym. Inequities in acc...»59, «Putrik P, Ramiro S, Kvien TK ym. Variations in cri...»60. Biologics do not necessarily guarantee a better outcome than effective use of conventional DMARDs «Sokka T, Haugeberg G, Asikainen J ym. Similar clin...»61.
Generic product | Group | Mode of action | Half life | Route of admin | Dose | Attention |
---|---|---|---|---|---|---|
Adalimumab | TNF-α blocker | Human monoclonal antibody | 10–18 days | sc | 40mg every two weeks | |
Etanercept | TNF-α blocker | p75 receptor fusionprotein | 3 days | sc | 50mg once a week or 25mg twice a week | |
Sertolitsumabpegol | TNF-α blocker | PEGylated Fab' fragment of a humanised TNF inhibitor monoclonal antibody | 14 days | sc | 200mg every 2 weeks or 400mg once a month | Starting dose to adults 400mg at weeks 0, 2, 4 |
Golimumab | TNF-α blocker | Human monoclonal antibody | 9–15 days | sc | 50mg once a month | If insufficient efficacy and patient's weight >100 kg, dose increase: 100mg once a month |
Infliksimab | TNF-α blocker | Chimeric, monoclonal antibody | 10 days | iv | 3mg/kg in weeks 0, 2, 6, thereafter every 8 weeks | |
Rituksimab | B-cell inhibitor | CD20 chimeric, monoclonal antibody | 3–4 days | iv | 500–1 000mg 2 weeks apart, repeated after 6–12 months | IgG levels at baseline and before every infusion |
Infection and malignancy risk of biologics
- All biologics pose an increased risk of infection «Kaikkiin nivelreuman hoitoon käytettyihin biologisiin lääkkeisiin liittyy kohonnut infektion riski.»A, which varies by biologic. The risk of opportunistic infections, like mycobacterial and viral infections (herpes, in particular), is increased with the use of TNF-α blockers «TNF-alfaestäjien käyttöön liittyy nivelreumapotilailla kohonnut mykobakteerin ja virusinfektion riski.»A.
- The risk of malignancy is not statistically significantly increased when bDMARDs are used short-term, according to a 3-year follow-up study «Biologiseen lääkkeeseen tai sen yhdistelmään metotreksaattiin yhdistettynä ei liity tilastollisesti merkittävää maligniteetin riskiä kolmen vuoden seurannassa.»A. Information on the long-term risks is sparse.
- The risk of lymphoma is slightly increased in RA, but TNF-α blockers have not been shown to add to this risk «Kauppi M, Pukkala E, Isomäki H. Elevated incidence...»62, «Isomäki HA, Hakulinen T, Joutsenlahti U. Excess ri...»63.
- The risk of melanoma is not increased among patients on biologics, but the risk of non-melanoma skin cancer may be increased compared to patients on conventional DMARDs «Le Blay P, Mouterde G, Barnetche T ym. Risk of mal...»64.
TNF-α blockers
- The TNF-α blockers adalimumab, infliximab, etanercept «Biologiset lääkkeet (abatasepti, adalimumabi, anakinra, etanersepti, infliksimabi ja rituksimabi) ovat tehokkaita nivelreuman hoidossa.»A, golimumab «Golimumabi on tehokas ja turvallinen nivelreuman hoidossa.»A and certolizumab pegol «Sertolitsumabi on tehokas nivelreuman hoidossa»A are effective in the treatment of RA «Biologiset lääkkeet (abatasepti, adalimumabi, anakinra, etanersepti, infliksimabi ja rituksimabi) ovat tehokkaita nivelreuman hoidossa.»A.
- The infliximab biosimilar CT-P13 is similar to infliximab in terms of efficacy and safety, at least in the short-term «Infliksimabin biosimilaari (CT-P13) on tehon ja turvallisuuden suhteen nivelreuman hoidossa infliksimabin kaltainen ainakin lyhytaikaisessa käytössä.»B.
- The efficacy of TNF-α blockers is sustained in most patients in the long-term «Smolen JS, Aletaha D, Koeller M ym. New therapies ...»65.
- In some patients the emergence of anti-drug antibodies (ADAs) may contribute to a loss of efficacy.
- Assessment of drug concentrations and ADA levels may be helpful in the assessment of efficacy loss. Because of the unique structure of etanercept, the body does not generate neutralising antibodies against it «Isomäki P. Biologisten lääkkeiden vasta-aineet reu...»66, «Garcês S, Antunes M, Benito-Garcia E ym. A prelimi...»67.
- It is recommended that methotrexate or another immunosuppressive drug is used in combination with infliximab and adalimumab «Garcês S, Demengeot J, Benito-Garcia E. The immuno...»68. A low level of infliximab in the serum at the start of treatment is associated with later ADA formation «Bendtzen K, Geborek P, Svenson M ym. Individualize...»69, «Ducourau E, Mulleman D, Paintaud G ym. Antibodies ...»70. Therefore, drug holidays and prolonged intervals between administration of infliximab should be avoided to reduce the risk of ADAs. These observations are probably valid for golimumab and certolizumab pegol, as well.
- The administration of TNF-α blockers may cause local or systemic side effects and increase the risk of infections. Untreated infections, latent tuberculosis, manifest cardiac failure and de-myelinating diseases are contraindications to the use of TNF-α blockers «Keane J, Gershon S, Wise RP ym. Tuberculosis assoc...»71, «Mikuls TR, Moreland LW. Benefit-risk assessment of...»72, «Alldred A. Etanercept in rheumatoid arthritis. Exp...»73, «Konttinen Y, Nordström D, Honkanen V ym. Biologist...»74.
Interleukin 1 inhibitor (anakinra)
- The clinical response of patients with RA to anakinra is, on average, weaker than to TNF-α blockers «Anakinran teho nivelreuman hoidossa on vähäisempi kuin abataseptin, adalimumabin, etanerseptin, infliksimabin tai rituksimabin.»A.
Interleukin 6 inhibitor (tocilizumab)
- Tocilizumab is an effective treatment of RA «Tosiltsumabi on hyvä ja turvallinen lääke nivelreuman hoidossa.»A «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6, «Navarro-Millán I, Singh JA, Curtis JR. Systematic ...»75.
- The efficacy of tocilizumab administered subcutaneously is comparable to intravenous administration «Tosilitsumabi nivelreuman hoidossa on ihon alle annosteltuna samanveroinen kuin laskimoon annosteltuna.»B.
- Tocilizumab monotherapy may be as effective as tocilizumab in combination with methotrexate «Gabay C, Hasler P, Kyburz D ym. Biological agents ...»57.
- Tocilizumab may increase the concentrations of serum lipids.
- Tocilizumab effectively decreases CRP «Navarro-Millán I, Singh JA, Curtis JR. Systematic ...»75 and may prevent a rise of the CRP concentration «Bari SF, Khan A, Lawson T. C reactive protein may ...»76. This should be taken into account when assessing the severity of an infection.
B-cell blocker (rituximab)
- Rituximab is an effective treatment of RA «Edwards JC, Szczepanski L, Szechinski J ym. Effica...»77, «Cohen SB, Emery P, Greenwald MW ym. Rituximab for ...»78, but its efficacy is higher in seropositive than seronegative disease «Rituksimabi tehoaa seropositiivista nivelreumaa sairastavilla paremmin kuin seronegatiivista sairastavilla.»A.
- The treatment response is optimal only a few months after treatment start «Scher JU. B-cell therapies for rheumatoid arthriti...»79.
- Rituximab is usually administered as two infusions two weeks apart. This course may be repeated at intervals of six to twelve months or less often, as indicated by the patient's individual response to treatment and disease activity «Scher JU. B-cell therapies for rheumatoid arthriti...»79.
- Infusion reactions are common and therefore premedication (e.g., paracetamol [acetaminophen] 1g, methylprednisolone 125mg and antihistamines) is given before the infusion.
- Prior to rituximab treatment, the patient should be screened for hepatitides and HIV.
- Treatment with rituximab may decrease immunoglobulin levels. Hence, the immunoglobulin concentrations in the serum should be monitored «van Vollenhoven RF, Emery P, Bingham CO 3rd ym. Lo...»80 and immunoglobulin replacement treatment considered, if needed.
- If a patient has latent tuberculosis that cannot be treated, recent lymphoma, a history of demyelinating disease or has been living in an area where tuberculosis is endemic, rituximab may be considered as the first-choice biologic «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6.
T-cell blocker (abatacept)
- Abatacept is an effective treatment of RA «Abatasepti on tehokas nivelreuman hoidossa.»A.
- The efficacy of abatacept administered subcutaneously is comparable to intravenous administration «Kaine J, Gladstein G, Strusberg I ym. Evaluation o...»81, «Abatasepti voidaan annostella nivelreumapotilaan ihon alle.»B.
- Abatacept monotherapy may be as effective as abatacept in combination with methotrexate «Gabay C, Hasler P, Kyburz D ym. Biological agents ...»57.
Glucocorticosteroids
- Oral glucocorticosteroids (≤ 7.5mg prednisolone or equivalent glucocorticosteroid per day) and intra-articular glucocorticosteroid injections are an essential part of the treatment of RA «Smolen JS, Landewé R, Breedveld FC ym. EULAR recom...»6.
- Systemic glucocorticosteroid treatment reduces the inflammatory symptoms of RA. In early RA, glucocorticosteroid treatment combined with DMARDs increases the rate of remissions and slows down the progression of articular destruction assessed radiographically «Systeeminen kortikoidihoito vähentää nivelreuman tulehdusoireita ja radiologisten vaurioiden etenemistä sekä lisää remissioita.»A.
- Intra-articular glucocorticosteroid injections abate arthritis symptoms rapidly. Long-term use of intra-articular glucocorticosteroid injections may increase the rate of remissions and slow down the progression of articular destruction assessed radiographically «Tulehtuneiden nivelten hoito kortikoidi-injektiolla saattaa vähentää radiologisia vaurioita nivelreumapotilailla.»C.
- Modified-release glucocorticosteroid tablets taken at bedtime decrease the duration of morning stiffness more than standard tablet formulations «Kortisonihoidon ajoitus yöhön modified release tabletilla lyhentää nivelreumapotilaiden kokemaa aamukankeutta tavalliseen aamulla annosteltavaan kortisoniin verrattuna.»A.
- Intra-articular injections are usually administered without sonographic guidance «Lopes RV, Furtado RN, Parmigiani L ym. Accuracy of...»82, but the use of sonography probably augments the efficacy of intra-articular injections «Sibbitt WL Jr, Peisajovich A, Michael AA ym. Does ...»83.
- Treatment of rheumatic gonitis with intra-articular glucocorticosteroid injections results probably in a better response than using the same dose of glucocorticosteroids systemically «Konai MS, Vilar Furtado RN, Dos Santos MF ym. Mono...»84. Solid studies for other joints than the knee are lacking.
- Immobilization of the upper extremity after an intra-articular glucocorticosteroid injection does not seem to improve the outcome «Weitoft T, Forsberg C. Importance of immobilizatio...»85. For weight-bearing joints, like the knees, rest after the injection is beneficial «Wallen M, Gillies D. Intra-articular steroids and ...»86.
- Among the known adverse events of glucocorticosteroid treatment are osteoporosis, cataract, diabetes and adrenal gland suppression. The occurrence and severity of these adverse events is proportional to the administered dose and the duration of treatment. Glucocorticosteroid treatment may also increase the cardiovascular risk in a dose-dependent fashion «Kortisonihoito saattaa annoksesta riippuen lisätä sydän- ja verisuonisairauksien riskiä nivelreumapotilailla.»C.
- The harmful effects of low-dose glucocorticosteroid on the skeleton «Matala-annoksisen kortikoidihoidon haitallinen vaikutus nivelreumapotilaan luustoon on ilmeisesti varsin vähäistä.»B and on glucose metabolism «Matala-annoksisen kortikoidihoidon epäedullinen vaikutus nivelreumapotilaan glukoosimetaboliaan lienee vähäinen.»C are probably slight.
- The risk of osteoporosis should always be assessed when the patient is on a glucocorticosteroid, and attention must be paid on sufficient vitamin D and calcium supplementation (Current Care Guidelines of osteoporosis «Osteoporoosi»3 in Finnish).
Non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics
- The patient will need NSAIDs until the pain and stiffness associated with active inflammation have resolved.
- NSAIDS are recommended only for use as needed.
- If the patient has night pains and pronounced morning stiffness, a long-acting NSAID taken in the evening is recommended.
- Different NSAIDs may have a different efficacy and side effect profiles «Coxib and traditional NSAID Trialists' (CNT) Colla...»87. In particular, the risk of gastrointestinal side effects needs to be taken into account «Radner H, Ramiro S, van der Heijde DM ym. How do g...»88. The risk can be reduced with the use of proton pump inhibitors «Brooks J, Warburton R, Beales IL. Prevention of up...»89. The cardiovascular risk associated with NSAIDs applies also to patients with RA «Marks JL, van der Heijde DM, Colebatch AN ym. Pain...»90.
- The efficacy of NSAIDs may improve when they are used in combination with paracetamol (acetaminophen) but, at the same time, the risk of adverse events will increase «Doherty M, Hawkey C, Goulder M ym. A randomised co...»91.
- The efficacy of opioids in the treatment of RA has no robust evidence base, and the risk of adverse events is high «Whittle SL, Richards BL, van der Heijde DM ym. The...»92. The indication of opioid treatment, if started, needs to be clear and the goals of treatment and how it is carried out need to be agreed on with the patient.
- There is lack of evidence of benefits, if any, of combining NSAIDs with opioids «Ramiro S, Radner H, van der Heijde DM ym. Combinat...»93.
Prevention of osteoporosis
- The rheumatic inflammation and glucocorticosteroid treatment subject the patient to secondary osteoporosis. Glucocorticosteroids increase the risk of osteoporosis dose-dependently and the risk of fractures. Therefore, prevention of osteoporosis is important for patients on pharmacotherapy for RA (Current Care Guidelines of osteoporosis «Osteoporoosi»3 in Finnish).
Addressing the atherosclerosis risk
- The rheumatoid inflammation is harmful to the function of the vascular endothelium and raises the patient's cardiovascular risk «Solomon DH, Karlson EW, Rimm EB ym. Cardiovascular...»94, «Chung CP, Oeser A, Raggi P ym. Increased coronary-...»95, «Bergholm R, Leirisalo-Repo M, Vehkavaara S ym. Imp...»96, «Park YB, Lee SK, Lee WK ym. Lipid profiles in untr...»97, «Aviña-Zubieta JA, Choi HK, Sadatsafavi M ym. Risk ...»98.
- Effective suppression of the rheumatoid inflammation is crucial for preventing atherosclerosis. Methotrexate and, of the biologics, at least the TNF-α blockers reduce the risk of cardiovascular events «Metotreksaatti ja biologisista lääkkeistä ainakin TNF-salpaajat vähentävät kardiovaskulaaritapahtumien vaaraa.»A.
- Hydroxychloroquine has a beneficial effect on the lipid profile «Tam LS, Gladman DD, Hallett DC ym. Effect of antim...»99.
- Low-dose glucocorticosteroid (e.g., prednisolone ≤7.5mg/day or equivalent glucocorticosteroid) is often needed as a part of combination treatment, but the treatment duration should be kept to a minimum to minimize the atherosclerosis risk «Kortisonihoito saattaa annoksesta riippuen lisätä sydän- ja verisuonisairauksien riskiä nivelreumapotilailla.»C.
- Evaluation of the patient's cardiovascular risk is a part of the overall assessment of the RA patient. The target lipid level should be the same as for other high-risk patients «Koivuniemi R ja Leirisalo-Repo M.Tulehduksellisiin...»101 (Current Care Guidelines in dyslipidaemias «Dyslipidemiat»4 in Finnish). Assessment of the lipid profile and glucose level should be undertaken only after the acute inflammation has resolved, e.g., three months after treatment start.
The impact of diet on rheumatoid symptoms
- Special dietary interventions are not recommended for the treatment of RA. The effect of specific dietary regimens (vegetarian, Mediterranean, elemental, elimination diets) on the symptoms of RA (pain, stiffness, function) is uncertain «Hagen KB, Byfuglien MG, Falzon L ym. Dietary inter...»100. Studies have been small and their reliability affected by systematic errors of study designs.
Rheumatoid orthopaedic surgery
- The goal of active anti-rheumatic medication is to obviate the need for operative treatment.
- Statistics show that rheumaorthopaedic operations have declined notably during last 20 years due to more effective medication «Jämsen E, Virta LJ, Hakala M ym. The decline in jo...»102. Patients with chronic RA may have joint changes which may be relieved with orthopaedic surgery «Matti U.K. Lehto. Reumaortopedian valtakunnallinen...»103.
- Synovectomy (today usually arthroscopic synovectomy) is indicated, if the inflammation in a single joint continues despite active anti-rheumatic pharmacotherapy. Synovectomy relieves often joint pain and stiffness. Postoperatively, effective anti-rheumatic pharmacotherapy should be continued to prevent re-synovitis. If the cartilage surface of the joint is in poor condition before synovectomy, the operative result may be poor or brief. A treatment option for "drug-therapy refractory synovitis" of the knee joint is radiosynovectomy, where a short-lived radionuclide is injected into the knee joint and removed after a while. This option is available only in some university hospitals in Finland.
- Tenosynovitis and nodules in the tendons refractory to conservative therapy limit the movement of joints and may be treated surgically with tenosynovectomy. If tenosynovectomy is done to the flexor tendons of the wrist, the carpal canal is usually also opened and the median nerve liberated «Simmen BR, Bogoch ER, Goldhahn J. Surgery Insight:...»104.
- Arthrodesis may relieve the pain of a severely destroyed joint and improve function of the whole extremity. Arthrodeses may correct severe deformities and prevent the progression of deformities. Usually, arthrodeses are performed in the wrist, subtalar joint, first metatarsophalangeal joint and sometimes in the finger joints.
- Severe deformity in the cervical spine may be an indication for operative treatment. Severe anterior atlanto-axial subluxation (AAS) is usually treated surgically by fusing vertebrae C1 and C2.
- The results of total hip and knee arthroplasties are good «Simmen BR, Bogoch ER, Goldhahn J. Surgery Insight:...»104. The prosthesis type for glenohumeral arthroplasty is selected individually. For patients with a severly degenerated rotator cuff, a reverse shoulder arthroplasty prosthesis is often used, because then the shoulder muscles may compensate for the loss of rotator cull function and generate satisfactory ranges of movement. The 10-year survival rate of prostheses of the large joints is 85–95% «Ikävalko M. Rheumatoid Elbow Destruction and its T...»105.
- Prosthesis of the ankle, wrist and fingers may be used in selected RA cases.
- Rheumaorthopaedic revision operations are often challenging «Simmen BR, Bogoch ER, Goldhahn J. Surgery Insight:...»104.
- Painful rheumatoid nodules and bursae may require operative treatment.
- The postoperative infection risk of patients with RA is elevated if the patient has certain concomitant diseases, like diabetes, impaired circulation in the operated limb and a history of infections after previous operations.
- DMARDs, and especially biologics, often increase the risk of infections, which has to be taken into account when the surgical risks are evaluated. The biologics may be paused before and after an operation, depending on the patient and the DMARDs. The downside of discontinuing antirheumatic pharmacotherapy are, however, an increased risk of rheumatoid flare, an impaired surgical outcome and even an increased risk of infection. There is an abundant literature on how to discontinue antirheumatic pharmacotherapy before surgery, but strong evidence for the benefit of such a discontinuation is lacking. In general, it is reasonable to withhold biologics for 1–2 weeks before surgery and for the time after surgery until the surgical wound shows signs of good primary healing. Biologics need not be discontinued for minor, clean operations.
Patient education
- Patient education improves compliance with drug treatment «Hill J, Bird H, Johnson S. Effect of patient educa...»106 and improves the patient's state of health, at least in the short term «Potilasohjaus vaikuttaa ainakin lyhyellä tähtäimellä edullisesti nivelreumapotilaiden terveydentilaan.»A.
- The treatment of RA is based on a shared decisions between the patient and the treating physician. This presupposes that the patient knows the risks and benefits of the intended treatment «Smolen JS, Aletaha D, Bijlsma JW ym. Treating rheu...»107.
- The role of the rheumatology nurse for efficient patient education is crucial.
- The patient needs to understand:
- the nature of RA and how it progresses, if untreated
- how RA is treated
- that remission is a realistic target in early disease and that stringent adherence by the patient to the prescribed medication is important
- that the medication might have side effects and patients may need to switch medications, but the risks of having RA untreated are manyfold compared to the risks of the medication.
- Smoking is a risk for RA.
- Patient education needs to be comprehensive, well-structured and comprehensive. A supportive attitude of the treating physician and the rheumatology nurse is essential.
- A physiotherapist should provide education on physical exercise.
- As needed, the patient should be referred to an occupational therapist, podiatrist, dietician, psychotherapist or social worker.
- The patient needs to have an assigned health care professional as a contact person.
- Patient education may be provided following the motivational interview strategy «Lahti J, Maria R, Koski-Jännes A. Motivoiva haasta...»108. [HUOM! Motivoiva keskustelu; lisätäänkö linkki Oppiporttiin?]
- Treatment pathway. [HUOM! Tässä kohtaa on suomenkielisessä suosituksessa linkki powerpoint-esitykseen]
Patient follow-up
- We recommend that each rheumatology unit follows a clinical pathway for the care of
patients with early RA. The objectives of following such a pathway are to guarantee
that:
- the patient starts the medication agreed on
- possible adverse events are balanced against effective drug treatment
- the treatment target is remission during the first few months of treatment
- remission is sustained.
- When the RA-patient attends for follow-up, disease activity is measured with the following
scales:
- Patient-reported outcomes: function (HAQ- «http://www.terveysportti.fi/xmedia/hoi/hoi21010b.pdf»9), pain (VAS «http://www.terveysportti.fi/xmedia/hoi/hoi21010c.pdf»10 (forms in Finnish)), fatigue, patient global assessment of disease activity, symptomatic joints and analgetic use
- Physician-reported outcomes: swollen and tender joints according to the 46 joint count (MTP joints included) and physician global assessment of disease activity
- Laboratory values: ESR, CRP
- Disease activity index (DAS28 «http://www.terveysportti.fi/dtk/ltk/avaa?p_artikkeli=pgr00042&p_haku=laskuri»3; form in Finnish, only for subscribers)
- The recommendation is to take radiographs of the hands and feet at baseline (at the time of diagnosis), at the two-year follow-up visit and thereafter as dictated by the patient's symptoms.
- This working group recommends that the rheumatology unit ensures sustained remission for up to two years. Following this, the patient should have annual follow-up visits at a physician with a good understanding of rheumatology «Aktiivinen ote nivelreumapotilaan hoitoon parantaa merkitsevästi hoitotulosta.»A.
- Blood tests for drug safety should be taken and assessed by a physician in primary care.
- For use of medication during pregnancy and lactation see GRAVBASE-database «http://www.terveysportti.fi/terveysportti/dlv.koti?p_kielikoodi=fi&p_sovellustunnus=RI&p_mainos=E»11 (in Finnish, only for subscribers).
- The risk of infection must be considered when biologics are used and appropriate vaccinations need to be guaranteed.
- Close collaboration between the rheumatology unit and primary care is crucial since treatment of RA will go on for years and decades.
- If the overall treatment is to be successful, relapses of RA must be recognised in primary care.
- The patient is referred to a rheumatologist, if the relapse is not adequately controlled by the measures provided by the "toolbox" (see Table «GP's tool box...»15).
GP's tool box: | |
---|---|
RA flares, what to do: | |
|
|
Increased symptoms without signs of RA activity: | |
|
Cost-effectiveness of the pharmacotherapy of RA
- RA incurs high societal costs, including direct costs from increased health care resource use and indirect costs from reduced work productivity.
- The early treatment outcome of RA is strongly predictive of direct and indirect costs «Puolakka K, Kautiainen H, Mottonen T ym. Use of th...»109, «Hallert E, Husberg M, Skogh T. 28-Joint count dise...»110. Early remission ensures maintained working capacity «Puolakka K, Kautiainen H, Möttönen T ym. Early sup...»49.
- A good early treatment outcome, remission at best, prevents high costs and enhances the patient's quality of life.
- If the activity of RA continues unabated, the patient is at risk of joint damage, loss of function and loss of working capacity. Work productivity costs have long since been the major part of the total costs «Kobelt G, Eberhardt K, Jönsson L ym. Economic cons...»111.
- If conventional synthetic anti-rheumatic pharmacotherapy is not effective, even an expensive medication is cost-effective if it prevents disability and early work incapacitation and retirement.
- Costs due to work incapacity are reduced also if pharmacotherapy is upgraded later during the disease process, if this allows the patient to regain his or her functional capacity to a level compatible with the requirements of the patient's assignments «Augustsson J, Neovius M, Cullinane-Carli C ym. Pat...»112.
- Several studies have shown that the functional capacity of RA patients has, on average, improved in the past two decades. For those diagnosed with RA after the turn of millennium, the risk of work disability is smaller than for those diagnosed before than «Rantalaiho VM, Kautiainen H, Järvenpää S ym. Decli...»113.
- There are several studies on the cost-effectiveness of different medications and combinations, but usually they have been comparisons between methotrexate monotherapy and other pharmacotherapeutic regimens in cases of methotrexate failure. They are not relevant for Finnish practice. Comparisons of various biologics have been based on short-term treatment studies, and the patient cohorts have not often been comparable.
Working group appointed by the Finnish Medical Society Duodecim and the Finnish Society for Rheumatology
Chair:
Kari Puolakka, MD, PhD, Adjunct professor, Specialist in Internal Medicine and Rheumatology, South Karelia Social and Health Care District (Eksote), Head of Department; Lappeenranta
Members:
Markku Hakala, MD, PhD, Adjunct professor, Specialist in Internal Medicine and Rheumatology; Tampere
Markku Kauppi, MD, PhD, Specialist in Internal Medicine and Rheumatology, Professor, Head of the rheumatology unitUniversity of Tampere and Päijät-Häme Central Hospital,Lahti, Finland.
Eero Mervaala, MD, PhD, Professor, University of Helsinki, Faculty of Medicine, Department of Pharmacology and FInnish Medical Society Duodecim (Current Care Editor)
Laura Pirilä, MD, PhD, Adjunct professor, Specialist in Internal Medicine, Geriatrics and Rheumatology; Head of Deparment of Rheumatology, Turku University Hospital, Division of Medicine, Hospital District of Southwest Finland
Tuulikki Sokka-Isler, MD, PhD, Professor, Specialist in Internal Medicine and Rheumatology, Head of Department; Central Finland Central Hospital and University of Eastern Finland
Klaus Suni, MD, Specialist in General Practise, health centre physician; Health Care Centre of the Jyväskylä Region
Consultant:
Raine Tiihonen, MD, PhD, Specialist in orthopedics and traumatology, Head of Department; Päijät-Häme Cental Hospital, Lahti, Finland
Disclosures
Markku Hakala: Grant (Pirkanmaa Hospital District), Consultanting fees (Finnish Rheumatism Association), membersip of a board or equal (Finnish Rheumatism Association), Speaking fees (MSD, Fysioline, GSK), License royalties (Duodecim)
Markku Kauppi: Consultanting fees (AbbVie, BMS, Berlin Chemie Menarin, MSD, Pfizer, Roche, UCB), Speaking fees (AbbVie, BMS, Berlin-Chemie Menarini, GSK, MSD, Pfizer, Roche, Sanofi, UCB), Reimbursement for attending meetings (BMS, Berlin-Chemie Meniarini, MSD, Pfizer, UCB)
Eero Mervaala: Consultanting fees (Kustannus Medicina Oy), Employment (Yhtyneet Medix Laboratoriot), Speaking fees (Pharmaceutical Information Centre Ltd)
Laura Pirilä: Consultanting fees (Pfizer Oy), Speaking fees (AbbVie oy, Bristol-Myers Squibb (Finland), GlaxoSmithKline OY, Labquality Days/Labquality oy, Pfizer Oy, Pohjois-Savon sairaahoitopiiri, Roche oy, the Scandinavian Neuropathological Society, the Finnish Society for Rheumatolgy, University of Turku, Turunmaan Duodecim ry, UCB Pharma Oy Finland), Reimbursement for attending meetings (Actellion Pharmaceuticals Finland, Bristol Myer Squibb Finland, Roche Oy, UCB Pharma Oy Finland)
Kari Puolakka: Grant (Pfizer), Consultanting fees (Abbvie, Bristol-Myers Squibb, MSD, Pfizer, Roche, UCB), Speaking fees (Bristol-Myers Squibb, Pfizer, UCB), Reimbursement for attending meetings (Bristol-Myers Squibb, Pfizer, Roche)
Tuulikki Sokka-Isler: Grant (Abbvie, Hospira, Pfizer), Consultanting fees (Hospira, Novartis, Orion, Pfizer, UCB), Speaking fees (Abbvie, BMS, Hospira, MSD, Medac, Pfizer, Roche, UCB)
Klaus Suni: Reimbursement for attending meetings (MSD, Pfizer)
Translation
Elena Nikiphorou MBBS/BSc, MRCP, PGCME, MD (Res), FHEA
Tuulikki Sokka-Isler
Laura Pirilä
Markku Hakala
Kari Puolakka
Language revision:
MediDocs Ltd, Robert Paul
Limitation of responsibility
The clinical practice guidelines of the Finnish Medical Society Duodecim are summaries on the diagnostics and effectiveness of therapy on single diseases and are produced by experts. They do not replace the judgement of a physician or other healthcare specialist on the best possible diagnostics and therapy of an individual patient.
References
- Deane KD. Preclinical rheumatoid arthritis (autoantibodies): an updated review. Curr Rheumatol Rep 2014;16:419 «PMID: 24643396»PubMed
- Nielsen SF, Bojesen SE, Schnohr P ym. Elevated rheumatoid factor and long term risk of rheumatoid arthritis: a prospective cohort study. BMJ 2012;345:e5244 «PMID: 22956589»PubMed
- Hazes JM, Luime JJ. The epidemiology of early inflammatory arthritis. Nat Rev Rheumatol 2011;7:381-90 «PMID: 21670767»PubMed
- Wevers-de Boer KV, Heimans L, Huizinga TW ym. Drug therapy in undifferentiated arthritis: a systematic literature review. Ann Rheum Dis 2013;72:1436-44 «PMID: 23744979»PubMed
- Rantalaiho, Pirilä, Kautiainen Puolakka. Miten tuoretta nivelreumaa hoidetaan Suomessa. Suom Lääkäril 2013;44:2833-38
- Smolen JS, Landewé R, Breedveld FC ym. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492-509 «PMID: 24161836»PubMed
- Aletaha D, Neogi T, Silman AJ ym. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81 «PMID: 20872595»PubMed
- Rossini M, Rossi E, Bernardi D ym. Prevalence and incidence of rheumatoid arthritis in Italy. Rheumatol Int 2014;34:659-64 «PMID: 24610538»PubMed
- Humphreys JH, Verstappen SM, Hyrich KL ym. The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register. Ann Rheum Dis 2013;72:1315-20 «PMID: 22945499»PubMed
- Englund M, Jöud A, Geborek P ym. Prevalence and incidence of rheumatoid arthritis in southern Sweden 2008 and their relation to prescribed biologics. Rheumatology (Oxford) 2010;49:1563-9 «PMID: 20444855»PubMed
- Puolakka K, Kautiainen H, Pohjolainen T ym. Rheumatoid arthritis (RA) remains a threat to work productivity: a nationwide register-based incidence study from Finland. Scand J Rheumatol 2010;39:436-8 «PMID: 20513211»PubMed
- Aho K, Kaipiainen-Seppänen O, Heliövaara M ym. Epidemiology of rheumatoid arthritis in Finland. Semin Arthritis Rheum 1998;27:325-34 «PMID: 9572714»PubMed
- Pedersen JK, Svendsen AJ, Hørslev-Petersen K. Prevalence of rheumatoid arthritis in the southern part of denmark. Open Rheumatol J 2011;5:91-7 «PMID: 22216071»PubMed
- Neovius M, Simard JF, Askling J ym. Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs in Sweden. Ann Rheum Dis 2011;70:624-9 «PMID: 21149495»PubMed
- Biver E, Beague V, Verloop D ym. Low and stable prevalence of rheumatoid arthritis in northern France. Joint Bone Spine 2009;76:497-500 «PMID: 19767228»PubMed
- Widdifield J, Paterson JM, Bernatsky S ym. The rising burden of rheumatoid arthritis surpasses rheumatology supply in Ontario. Can J Public Health 2013;104:e450-5 «PMID: 24495819»PubMed
- Gabriel SE, Michaud K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res Ther 2009;11:229 «PMID: 19519924»PubMed
- Cross M, Smith E, Hoy D ym. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014;73:1316-22 «PMID: 24550173»PubMed
- Wallenius M, Skomsvoll JF, Irgens LM ym. Postpartum onset of rheumatoid arthritis and other chronic arthritides: results from a patient register linked to a medical birth registry. Ann Rheum Dis 2010;69:332-6 «PMID: 19717397»PubMed
- Kurkó J, Besenyei T, Laki J ym. Genetics of rheumatoid arthritis - a comprehensive review. Clin Rev Allergy Immunol 2013;45:170-9 «PMID: 23288628»PubMed
- Aho K, Koskenvuo M, Tuominen J ym. Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol 1986;13:899-902 «PMID: 3820198»PubMed
- Silman AJ, MacGregor AJ, Thomson W ym. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol 1993;32:903-7 «PMID: 8402000»PubMed
- Hensvold AH, Magnusson PK, Joshua V ym. Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins. Ann Rheum Dis 2015;74:375-80 «PMID: 24276366»PubMed
- Klareskog L, Stolt P, Lundberg K ym. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54:38-46 «PMID: 16385494»PubMed
- Padyukov L, Silva C, Stolt P ym. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum 2004;50:3085-92 «PMID: 15476204»PubMed
- Huizinga TW, Amos CI, van der Helm-van Mil AH ym. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum 2005;52:3433-8 «PMID: 16255021»PubMed
- Myllykangas-Luosujärvi R. Mortality and causes of death in rheumatoid arthritis in Finland in 1989. Väitöskirja. Acta Universitatis Tamperensis. Ser A vol 461, 1995
- Sihvonen S, Korpela M, Laippala P ym. Death rates and causes of death in patients with rheumatoid arthritis: a population-based study. Scand J Rheumatol 2004;33:221-7 «PMID: 15370716»PubMed
- Dadoun S, Zeboulon-Ktorza N, Combescure C ym. Mortality in rheumatoid arthritis over the last fifty years: systematic review and meta-analysis. Joint Bone Spine 2013;80:29-33 «PMID: 22459416»PubMed
- Ogdie A, Haynes K, Troxel AB ym. Risk of mortality in patients with psoriatic arthritis, rheumatoid arthritis and psoriasis: a longitudinal cohort study. Ann Rheum Dis 2014;73:149-53 «PMID: 23264338»PubMed
- Kuller LH, Mackey RH, Walitt BT ym. Determinants of mortality among postmenopausal women in the women's health initiative who report rheumatoid arthritis. Arthritis Rheumatol 2014;66:497-507 «PMID: 24574208»PubMed
- Listing J, Kekow J, Manger B ym. Mortality in rheumatoid arthritis: the impact of disease activity, treatment with glucocorticoids, TNFa inhibitors and rituximab. Ann Rheum Dis 2015;74:415-21 «PMID: 24291654»PubMed
- Wasko MC, Dasgupta A, Hubert H ym. Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum 2013;65:334-42 «PMID: 23044791»PubMed
- van Tuyl LH, Boers M, Lems WF ym. Survival, comorbidities and joint damage 11 years after the COBRA combination therapy trial in early rheumatoid arthritis. Ann Rheum Dis 2010;69:807-12 «PMID: 19451137»PubMed
- Nakajima A, Saito K, Kojima T ym. No increased mortality in patients with rheumatoid arthritis treated with biologics: results from the biologics register of six rheumatology institutes in Japan. Mod Rheumatol 2013;23:945-52 «PMID: 23073692»PubMed
- Simard JF, Neovius M, Askling J ym. Mortality rates in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: drug-specific comparisons in the Swedish Biologics Register. Arthritis Rheum 2012;64:3502-10 «PMID: 22886739»PubMed
- Humphreys JH, Warner A, Chipping J ym. Mortality trends in patients with early rheumatoid arthritis over 20 years: results from the Norfolk Arthritis Register. Arthritis Care Res (Hoboken) 2014;66:1296-301 «PMID: 24497371»PubMed
- Masuda H, Miyazaki T, Shimada K ym. Disease duration and severity impacts on long-term cardiovascular events in Japanese patients with rheumatoid arthritis. J Cardiol 2014;64:366-70 «PMID: 24685688»PubMed
- Puolakka K, Kautiainen H, Pohjolainen T ym. No increased mortality in incident cases of rheumatoid arthritis during the new millennium. Ann Rheum Dis 2010;69:2057-8 «PMID: 20448281»PubMed
- Kerola AM, Nieminen TVM, Virta LJ, Kautiainen H, Kerola T, Pohjolainen T, Kauppi MJ, Puolakka K: No Increased Cardiovascular Mortality among Early Rheumatoid Arthritis Patients - a Nationwide Register Study in 2000 - 2008. Clin Exp Rheumatol 2015, painossa.
- Sokka T, Pincus T. Erythrocyte sedimentation rate, C-reactive protein, or rheumatoid factor are normal at presentation in 35%-45% of patients with rheumatoid arthritis seen between 1980 and 2004: analyses from Finland and the United States. J Rheumatol 2009;36:1387-90 «PMID: 19411389»PubMed
- Möttönen T, Paimela L, Leirisalo-Repo M ym. Only high disease activity and positive rheumatoid factor indicate poor prognosis in patients with early rheumatoid arthritis treated with "sawtooth" strategy. Ann Rheum Dis 1998;57:533-9 «PMID: 9849312»PubMed
- Luosujärvi Riitta. Niveltensisäinen kortisonihoito. SLL 2015;70:1165-1170
- Laasonen L. Tavanomainen röntgentutkimus perifeeristen artriittien diagnostiikassa. Suom Lääkäril 1992;47:487
- van der Heijde DM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol 1995;34 Suppl 2:74-8 «PMID: 8535653»PubMed
- Graudal NA, Jurik AG, de Carvalho A ym. Radiographic progression in rheumatoid arthritis: a long-term prospective study of 109 patients. Arthritis Rheum 1998;41:1470-80 «PMID: 9704647»PubMed
- Sokka T. Näkökulma. T2T-manifesti tähtää nivelreuman parempaan hoitoon. Suom Lääkäril 2011;18:1472-3
- Rantalaiho V, Puolakka K, Korpela M ym. Long-term results of the FIN-RACo trial; treatment with a combination of traditional disease-modifying anti-rheumatic drugs is an excellent option in early rheumatoid arthritis. Clin Exp Rheumatol 2012;30:S27-31 «PMID: 23073350»PubMed
- Puolakka K, Kautiainen H, Möttönen T ym. Early suppression of disease activity is essential for maintenance of work capacity in patients with recent-onset rheumatoid arthritis: five-year experience from the FIN-RACo trial. Arthritis Rheum 2005;52:36-41 «PMID: 15641055»PubMed
- Möttönen T, Hannonen P, Leirisalo-Repo M ym. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 1999;353:1568-73 «PMID: 10334255»PubMed
- Bingham SJ, Buch MH, Lindsay S ym. Parenteral methotrexate should be given before biological therapy. Rheumatology (Oxford) 2003;42:1009-10 «PMID: 12869673»PubMed
- The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. Rheumatoid Arthritis Clinical Trial Archive Group. J Rheumatol 1995;22:218-23 «PMID: 7738941»PubMed
- Malm H. Isän kautta välittyvä teratogeneesi - aiheetonta pelkoa syytä välttää. Suom Lääkäril 2009;11:1036-7
- Vliet Vlieland TP, van den Ende CH. Nonpharmacological treatment of rheumatoid arthritis. Curr Opin Rheumatol 2011;23:259-64 «PMID: 21346575»PubMed
- van den Hout WB, Tijhuis GJ, Hazes JM ym. Cost effectiveness and cost utility analysis of multidisciplinary care in patients with rheumatoid arthritis: a randomised comparison of clinical nurse specialist care, inpatient team care, and day patient team care. Ann Rheum Dis 2003;62:308-15 «PMID: 12634227»PubMed
- Puolakka K, Kautiainen H, Möttönen T ym. Cost of Finnish statutory inpatient rehabilitation and its impact on functional and work capacity of patients with early rheumatoid arthritis: experience from the FIN-RACo trial. Scand J Rheumatol 2007;36:270-7 «PMID: 17763204»PubMed
- Gabay C, Hasler P, Kyburz D ym. Biological agents in monotherapy for the treatment of rheumatoid arthritis. Swiss Med Wkly 2014;144:w13950 «PMID: 24723273»PubMed
- Sokka T, Kautiainen H, Pincus T ym. Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST-RA database. Ann Rheum Dis 2009;68:1666-72 «PMID: 19643759»PubMed
- Putrik P, Ramiro S, Kvien TK ym. Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis 2014;73:198-206 «PMID: 23467636»PubMed
- Putrik P, Ramiro S, Kvien TK ym. Variations in criteria regulating treatment with reimbursed biologic DMARDs across European countries. Are differences related to country's wealth? Ann Rheum Dis 2014;73:2010-21 «PMID: 23940213»PubMed
- Sokka T, Haugeberg G, Asikainen J ym. Similar clinical outcomes in rheumatoid arthritis with more versus less expensive treatment strategies. Observational data from two rheumatology clinics. Clin Exp Rheumatol 2013;31:409-14 «PMID: 23415074»PubMed
- Kauppi M, Pukkala E, Isomäki H. Elevated incidence of hematologic malignancies in patients with Sjögren's syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control 1997;8:201-4 «PMID: 9134244»PubMed
- Isomäki HA, Hakulinen T, Joutsenlahti U. Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis. J Chronic Dis 1978;31:691-6 «PMID: 730824»PubMed
- Le Blay P, Mouterde G, Barnetche T ym. Risk of malignancy including non-melanoma skin cancers with anti-tumor necrosis factor therapy in patients with rheumatoid arthritis: meta-analysis of registries and systematic review of long-term extension studies. Clin Exp Rheumatol 2012;30:756-64 «PMID: 22766000»PubMed
- Smolen JS, Aletaha D, Koeller M ym. New therapies for treatment of rheumatoid arthritis. Lancet 2007;370:1861-74 «PMID: 17570481»PubMed
- Isomäki P. Biologisten lääkkeiden vasta-aineet reumataudeissa - teho katoaa? Suom Lääkär 2014;34:2013
- Garcês S, Antunes M, Benito-Garcia E ym. A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis 2014;73:1138-43 «PMID: 23666932»PubMed
- Garcês S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis 2013;72:1947-55 «PMID: 23223420»PubMed
- Bendtzen K, Geborek P, Svenson M ym. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 2006;54:3782-9 «PMID: 17133559»PubMed
- Ducourau E, Mulleman D, Paintaud G ym. Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. Arthritis Res Ther 2011;13:R105 «PMID: 21708018»PubMed
- Keane J, Gershon S, Wise RP ym. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-104 «PMID: 11596589»PubMed
- Mikuls TR, Moreland LW. Benefit-risk assessment of infliximab in the treatment of rheumatoid arthritis. Drug Saf 2003;26:23-32 «PMID: 12495361»PubMed
- Alldred A. Etanercept in rheumatoid arthritis. Expert Opin Pharmacother 2001;2:1137-48 «PMID: 11583065»PubMed
- Konttinen Y, Nordström D, Honkanen V ym. Biologisten reumalääkkeiden käyttöön liittyvät riskit. Lääkärilehti 2004:43:4129-36
- Navarro-Millán I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther 2012;34:788-802.e3 «PMID: 22444783»PubMed
- Bari SF, Khan A, Lawson T. C reactive protein may not be reliable as a marker of severe bacterial infection in patients receiving tocilizumab. BMJ Case Rep 2013;2013: «PMID: 24177456»PubMed
- Edwards JC, Szczepanski L, Szechinski J ym. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81 «PMID: 15201414»PubMed
- Cohen SB, Emery P, Greenwald MW ym. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793-806 «PMID: 16947627»PubMed
- Scher JU. B-cell therapies for rheumatoid arthritis. Bull NYU Hosp Jt Dis 2012;70:200-3 «PMID: 23259629»PubMed
- van Vollenhoven RF, Emery P, Bingham CO 3rd ym. Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol 2010;37:558-67 «PMID: 20110520»PubMed
- Kaine J, Gladstein G, Strusberg I ym. Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study). Ann Rheum Dis 2012;71:38-44 «PMID: 21917824»PubMed
- Lopes RV, Furtado RN, Parmigiani L ym. Accuracy of intra-articular injections in peripheral joints performed blindly in patients with rheumatoid arthritis. Rheumatology (Oxford) 2008;47:1792-4 «PMID: 18820311»PubMed
- Sibbitt WL Jr, Peisajovich A, Michael AA ym. Does sonographic needle guidance affect the clinical outcome of intraarticular injections? J Rheumatol 2009;36:1892-902 «PMID: 19648304»PubMed
- Konai MS, Vilar Furtado RN, Dos Santos MF ym. Monoarticular corticosteroid injection versus systemic administration in the treatment of rheumatoid arthritis patients: a randomized double-blind controlled study. Clin Exp Rheumatol 2009;27:214-21 «PMID: 19473560»PubMed
- Weitoft T, Forsberg C. Importance of immobilization after intraarticular glucocorticoid treatment for elbow synovitis: a randomized controlled study. Arthritis Care Res (Hoboken) 2010;62:735-7 «PMID: 20461791»PubMed
- Wallen M, Gillies D. Intra-articular steroids and splints/rest for children with juvenile idiopathic arthritis and adults with rheumatoid arthritis. Cochrane Database Syst Rev 2006;:CD002824 «PMID: 16437446»PubMed
- Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J ym. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013;382:769-79 «PMID: 23726390»PubMed
- Radner H, Ramiro S, van der Heijde DM ym. How do gastrointestinal or liver comorbidities influence the choice of pain treatment in inflammatory arthritis? A Cochrane systematic review. J Rheumatol Suppl 2012;90:74-80 «PMID: 22942333»PubMed
- Brooks J, Warburton R, Beales IL. Prevention of upper gastrointestinal haemorrhage: current controversies and clinical guidance. Ther Adv Chronic Dis 2013;4:206-22 «PMID: 23997925»PubMed
- Marks JL, van der Heijde DM, Colebatch AN ym. Pain pharmacotherapy in patients with inflammatory arthritis and concurrent cardiovascular or renal disease: a Cochrane systematic review. J Rheumatol Suppl 2012;90:81-4 «PMID: 22942334»PubMed
- Doherty M, Hawkey C, Goulder M ym. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis 2011;70:1534-41 «PMID: 21804100»PubMed
- Whittle SL, Richards BL, van der Heijde DM ym. The efficacy and safety of opioids in inflammatory arthritis: a Cochrane systematic review. J Rheumatol Suppl 2012;90:40-6 «PMID: 22942328»PubMed
- Ramiro S, Radner H, van der Heijde DM ym. Combination therapy for pain management in inflammatory arthritis: a Cochrane systematic review. J Rheumatol Suppl 2012;90:47-55 «PMID: 22942329»PubMed
- Solomon DH, Karlson EW, Rimm EB ym. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107:1303-7 «PMID: 12628952»PubMed
- Chung CP, Oeser A, Raggi P ym. Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors. Arthritis Rheum 2005;52:3045-53 «PMID: 16200609»PubMed
- Bergholm R, Leirisalo-Repo M, Vehkavaara S ym. Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis. Arterioscler Thromb Vasc Biol 2002;22:1637-41 «PMID: 12377742»PubMed
- Park YB, Lee SK, Lee WK ym. Lipid profiles in untreated patients with rheumatoid arthritis. J Rheumatol 1999;26:1701-4 «PMID: 10451065»PubMed
- Aviña-Zubieta JA, Choi HK, Sadatsafavi M ym. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008;59:1690-7 «PMID: 19035419»PubMed
- Tam LS, Gladman DD, Hallett DC ym. Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J Rheumatol 2000;27:2142-5 «PMID: 10990225»PubMed
- Hagen KB, Byfuglien MG, Falzon L ym. Dietary interventions for rheumatoid arthritis. Cochrane Database Syst Rev 2009;:CD006400 «PMID: 19160281»PubMed
- Koivuniemi R ja Leirisalo-Repo M.Tulehduksellisiin reumasairauksiin liittyy suurentunut sydän- ja verisuinisairauksien riski. S Lääkäril 2015; 70:711-5
- Jämsen E, Virta LJ, Hakala M ym. The decline in joint replacement surgery in rheumatoid arthritis is associated with a concomitant increase in the intensity of anti-rheumatic therapy: a nationwide register-based study from 1995 through 2010. Acta Orthop 2013;84:331-7 «PMID: 23992137»PubMed
- Matti U.K. Lehto. Reumaortopedian valtakunnallinen toteuttaminen. Selvitysmiehen raportti.67s. Sosiaali- ja terveysministeriön raportteja ja muistioita 2012:3. «http://urn.fi/URN:ISBN:958-952-00-3206-7»12
- Simmen BR, Bogoch ER, Goldhahn J. Surgery Insight: orthopedic treatment options in rheumatoid arthritis. Nat Clin Pract Rheumatol 2008;4:266-73 «PMID: 18334981»PubMed
- Ikävalko M. Rheumatoid Elbow Destruction and its Treatment with Souter-Strathclyde Arthroplasty. Acta Universitatis Tamperensis; 1014, Tampereen yliopisto, Tampere 2004.
- Hill J, Bird H, Johnson S. Effect of patient education on adherence to drug treatment for rheumatoid arthritis: a randomised controlled trial. Ann Rheum Dis 2001;60:869-75 «PMID: 11502614»PubMed
- Smolen JS, Aletaha D, Bijlsma JW ym. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010;69:631-7 «PMID: 20215140»PubMed
- Lahti J, Maria R, Koski-Jännes A. Motivoiva haastattelu kaksoisdiagnoosipotilaiden hoidossa. Duodecim 2013;129:2063-9 «http://www.duodecimlehti.fi/web/guest/etusivu/artikkeli?tunnus=duo11266»13
- Puolakka K, Kautiainen H, Mottonen T ym. Use of the Stanford Health Assessment Questionnaire in estimation of long-term productivity costs in patients with recent-onset rheumatoid arthritis. Scand J Rheumatol 2009;38:96-103 «PMID: 19274516»PubMed
- Hallert E, Husberg M, Skogh T. 28-Joint count disease activity score at 3 months after diagnosis of early rheumatoid arthritis is strongly associated with direct and indirect costs over the following 4 years: the Swedish TIRA project. Rheumatology (Oxford) 2011;50:1259-67 «PMID: 21292734»PubMed
- Kobelt G, Eberhardt K, Jönsson L ym. Economic consequences of the progression of rheumatoid arthritis in Sweden. Arthritis Rheum 1999;42:347-56 «PMID: 10025930»PubMed
- Augustsson J, Neovius M, Cullinane-Carli C ym. Patients with rheumatoid arthritis treated with tumour necrosis factor antagonists increase their participation in the workforce: potential for significant long-term indirect cost gains (data from a population-based registry). Ann Rheum Dis 2010;69:126-31 «PMID: 19470527»PubMed
- Rantalaiho VM, Kautiainen H, Järvenpää S ym. Decline in work disability caused by early rheumatoid arthritis: results from a nationwide Finnish register, 2000-8. Ann Rheum Dis 2013;72:672-7 «PMID: 22679306»PubMed
- Marmor MF, Kellner U, Lai TY ym. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118:415-22 «PMID: 21292109»PubMed
- Bykerk VP, Akhavan P, Hazlewood GS ym. Canadian Rheumatology Association recommendations for pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs. J Rheumatol 2012;39:1559-82 «PMID: 21921096»PubMed
- Ajeganova S, Svensson B, Hafström I ym. Low-dose prednisolone treatment of early rheumatoid arthritis and late cardiovascular outcome and survival: 10-year follow-up of a 2-year randomised trial. BMJ Open 2014;4:e004259 «PMID: 24710131»PubMed
- Alasaarela E, Takalo R, Tervonen O ym. Sonography and MRI in the evaluation of painful arthritic shoulder. Br J Rheumatol 1997;36:996-1000 «PMID: 9376998»PubMed
- Aletaha D, Funovits J, Breedveld FC ym. Rheumatoid arthritis joint progression in sustained remission is determined by disease activity levels preceding the period of radiographic assessment. Arthritis Rheum 2009;60:1242-9 «PMID: 19404938»PubMed
- Allaire SH, Li W, LaValley MP. Reduction of job loss in persons with rheumatic diseases receiving vocational rehabilitation: a randomized controlled trial. Arthritis Rheum 2003;48:3212-8 «PMID: 14613285»PubMed
- Anderson JJ, Wells G, Verhoeven AC ym. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum 2000;43:22-9 «PMID: 10643696»PubMed
- Arvidsson S, Bergman S, Arvidsson B ym. Effects of a self-care promoting problem-based learning programme in people with rheumatic diseases: a randomized controlled study. J Adv Nurs 2013;69:1500-14 «PMID: 22973890»PubMed
- Aviña-Zubieta JA, Abrahamowicz M, De Vera MA ym. Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study. Rheumatology (Oxford) 2013;52:68-75 «PMID: 23192907»PubMed
- Bae SC, Gun SC, Mok CC ym. Improved health outcomes with etanercept versus usual DMARD therapy in an Asian population with established rheumatoid arthritis. BMC Musculoskelet Disord 2013;14:13 «PMID: 23294908»PubMed
- Benbouazza K, Benchekroun B, Rkain H ym. Profile and course of early rheumatoid arthritis in Morocco: a two-year follow-up study. BMC Musculoskelet Disord 2011;12:266 «PMID: 22111841»PubMed
- Bijlsma JW. Disease control with glucocorticoid therapy in rheumatoid arthritis. Rheumatology (Oxford) 2012;51 Suppl 4:iv9-13 «PMID: 22685274»PubMed
- Bilberg A, Ahlmén M, Mannerkorpi K. Moderately intensive exercise in a temperate pool for patients with rheumatoid arthritis: a randomized controlled study. Rheumatology (Oxford) 2005;44:502-8 «PMID: 15728422»PubMed
- Boers M, Verhoeven AC, Markusse HM ym. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350:309-18 «PMID: 9251634»PubMed
- Boers M. Drugs and cardiovascular risk in inflammatory arthritis: another case of glucocorticoid-bashing? Ann Rheum Dis 2015;74:e33 «PMID: 25714930»PubMed
- Braun J, Kästner P, Flaxenberg P ym. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum 2008;58:73-81 «PMID: 18163521»PubMed
- Brosseau L, Judd MG, Marchand S ym. Transcutaneous electrical nerve stimulation (TENS) for the treatment of rheumatoid arthritis in the hand. Cochrane Database Syst Rev 2003;:CD004377 «PMID: 12918009»PubMed
- Brosseau L, Robinson V, Wells G ym. Low level laser therapy (Classes I, II and III) for treating rheumatoid arthritis. Cochrane Database Syst Rev 2005;:CD002049 «PMID: 16235295»PubMed
- Buckland-Wright JC, Clarke GS, Chikanza IC ym. Quantitative microfocal radiography detects changes in erosion area in patients with early rheumatoid arthritis treated with myocrisine. J Rheumatol 1993;20:243-7 «PMID: 8474059»PubMed
- Burmester GR, Rubbert-Roth A, Cantagrel A ym. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis 2014;73:69-74 «PMID: 23904473»PubMed
- Buttgereit F, Doering G, Schaeffler A ym. Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial. Lancet 2008;371:205-14 «PMID: 18207016»PubMed
- Buttgereit F, Doering G, Schaeffler A ym. Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis. Ann Rheum Dis 2010;69:1275-80 «PMID: 20542963»PubMed
- Buttgereit F, Mehta D, Kirwan J ym. Low-dose prednisone chronotherapy for rheumatoid arthritis: a randomised clinical trial (CAPRA-2). Ann Rheum Dis 2013;72:204-10 «PMID: 22562974»PubMed
- Campbell L, Chen C, Bhagat SS ym. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology (Oxford) 2011;50:552-62 «PMID: 21078627»PubMed
- Casimiro L, Brosseau L, Robinson V ym. Therapeutic ultrasound for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 2002;:CD003787 «PMID: 12137714»PubMed
- Chalmers AC, Busby C, Goyert J ym. Metatarsalgia and rheumatoid arthritis--a randomized, single blind, sequential trial comparing 2 types of foot orthoses and supportive shoes. J Rheumatol 2000;27:1643-7 «PMID: 10914845»PubMed
- Chatzidionysiou K, Lie E, Nasonov E ym. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Ann Rheum Dis 2011;70:1575-80 «PMID: 21571731»PubMed
- Cho NS, Hwang JH, Chang HJ ym. Randomized controlled trial for clinical effects of varying types of insoles combined with specialized shoes in patients with rheumatoid arthritis of the foot. Clin Rehabil 2009;23:512-21 «PMID: 19403553»PubMed
- Choy EH, Smith CM, Farewell V ym. Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis 2008;67:656-63 «PMID: 17768173»PubMed
- Conrad KJ, Budiman-Mak E, Roach KE ym. Impacts of foot orthoses on pain and disability in rheumatoid arthritics. J Clin Epidemiol 1996;49:1-7 «PMID: 8598501»PubMed
- Cutolo M, Iaccarino L, Doria A ym. Efficacy of the switch to modified-release prednisone in rheumatoid arthritis patients treated with standard glucocorticoids. Clin Exp Rheumatol 2013;31:498-505 «PMID: 23415134»PubMed
- de Buck PD, le Cessie S, van den Hout WB ym. Randomized comparison of a multidisciplinary job-retention vocational rehabilitation program with usual outpatient care in patients with chronic arthritis at risk for job loss. Arthritis Rheum 2005;53:682-90 «PMID: 16208658»PubMed
- de Jong PH, Hazes JM, Barendregt PJ ym. Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: first results of the tREACH trial. Ann Rheum Dis 2013;72:72-8 «PMID: 22679301»PubMed
- del Rincón I, Battafarano DF, Restrepo JF ym. Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol 2014;66:264-72 «PMID: 24504798»PubMed
- Dellhag B, Wollersjö I, Bjelle A. Effect of active hand exercise and wax bath treatment in rheumatoid arthritis patients. Arthritis Care Res 1992;5:87-92 «PMID: 1390969»PubMed
- den Uyl D, van Raalte DH, Nurmohamed MT ym. Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: balance between diabetogenic effects and inflammation reduction. Arthritis Rheum 2012;64:639-46 «PMID: 21953589»PubMed
- Egsmose C, Lund B, Borg G ym. Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5 year followup of a prospective double blind placebo controlled study. J Rheumatol 1995;22:2208-13 «PMID: 8835550»PubMed
- Engvall IL, Brismar K, Hafström I ym. Treatment with low-dose prednisolone is associated with altered body composition but no difference in bone mineral density in rheumatoid arthritis patients: a controlled cross-sectional study. Scand J Rheumatol 2011;40:161-8 «PMID: 21077801»PubMed
- Engvall IL, Svensson B, Tengstrand B ym. Impact of low-dose prednisolone on bone synthesis and resorption in early rheumatoid arthritis: experiences from a two-year randomized study. Arthritis Res Ther 2008;10:R128 «PMID: 18986531»PubMed
- Feldman DE, Bernatsky S, Houde M ym. Early consultation with a rheumatologist for RA: does it reduce subsequent use of orthopaedic surgery? Rheumatology (Oxford) 2013;52:452-9 «PMID: 22949726»PubMed
- Gaujoux-Viala C, Nam J, Ramiro S ym. Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2014;73:510-5 «PMID: 24395555»PubMed
- Genovese MC, Covarrubias A, Leon G ym. Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis Rheum 2011;63:2854-64 «PMID: 21618201»PubMed
- Ghazi M, Kolta S, Briot K ym. Prevalence of vertebral fractures in patients with rheumatoid arthritis: revisiting the role of glucocorticoids. Osteoporos Int 2012;23:581-7 «PMID: 21350894»PubMed
- Giraudet-Le Quintrec JS, Mayoux-Benhamou A, Ravaud P ym. Effect of a collective educational program for patients with rheumatoid arthritis: a prospective 12-month randomized controlled trial. J Rheumatol 2007;34:1684-91 «PMID: 17610321»PubMed
- Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF ym. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005;52:3381-90 «PMID: 16258899»PubMed
- Gorter SL, Bijlsma JW, Cutolo M ym. Current evidence for the management of rheumatoid arthritis with glucocorticoids: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2010;69:1010-4 «PMID: 20448288»PubMed
- Graudal N, Jürgens G. Similar effects of disease-modifying antirheumatic drugs, glucocorticoids, and biologic agents on radiographic progression in rheumatoid arthritis: meta-analysis of 70 randomized placebo-controlled or drug-controlled studies, including 112 comparisons. Arthritis Rheum 2010;62:2852-63 «PMID: 20560138»PubMed
- Gremese E, Salaffi F, Bosello SL ym. Very early rheumatoid arthritis as a predictor of remission: a multicentre real life prospective study. Ann Rheum Dis 2013;72:858-62 «PMID: 22798566»PubMed
- Grigor C, Capell H, Stirling A ym. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004;364:263-9 «PMID: 15262104»PubMed
- Grønning K, Rannestad T, Skomsvoll JF ym. Long-term effects of a nurse-led group and individual patient education programme for patients with chronic inflammatory polyarthritis - a randomised controlled trial. J Clin Nurs 2014;23:1005-17 «PMID: 23875718»PubMed
- Grønning K, Skomsvoll JF, Rannestad T ym. The effect of an educational programme consisting of group and individual arthritis education for patients with polyarthritis--a randomised controlled trial. Patient Educ Couns 2012;88:113-20 «PMID: 22277625»PubMed
- Hafström I, Albertsson K, Boonen A ym. Remission achieved after 2 years treatment with low-dose prednisolone in addition to disease-modifying anti-rheumatic drugs in early rheumatoid arthritis is associated with reduced joint destruction still present after 4 years: an open 2-year continuation study. Ann Rheum Dis 2009;68:508-13 «PMID: 18420939»PubMed
- Hall J, Skevington SM, Maddison PJ ym. A randomized and controlled trial of hydrotherapy in rheumatoid arthritis. Arthritis Care Res 1996;9:206-15 «PMID: 8971230»PubMed
- Hall J, Swinkels A, Briddon J ym. Does aquatic exercise relieve pain in adults with neurologic or musculoskeletal disease? A systematic review and meta-analysis of randomized controlled trials. Arch Phys Med Rehabil 2008;89:873-83 «PMID: 18452734»PubMed
- Hammond A, Freeman K. The long-term outcomes from a randomized controlled trial of an educational-behavioural joint protection programme for people with rheumatoid arthritis. Clin Rehabil 2004;18:520-8 «PMID: 15293486»PubMed
- Harris JA, Bykerk VP, Hitchon CA ym. Determining best practices in early rheumatoid arthritis by comparing differences in treatment at sites in the Canadian Early Arthritis Cohort. J Rheumatol 2013;40:1823-30 «PMID: 24037554»PubMed
- Harrison BJ, Symmons DP, Brennan P ym. Natural remission in inflammatory polyarthritis: issues of definition and prediction. Br J Rheumatol 1996;35:1096-100 «PMID: 8948295»PubMed
- Haugeberg G, Morton S, Emery P ym. Effect of intra-articular corticosteroid injections and inflammation on periarticular and generalised bone loss in early rheumatoid arthritis. Ann Rheum Dis 2011;70:184-7 «PMID: 20805297»PubMed
- Hawke F, Burns J, Radford JA ym. Custom-made foot orthoses for the treatment of foot pain. Cochrane Database Syst Rev 2008;:CD006801 «PMID: 18646168»PubMed
- Hetland ML, Hørslev-Petersen K. The CIMESTRA study: intra-articular glucocorticosteroids and synthetic DMARDs in a treat-to-target strategy in early rheumatoid arhtritis. Clin Exp Rheumatol 2012;30:S44-9 «PMID: 23079125»PubMed
- Hetland ML, Stengaard-Pedersen K, Junker P ym. Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study. Ann Rheum Dis 2008;67:815-22 «PMID: 17878209»PubMed
- Hetland ML, Stengaard-Pedersen K, Junker P ym. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum 2006;54:1401-9 «PMID: 16645967»PubMed
- Hetland ML, Østergaard M, Ejbjerg B ym. Short- and long-term efficacy of intra-articular injections with betamethasone as part of a treat-to-target strategy in early rheumatoid arthritis: impact of joint area, repeated injections, MRI findings, anti-CCP, IgM-RF and CRP. Ann Rheum Dis 2012;71:851-6 «PMID: 22302316»PubMed
- Hirvonen HE, Mikkelsson MK, Kautiainen H ym. Effectiveness of different cryotherapies on pain and disease activity in active rheumatoid arthritis. A randomised single blinded controlled trial. Clin Exp Rheumatol 2006;24:295-301 «PMID: 16870097»PubMed
- Hoekstra M, Haagsma C, Neef C ym. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol 2004;31:645-8 «PMID: 15088287»PubMed
- Hoes JN, van der Goes MC, van Raalte DH ym. Glucose tolerance, insulin sensitivity and ß-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids. Ann Rheum Dis 2011;70:1887-94 «PMID: 21908880»PubMed
- Houssien DA, Scott DL. Early referral and outcome in rheumatoid arthritis. Scand J Rheumatol 1998;27:300-2 «PMID: 9751472»PubMed
- Hurkmans E, van der Giesen FJ, Vliet Vlieland TP ym. Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis. Cochrane Database Syst Rev 2009;:CD006853 «PMID: 19821388»PubMed
- Hørslev-Petersen K, Hetland ML, Junker P ym. Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial. Ann Rheum Dis 2014;73:654-61 «PMID: 23434570»PubMed
- Isaacs JD, Cohen SB, Emery P ym. Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis. Ann Rheum Dis 2013;72:329-36 «PMID: 22689315»PubMed
- Jansen LM, van Schaardenburg D, van Der Horst-Bruinsma IE ym. Predictors of functional status in patients with early rheumatoid arthritis. Ann Rheum Dis 2000;59:223-6 «PMID: 10700432»PubMed
- John H, Hale ED, Treharne GJ ym. A randomized controlled trial of a cognitive behavioural patient education intervention vs a traditional information leaflet to address the cardiovascular aspects of rheumatoid disease. Rheumatology (Oxford) 2013;52:81-90 «PMID: 22942402»PubMed
- Kellner H, Bornholdt K, Hein G. Leflunomide in the treatment of patients with early rheumatoid arthritis--results of a prospective non-interventional study. Clin Rheumatol 2010;29:913-20 «PMID: 20496042»PubMed
- Kirwan JR, Hewlett S, Cockshott Z ym. Clinical and psychological outcomes of patient education in rheumatoid arthritis. Musculoskeletal Care 2005;3:1-16 «PMID: 17041989»PubMed
- Klarenbeek NB, van der Kooij SM, Güler-Yüksel M ym. Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study. Ann Rheum Dis 2011;70:315-9 «PMID: 21068104»PubMed
- Kourbeti IS, Ziakas PD, Mylonakis E. Biologic therapies in rheumatoid arthritis and the risk of opportunistic infections: a meta-analysis. Clin Infect Dis 2014;58:1649-57 «PMID: 24647016»PubMed
- Laiho K, Soini I, Kautiainen H ym. Can we rely on magnetic resonance imaging when evaluating unstable atlantoaxial subluxation? Ann Rheum Dis 2003;62:254-6 «PMID: 12594114»PubMed
- Lard LR, Visser H, Speyer I ym. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med 2001;111:446-51 «PMID: 11690569»PubMed
- Launois R, Avouac B, Berenbaum F ym. Comparison of certolizumab pegol with other anticytokine agents for treatment of rheumatoid arthritis: a multiple-treatment Bayesian metaanalysis. J Rheumatol 2011;38:835-45 «PMID: 21239748»PubMed
- LE Blay P, Mouterde G, Barnetche T ym. Short-term risk of total malignancy and nonmelanoma skin cancers with certolizumab and golimumab in patients with rheumatoid arthritis: metaanalysis of randomized controlled trials. J Rheumatol 2012;39:712-5 «PMID: 22382344»PubMed
- Leirisalo-Repo M, Kautiainen H, Laasonen L ym. Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study). Ann Rheum Dis 2013;72:851-7 «PMID: 22753402»PubMed
- Ljung L, Askling J, Rantapää-Dahlqvist S ym. The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study. Arthritis Res Ther 2014;16:R127 «PMID: 24941916»PubMed
- Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA ym. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 2012;308:898-908 «PMID: 22948700»PubMed
- Luukkainen R, Isomäki H, Kajander A. Effect of gold treatment on the progression of erosions in RA patients. Scand J Rheumatol 1977;6:123-7 «PMID: 897587»PubMed
- Machado DA, Guzman RM, Xavier RM ym. Open-label observation of addition of etanercept versus a conventional disease-modifying antirheumatic drug in subjects with active rheumatoid arthritis despite methotrexate therapy in the Latin American region. J Clin Rheumatol 2014;20:25-33 «PMID: 24356474»PubMed
- Mathieux R, Marotte H, Battistini L ym. Early occupational therapy programme increases hand grip strength at 3 months: results from a randomised, blind, controlled study in early rheumatoid arthritis. Ann Rheum Dis 2009;68:400-3 «PMID: 19015209»PubMed
- Maxwell L, Singh JA. Abatacept for rheumatoid arthritis. Cochrane Database Syst Rev 2009;:CD007277 «PMID: 19821401»PubMed
- Mazzantini M, Talarico R, Doveri M ym. Incident comorbidity among patients with rheumatoid arthritis treated or not with low-dose glucocorticoids: a retrospective study. J Rheumatol 2010;37:2232-6 «PMID: 20843913»PubMed
- McCluggage LK, Scholtz JM. Golimumab: a tumor necrosis factor alpha inhibitor for the treatment of rheumatoid arthritis. Ann Pharmacother 2010;44:135-44 «PMID: 20118145»PubMed
- McQueen FM, Stewart N, Crabbe J ym. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis 1998;57:350-6 «PMID: 9771209»PubMed
- Moreland LW, O'Dell JR, Paulus HE ym. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum 2012;64:2824-35 «PMID: 22508468»PubMed
- Moulis G, Sommet A, Béné J ym. Cancer risk of anti-TNF-a at recommended doses in adult rheumatoid arthritis: a meta-analysis with intention to treat and per protocol analyses. PLoS One 2012;7:e48991 «PMID: 23155441»PubMed
- Munro R, Hampson R, McEntegart A ym. Improved functional outcome in patients with early rheumatoid arthritis treated with intramuscular gold: results of a five year prospective study. Ann Rheum Dis 1998;57:88-93 «PMID: 9613337»PubMed
- Mäkinen H, Kautiainen H, Hannonen P ym. Sustained remission and reduced radiographic progression with combination disease modifying antirheumatic drugs in early rheumatoid arthritis. J Rheumatol 2007;34:316-21 «PMID: 17183623»PubMed
- Möttönen TT, Hannonen P, Toivanen J ym. Value of joint scintigraphy in the prediction of erosiveness in early rheumatoid arthritis. Ann Rheum Dis 1988;47:183-9 «PMID: 3355257»PubMed
- Nam JL, Ramiro S, Gaujoux-Viala C ym. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2014;73:516-28 «PMID: 24399231»PubMed
- Nell VP, Machold KP, Eberl G ym. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 2004;43:906-14 «PMID: 15113999»PubMed
- O'Dell JR, Mikuls TR, Taylor TH ym. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med 2013;369:307-18 «PMID: 23755969»PubMed
- Ogata A, Tanimura K, Sugimoto T ym. Phase III study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014;66:344-54 «PMID: 23983039»PubMed
- Paimela L. The radiographic criterion in the 1987 revised criteria for rheumatoid arthritis. Reassessment in a prospective study of early disease. Arthritis Rheum 1992;35:255-8 «PMID: 1536665»PubMed
- Pavy S, Constantin A, Pham T ym. Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion. Joint Bone Spine 2006;73:388-95 «PMID: 16626993»PubMed
- Penesová A, Rádiková Z, Vlcek M ym. Chronic inflammation and low-dose glucocorticoid effects on glucose metabolism in premenopausal females with rheumatoid arthritis free of conventional metabolic risk factors. Physiol Res 2013;62:75-83 «PMID: 23173679»PubMed
- Puolakka K, Kautiainen H, Möttönen T ym. Predictors of productivity loss in early rheumatoid arthritis: a 5 year follow up study. Ann Rheum Dis 2005;64:130-3 «PMID: 15608311»PubMed
- Rantalaiho V, Kautiainen H, Korpela M ym. Physicians' adherence to tight control treatment strategy and combination DMARD therapy are additively important for reaching remission and maintaining working ability in early rheumatoid arthritis: a subanalysis of the FIN-RACo trial. Ann Rheum Dis 2014;73:788-90 «PMID: 24297374»PubMed
- Rembe EC. Use of cryotherapy on the postsurgical rheumatoid hand. Phys Ther 1970;50:19-23 «PMID: 5414653»PubMed
- Riemsma RP, Taal E, Kirwan JR ym. Systematic review of rheumatoid arthritis patient education. Arthritis Rheum 2004;51:1045-59 «PMID: 15593105»PubMed
- Roubille C, Richer V, Starnino T ym. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2015;74:480-9 «PMID: 25561362»PubMed
- Ruiz Garcia V, Jobanputra P, Burls A ym. Certolizumab pegol (CDP870) for rheumatoid arthritis in adults. Cochrane Database Syst Rev 2011;:CD007649 «PMID: 21328299»PubMed
- Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis 2009;68:25-32 «PMID: 18203761»PubMed
- Santiago T, da Silva JA. Safety of low- to medium-dose glucocorticoid treatment in rheumatoid arthritis: myths and reality over the years. Ann N Y Acad Sci 2014;1318:41-9 «PMID: 24814757»PubMed
- Scheel AK, Schmidt WA, Hermann KG ym. Interobserver reliability of rheumatologists performing musculoskeletal ultrasonography: results from a EULAR "Train the trainers" course. Ann Rheum Dis 2005;64:1043-9 «PMID: 15640263»PubMed
- Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses =15 mg may be overcome with subcutaneous administration. Ann Rheum Dis 2014;73:1549-51 «PMID: 24728329»PubMed
- Schipper LG, Fransen J, den Broeder AA ym. Time to achieve remission determines time to be in remission. Arthritis Res Ther 2010;12:R97 «PMID: 20487520»PubMed
- Schoels MM, van der Heijde D, Breedveld FC ym. Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement. Ann Rheum Dis 2013;72:583-9 «PMID: 23144446»PubMed
- Scirè CA, Lunt M, Marshall T ym. Early remission is associated with improved survival in patients with inflammatory polyarthritis: results from the Norfolk Arthritis Register. Ann Rheum Dis 2014;73:1677-82 «PMID: 23749581»PubMed
- Scirè CA, Verstappen SM, Mirjafari H ym. Reduction of long-term disability in inflammatory polyarthritis by early and persistent suppression of joint inflammation: results from the Norfolk Arthritis Register. Arthritis Care Res (Hoboken) 2011;63:945-52 «PMID: 21337726»PubMed
- Scott DL, Ibrahim F, Farewell V ym. Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial. BMJ 2015;350:h1046 «PMID: 25769495»PubMed
- Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis. Cochrane Database Syst Rev 2010;:CD008331 «PMID: 20614469»PubMed
- Singh JA, Christensen R, Wells GA ym. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev 2009;:CD007848 «PMID: 19821440»PubMed
- Singh JA, Noorbaloochi S, Singh G. Golimumab for rheumatoid arthritis: a systematic review. J Rheumatol 2010;37:1096-104 «PMID: 20436075»PubMed
- Singh JA, Wells GA, Christensen R ym. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev 2011;:CD008794 «PMID: 21328309»PubMed
- Smith HJ. Contrast-enhanced MRI of rheumatic joint disease. Br J Rheumatol 1996;35 Suppl 3:45-7 «PMID: 9010090»PubMed
- Soini I, Kotaniemi A, Kautiainen H ym. US assessment of hip joint synovitis in rheumatic diseases. A comparison with MR imaging. Acta Radiol 2003;44:72-8 «PMID: 12631003»PubMed
- Stavropoulos-Kalinoglou A, Metsios GS, Veldhuijzen van Zanten JJ ym. Individualised aerobic and resistance exercise training improves cardiorespiratory fitness and reduces cardiovascular risk in patients with rheumatoid arthritis. Ann Rheum Dis 2013;72:1819-25 «PMID: 23155222»PubMed
- Steultjens EM, Dekker J, Bouter LM ym. Occupational therapy for rheumatoid arthritis. Cochrane Database Syst Rev 2004;:CD003114 «PMID: 14974005»PubMed
- Svensson B, Andersson ML, Bala SV ym. Long-term sustained remission in a cohort study of patients with rheumatoid arthritis: choice of remission criteria. BMJ Open 2013;3:e003554 «PMID: 24022393»PubMed
- Szkudlarek M, Narvestad E, Klarlund M ym. Ultrasonography of the metatarsophalangeal joints in rheumatoid arthritis: comparison with magnetic resonance imaging, conventional radiography, and clinical examination. Arthritis Rheum 2004;50:2103-12 «PMID: 15248207»PubMed
- Thompson AE, Rieder SW, Pope JE. Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum 2011;63:1479-85 «PMID: 21360522»PubMed
- Tiippana-Kinnunen T, Laasonen L, Kautiainen H ym. Impact of early radiographic remission on the 15-year radiographic outcome in patients with rheumatoid arthritis. Scand J Rheumatol 2011;40:263-8 «PMID: 21417549»PubMed
- Tiippana-Kinnunen T, Paimela L, Kautiainen H ym. Can disease-modifying anti-rheumatic drugs be discontinued in long-standing rheumatoid arthritis? A 15-year follow-up. Scand J Rheumatol 2010;39:12-8 «PMID: 20132065»PubMed
- Toms TE, Panoulas VF, Douglas KM ym. Lack of association between glucocorticoid use and presence of the metabolic syndrome in patients with rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther 2008;10:R145 «PMID: 19091101»PubMed
- Tsakonas E, Fitzgerald AA, Fitzcharles MA ym. Consequences of delayed therapy with second-line agents in rheumatoid arthritis: a 3 year followup on the hydroxychloroquine in early rheumatoid arthritis (HERA) study. J Rheumatol 2000;27:623-9 «PMID: 10743799»PubMed
- van Aken J, Heimans L, Gillet-van Dongen H ym. Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study). Ann Rheum Dis 2014;73:396-400 «PMID: 23334213»PubMed
- van den Broek M, Huizinga TW, Dijkmans BA ym. Drug-free remission: is it already possible? Curr Opin Rheumatol 2011;23:266-72 «PMID: 21427578»PubMed
- van der Heide A, Jacobs JW, Bijlsma JW ym. The effectiveness of early treatment with "second-line" antirheumatic drugs. A randomized, controlled trial. Ann Intern Med 1996;124:699-707 «PMID: 8633829»PubMed
- van der Linden MP, le Cessie S, Raza K ym. Long-term impact of delay in assessment of patients with early arthritis. Arthritis Rheum 2010;62:3537-46 «PMID: 20722031»PubMed
- van der Woude D, Visser K, Klarenbeek NB ym. Sustained drug-free remission in rheumatoid arthritis after DAS-driven or non-DAS-driven therapy: a comparison of two cohort studies. Rheumatology (Oxford) 2012;51:1120-8 «PMID: 22337939»PubMed
- van Dongen H, van Aken J, Lard LR ym. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2007;56:1424-32 «PMID: 17469099»PubMed
- van Nies JA, van der Helm-van Mil AH. Is early remission associated with improved survival or is arthritis persistency associated with increased mortality in early arthritis? Comparisons with the general population. Ann Rheum Dis 2013;72:e25 «PMID: 23852696»PubMed
- van Vollenhoven RF, Ernestam S, Geborek P ym. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet 2009;374:459-66 «PMID: 19665644»PubMed
- Ward MM, Leigh JP, Fries JF. Progression of functional disability in patients with rheumatoid arthritis. Associations with rheumatology subspecialty care. Arch Intern Med 1993;153:2229-37 «PMID: 8215726»PubMed
- Ward MM. Rheumatology visit frequency and changes in functional disability and pain in patients with rheumatoid arthritis. J Rheumatol 1997;24:35-42 «PMID: 9002008»PubMed
- Wassenberg S, Rau R, Zeidler H ym. A dose of only 5 mg prednisolone daily retards radiographic progression in early rheumatoid arthritis - the Low-Dose Prednisolone Trial. Clin Exp Rheumatol 2011;29:S68-72 «PMID: 22018187»PubMed
- Welch V, Brosseau L, Shea B ym. Thermotherapy for treating rheumatoid arthritis. Cochrane Database Syst Rev 2001;:CD002826 «PMID: 11406046»PubMed
- Verstappen SM, van Albada-Kuipers GA, Bijlsma JW ym. A good response to early DMARD treatment of patients with rheumatoid arthritis in the first year predicts remission during follow up. Ann Rheum Dis 2005;64:38-43 «PMID: 15130899»PubMed
- Wevers-de Boer K, Visser K, Heimans L ym. Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study). Ann Rheum Dis 2012;71:1472-7 «PMID: 22402145»PubMed
- Wolfe F, Hawley DJ, Cathey MA. Clinical and health status measures over time: prognosis and outcome assessment in rheumatoid arthritis. J Rheumatol 1991;18:1290-7 «PMID: 1757927»PubMed
- Wong AK, Kerkoutian S, Said J ym. Risk of lymphoma in patients receiving antitumor necrosis factor therapy: a meta-analysis of published randomized controlled studies. Clin Rheumatol 2012;31:631-6 «PMID: 22147207»PubMed
- Woodburn J, Barker S, Helliwell PS. A randomized controlled trial of foot orthoses in rheumatoid arthritis. J Rheumatol 2002;29:1377-83 «PMID: 12136891»PubMed
- Yoo DH, Hrycaj P, Miranda P ym. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013;72:1613-20 «PMID: 23687260»PubMed