Multiple Disease-modifying Antirheumatic Drugs Research Articles

An ADAM10 Exosite Inhibitor Is Efficacious in an In Vivo Collagen-Induced Arthritis Model.

Rheumatoid arthritis is a systemic autoimmune inflammatory disease that affects millions of people worldwide. There are multiple disease-modifying anti-rheumatic drugs available; however, many patients do not respond to any treatment. A disintegrin and metalloproteinase 10 has been suggested as a potential new target for RA due to its role in the release of multiple pro- and anti-inflammatory factors from cell surfaces. In the present study, we determined the pharmacokinetic parameters and in vivo efficacy of a compound CID3117694 from a novel class of non-zinc-binding inhibitors. Oral bioavailability was demonstrated in the blood and synovial fluid after a 10 mg/kg dose. To test efficacy, we established the collagen-induced arthritis model in mice. CID3117694 was administered orally at 10, 30, and 50 mg/kg/day for 28 days. CID3117694 was able to dose-dependently improve the disease score, decrease RA markers in the blood, and decrease signs of inflammation, hyperplasia, pannus formation, and cartilage erosion in the affected joints compared to the untreated control. Additionally, mice treated with CID 3117694 did not exhibit any clinical signs of distress, suggesting low toxicity. The results of this study suggest that the inhibition of ADAM10 exosite can be a viable therapeutic approach to RA.

E67 Still's disease in children refractory to usual treatments: recourse to biotherapies: challenges and opportunities

Abstract Background Still's disease in children is a rare autoinflammatory disease with distinct characteristics from other forms of Juvenile Idiopathic Arthritis. A better understanding of its mechanism has led to the use of targeted therapies with a significant improvement in patient prognosis. Despite these advances, there are still subtypes of Still's disease refractory to the usual treatments with serious complications. Objective demonstrate therapeutic escalation in the Child’s Still Methods We report the case of a patient unresponsive to multiple disease-modifying antirheumatic drugs (DMARDs), who required high doses of steroids. The biological ones were an inevitable recourse to improve the vital and functional prognosis; with at the end, a therapeutic escape with anti IL1 after two years of favorable response. Case report 12-year-old girl with no particular family history, with Still's disease diagnosed at the age of nine with a typical clinical form: thermal steeple concomitant with a morbiliform and evanescent skin eruption, polyarthritis, with hepatosplenomegaly. The diagnosis was confirmed by a major biological inflammatory syndrome with raise serum ferritin, serum C-reactive protein level and sedimentation rate. Despite doses > 0.5 mg/kg/d of prednisone, she showed high-threshold sensitivity to corticosteroids with the appearance of deleterious effects: Cushingoid obesity, stretch marks and bilateral cataracts. Methotrexate was added at a dose of 12 m/m2/week, without clinical response. She eventually developed severe macrophage activation syndrome which was successfully treated with bolus corticosteroids. Faced with this systemic form refractory to the usual treatments; biotherapy was used. Anakinra was added to his treatment at a dose of 2 mg/kg/day. Impressive improvement in systemic and joint clinical signs occurred within the first few weeks of treatment and acute phase reactants returned to normal. Anakinra was well tolerated and no adverse effects were observed. After 24 months of follow-up and complete clinical remission, without corticosteroid therapy, she presented with a severe flare of her disease with severe inflammatory runaway (SMA) and disseminated intravascular coagulation. After controlling this acute clinical condition with intravenous corticosteroids and ciclosporin; we switched to antiIL6 with a good clinical and biological evolution. Discussion The excellent response to anakinra in this case refractory to conventional treatments suggests that IL1 inhibition could be an important therapeutic target in some patients. Nevertheless, some subtypes of Still's disease escape anakinra after a few years of good response and this has been suggested by some authors. Conclusion Pro-inflammatory cytokines such as interleukin IL1, IL6, and IL18 have been implicated in the pathogenesis of childhood Still's disease. In recent years, targeted biologics have been used with several cases of successful treatment in forms refractory to conventional drugs.

Active rheumatoid arthritis with multiple pulmonary nodules failure to multiple remissive therapy: Which is the solution?

We describe the case of a 63-year-old nonsmoker woman, with a long history of active seropositive rheumatoid arthritis, failure to multiple disease-modifying antirheumatic drugs due to both loss of efficacy and adverse drug reaction. She was exposed to silicon dust some years ago and has many pulmonary nodules, revealed by imaging studies as multiple cavitary lung nodules. Her initial pathological samples were negative for any infections and treatment against tuberculosis and anti-fungal therapy did not improve the appearance of the nodules. After an extensive reevaluation of pulmonary nodules, the Baricitinib treatment was started.

Predictors and temporal trend of flu vaccination in auto-immune rheumatic diseases in the UK: a nationwide prospective cohort study.

ObjectivesTo examine temporal trend in uptake of seasonal influenza vaccine (SIV) in the UK and explore disease and demographic factors associated with vaccination.MethodsFrom the Clinical Practice Research Datalink, 32 751 people with auto-immune rheumatic diseases prescribed DMARDs between 2006 and 2016 were identified. The proportion vaccinated between 1 September of one year and 31 March of the next year was calculated and stratified by age, other indications for vaccination, auto-immune rheumatic diseases type and number of DMARDs prescribed. Stata and Joinpoint regression programs were used.ResultsSIV uptake was high in those aged ⩾65 years (82.3 and 80.7% in 2006–07 and 2015–16, respectively). It was significantly lower in other age groups, but improved over time with 51.9 and 61.9% in the 45–64 year age group, and 32.3 and 50.1% in the <45 year age group being vaccinated in 2006–07 and 2015–16, respectively. While 64.9% of the vaccinations in those ⩾65 years old occurred by 3 November, in time to mount a protective immune response before the influenza activity becomes substantial in the UK, only 38.9% in the 45–64 year and 26.2% in the <45 year age group without any other reason for vaccination received SIV by this date. Women, those with additional indications for vaccination, on multiple DMARDs and with SLE were more likely to be vaccinated.ConclusionSIV uptake is low in the under 65s, and the majority of them are not vaccinated in time. Additional effort is required to promote timely uptake of SIV in this population.

Using subcutaneous methotrexate to prolong duration of methotrexate therapy in rheumatoid arthritis.

Our study aims to determine whether the use of subcutaneous methotrexate (SC MTX) is associated with prolonged MTX use and lower incidence of hepatotoxicity in rheumatoid arthritis (RA) patients on MTX monotherapy and multiple drug therapy. We conducted a retrospective cohort study using national databases of a large hospital system. Subjects had been diagnosed with RA and treated with MTX between September 30, 1999, and October 1, 2009. Outcomes of interest were the amount of time on MTX monotherapy or multiple disease-modifying anti-rheumatic drug (DMARD) therapy before addition of additional DMARDs or biologic agents, respectively. We conducted Cox regressions and Kaplan-Meier curves for association between SC MTX use and length of time before therapeutic change. We conducted chi-square tests for association between SC MTX use and elevated liver function tests (LFT). MTX monotherapy: SC MTX was associated with a significantly lower likelihood of therapeutic change (HR 0.64, 95% CI 0.52-0.78). Multiple DMARD therapy: SC MTX was not associated with a lower risk of adding a biologic (HR 1.13, 95% CI 0.97-1.31). Liver enzymes: There was no significant association between use of SC MTX and decreased frequency of abnormal LFTs [p=0.09 for alanine aminotransferase (ALT), p=0.924 for aspartate aminotransferase (AST)]. Use of SC MTX is associated with longer duration of MTX monotherapy before addition of other DMARDs/biologic agents in RA patients. Use of SC MTX is not associated with significantly longer duration of multiple DMARD therapy before addition of biologic agents. Use of oral MTX is not significantly associated with increased frequency of elevated LFTs.

Development of a web-based patient decision aid for initiating disease modifying anti-rheumatic drugs using user-centred design methods

BackgroundA main element of patient-centred care, Patient Decision Aids (PtDAs) facilitate shared decision-making (SDM). A recent update of the International Patient Decision Aids Standards (IPDAS) emphasised patient involvement during PtDA development, but omitted a methodology for doing so. This article reports on the value of user-centred design (UCD) methods for the development of a PtDA that aims to support inflammatory arthritis patients in their choice between disease modifying anti-rheumatic drugs (DMARDs).MethodsThe IPDAS development process model in combination with UCD methods were applied. The process was overseen by an eight-member multidisciplinary steering group. Patients and health professionals were iteratively consulted. Qualitative in-depth interviews combined with rapid prototyping were conducted with patients to assess their needs for specific functionality, content and design of the PtDA. Group meetings with health professionals were organized to assess patients’ needs and to determine how the PtDA should be integrated into patient pathways. The current literature was reviewed to determine the clinical evidence to include in the PtDA. To evaluate usability among patients, they were observed using the PtDA while thinking aloud and then interviewed.ResultsThe combination of patient interviews with rapid prototyping revealed that patients wanted to compare multiple DMARDs both for their clinical aspects and implications for daily life. Health professionals mainly wanted to refer patients to a reliable, easily adjustable source of information about DMARDs. A web-based PtDA was constructed consisting of four parts: 1) general information about SDM, inflammatory arthritis and DMARDs; 2) an application to compare particular DMARDs; 3) value clarification exercises; and 4) a printed summary of patients’ notes, preferences, worries and questions that they could bring to discuss with their rheumatologist.ConclusionsThe study demonstrated that UCD methods can be of great value for the development of PtDAs. The early, iterative involvement of patients and health professionals was helpful in developing a novel user-friendly PtDA that allowed patients to choose between DMARDs. The PtDA fits the values of all stakeholders and easily integrates with the patient pathway and daily workflow of health professionals. This collaborative designed PtDA may improve SDM and patient participation in arthritis care.

Sterile Osteitis and Suppurative Arthritis Associated with Pannus Responding to Colchicine

Sterile suppurative arthritis is characterized by neutrophilic infiltration of joints without any causative pathogen. Here, we present a 32-year-old man with refractory osteitis and erosive suppurative oligoarthritis with pannus. Treatments with multiple disease modifying antirheumatic drugs were all unsuccessful. However, he had clinical response to colchicine and the synovial hypertrophy and the pannus in the MRI of his left shoulder resolved. In this case, the effects of colchicine on neutrophils might have played a role in treating neutrophilic sterile suppurative arthritis, which, in adults, might be a distinct oligoarticular disease.

IMPROVED: Final Study Results of Combination Treatment in Patients with Early RA and UA

Final results of the Induction Therapy with Methotrexate and Prednisone in Rheumatoid or Very Early Arthritis Disease [IMPROVED] study showed that patients with rheumatoid arthritis and undifferentiated arthritis achieved similarly greater rates of remission after early initial treatment with combination therapy (methotrexate and prednisone). Patients who failed to achieve early remission benefited more when switched to a treatment strategy with adalimumab than with multiple disease modifying antirheumatic drugs, with virtually no radiographic damage progression in all patients.

Early Management of Newly Diagnosed Rheumatoid Arthritis by Canadian Rheumatologists: A National, Multicenter, Retrospective Cohort

To describe early rheumatologic management for newly diagnosed rheumatoid arthritis (RA) in Canada. A retrospective cohort of 339 randomly selected patients with RA diagnosed from 2001-2003 from 18 rheumatology practices was audited between 2005-2007. The most frequent initial disease-modifying antirheumatic drugs (DMARD) included hydroxychloroquine (55.5%) and methotrexate (40.1%). Initial therapy with multiple DMARD (15.6%) or single DMARD and corticosteroid combinations (30.7%) was infrequent. Formal assessment measures were noted infrequently, including the Health Assessment Questionnaire (34.6%) and Disease Activity Score for 28 joints (8.9%). Initial pharmacotherapy is consistent with guidelines from the period. The infrequent reporting of multiple DMARD combinations and formal assessment measures has implications for current clinical management and warrants contemporary reassessment.

高齢発症関節リウマチの治療

In addition to population-growth in the elderly, development of new therapeutic agents for rheumatoid arthritis (RA) contributes to an increase in the number of elderly patients with RA. It is also reported that the age of RA onset is going higher. Elderly-onset RA (EORA) is defined as RA developing after the age of 60 years. In RA patients, significant damage can be detected radiographically within the first 2 years after the initial presentation of symptoms; therefore, appropriate treatment should be administered at the earliest. Meanwhile, caution should be exercised in prescribing disease-modifying antirheumatic drugs (DMARDs) to elderly patients because the associated risk of adverse effects and toxicity is elevated in the elderly. However, excessive caution may prevent elderly patients from being implemented the ideal therapy. Compared to young patients with RA, patients with EORA are less frequently treated with biological agents or multiple DMARDs treatment and more frequently treated with prednisone. Some patients with EORA do not receive optimal treatment during the early stage of RA, when the disease is highly active and joint destruction rapidly progresses. EORA should be treated with appropriate DMARDs instead of corticosteroids in order to maintain the risk of infection minimal and the patients' physical function maximal.

Infliximab in the treatment of rheumatoid arthritis

Infliximab was the first monoclonal antibody to human necrosis factor alpha (TNFalpha) developed for treating rheumatoid arthritis (RA). This chimeric antibody binds with high affinity to both soluble and trans-membrane TNF and is able to reduce synovial inflammation, bone resorption and cartilage degradation. The efficacy of infliximab has been observed in active RA despite treatment with multiple disease modifying anti-rheumatic drugs (DMARDs), and in early disease with no prior treatment by methotrexate (MTX). Infliximab has been shown to reduce joint inflammation and to slow radiographic progression, in both clinical and non-clinical responders. Recent data suggest that using infliximab early in RA treatment increases the percentage of clinical remission and allows infliximab discontinuation. The recommended dosage of 3 mg/kg could be increased up to 10 mg/kg with partial efficacy of the dose escalation. Antibodies to infliximab have been observed in 7% to 61% of patients and are associated with a low trough level of infliximab and secondary response failure. Their occurrence could be prevented by co-medication with MTX. The combination of DMARDs other than MTX with infliximab was found to be safe and efficacious. Infections, principally tuberculosis, are increased in treated patients, and the risk is greater at higher dose. Even if the treatment is generally safe and well tolerated, patients treated with infliximab should be closely monitored.

Pulmonary Nodules in an Infliximab-Treated Rheumatoid Arthritis Patient

A 78-year-old African-American woman was diagnosed with rheumatoid arthritis (RA) in 1996 after she presented with a symmetrical polyarthritis of the hands. Over the next 4 years, she was treated with multiple disease-modifying antirheumatic drugs including methotrexate, hydroxychloroquine, gold, and leflunomide, all of which were stopped due to side effects or lack of response. She was started on low-dose prednisone in 1998, and was also maintained on low-dose azathioprine, which had been initiated in June. In October 2000, the patient developed a cervical myelopathy, manifested by ataxia and hyperreflexia. Magnetic resonance imaging of the cervical spine showed compression of the ventral cord by an enhancing epidural soft-tissue mass behind the odontoid, which was thought to be pannus, as well as multilevel spondylosis with cord compression at C5– 6. In December 2000, she underwent cervical spine decompression at the C5–6 level but was left with residual ataxia. In early 2000, the patient had begun to lose weight, and this worsened after her spine surgery; she lost 20 lb between August 1999 and April 2001. Computerized tomography (CT) scan of the chest, abdomen, and pelvis without contrast was normal in April 2001. Magnetic resonance imaging of the abdomen was unremarkable except for thickening of the gastric antrum. Endoscopy was normal. Bone-marrow biopsy showed no evidence of malignancy. Testing for antigliadin antibodies and human immunodeficiency virus (HIV) were negative. In May 2001, the patient was started on infliximab for the likelihood that RA activity was contributing to her weight loss and also because of the myelopathy due to the presence of pannus behind the odontoid process. She received the first three infusions but was lost to follow-up. She presented again in September 2001 with a further weight loss of 10 lb and was admitted for further evaluation. The patient_s prior medical history was significant for hypertension, osteoporosis, and a pancreatic cystic mass which, when aspirated in 1998, had revealed no malignant cells. There also was an allergy to contrast dye. Medications at the time of admission were Premarin 0.625 mg daily (qd), prednisone 5 mg qd, furosemide 20 mg qd, and atenolol 50 mg qd. On physical examination, the patient was cachectic, weighing 66 lb. Blood pressure was 110/80 mmHg, and she was afebrile. Significant findings included: chronic swan neck and boutonniere_s deformities of the hands but no active synovitis; hyperreflexia in the lower extremities with mild left-sided dysmetria; and negative Babinski signs. Abdominal examination revealed mild left upper-quadrant abdominal tenderness without masses. Cardiopulmonary examination was within normal limits, and hemoccult stool test was negative. The initial laboratory investigation demonstrated a leukocyte count of 3.7 10/l (normal 3.4–11.2 10/l) with a normal differential, hemoglobin 9.5 g/dl (normal 12–16 g/dl), and platelet count of 201 10/l (normal 150– 450 10/l). Liver, renal, and thyroid function tests, as well as urinalyses, were normal. Serum albumin was 2.9 g/dl, HSSJ (2007) 3: 119–125 DOI 10.1007/s11420-006-9032-1

Acute progression of interstitial lung disease: a complication of etanercept particularly in the presence of rheumatoid lung and methotrexate treatment

, We report two patients on etanercept who presented withsevere diffuse alveolar infiltrates culminating in ground-glasschange on high resolution computed tomography (HRCT) of thelung.The first, a 64-yr-old woman with an 11-yr-history of sero-negative rheumatoid arthritis (RA) had failed to achieve optimalcontrol of her RA with multiple disease modifying antirheumaticdrugs (DMARDs) and only showed a partial response to oralmethotrexate 22.5mg/week since 2002. Etanercept was introducedat 25mg twice a week. She developed acute breathlessness after sixinjections (3 weeks).She was an ex-smoker who had stopped 10yrs previously. Shehad no pre-existing rheumatoid lung disease but did have chronicobstructive pulmonary disease (COPD). Full pulmonary functiontests done 5yrs earlier showed the evidence of previous chronicobstructive airways disease, her corrected transfer factor (DLCO)corrected was 13.18 (55%) with a KCO 2.86 (62%). Chest X-ray(CXR) showed emphysema.She was admitted with a 3-day history of increasing shortness ofbreath (SOB) at rest without cough. HRCT of the chest showedwidespread ground-glass change throughout both lung bases, andchanges of bullous emphysema.Etanercept was discontinued. She was commenced on 40mgoral prednisolone and broad-spectrum antibiotics. Her SOBrecovered quickly but her joint symptoms flared and she wasrestarted on oral methotrexate 25mg/week to good effect. RepeatHRCT scan after 4 months showed significant improvement inground-glass changes with some minimal residual interstitialfibrotic change and bullae.The second case, a 61-yr-old lady, with RA for 10 yrs similarlyhad failed multiple DMARDS. A methotrexate dose of 25mg hadbeen started in 1999. She had known rheumatoid lung disease, andprevious pulmonary function tests showed restrictive lung diseasewith DLCO 2.06 (33%) and KCO 1.02 (63%). HRCT chestscan 1yr earlier prior to treatment showed pulmonary fibrosissuggestive of UIP, with no ground-glass change.She presented with a 2-week-history of breathlessness after 12injections (6 weeks) of etanercept, 25mg twice a week. There wasno evidence of infection or heart failure. CXR showed new diffusereticulonodular shadowing. CT pulmonary angiography (CTPA)confirmed widespread ground-glass change with no evidence ofpulmonary embolism.She was treated with broad spectrum intravenous antibiotics.The etanercept and methotrexate were stopped. Despite this andadding methylprednisolone 500mg/day for 3 days and changingantibiotics, she developed worsening hypoxia and was intubated.Bronchoalveolar lavage showed no evidence of TB, bacterial orpneumocystis Carinii infection.She developed metabolic acidosis, progressive renal failure andlater cardiacarrhythmias,anddespiteintensivetreatmentshe died.Both our patients had pre-existing lung disease, they hadenquiry into respiratory symptoms at 3 month intervals andannual CXR prior to the commencement of etanercept and weresymptomatically stable. Also,both wereonmethotrexate andbothdeveloped acute respiratory symptoms within 3 and 6 weeks ofcommencing etanercept, respectively, which culminated in accel-erated interstitial lung disease. The patient with COPD presentedearlier and recovered quickly with oral steroids aloneafter discontinuing etanercept and subsequently was able torecommence methotrexate 25mg/week with adequate joint diseasecontrol but no recurrence of respiratory symptoms. The patientwith poorer respiratory reserve developed progressive lung diseaseand died despite aggressive treatment.Lungdiseaseisawell-knowncomplicationofmethotrexate,andcases of accelerated methotrexate pneumonitis are also reportedwithin 2–3 doses of infliximab. Our patient who survived restartedmethotrexate safely, hence we do not postulate this as a cause [1].Infliximab has been reported to accelerate lung nodulosis [2, 3],and it has been reported as causing a reversible, biopsy proven,non-caseating granulomatous lung disease in RA [4]. In both ourpatients, lung biopsies were taken, which may have been thehistological change of the respiratory disease. Four further casesof reversible non-caseating granulomatous reaction temporallyrelatedtoetanercepttherapyhavealsobeenreported,twoofwhichhad previous pulmonary fibrosis [5]. Our two cases demonstrate alittle-known complication of etanercept, one of which was fatal. Itis noticeable that the patient who died also had rheumatoid lungdisease, whilst the patient with COPD survived. Previously reportsfrom the Biologics register [6], and published reports have raisedthe concern of increased mortality in patients with RA andpre-existing rheumatoid lung disease on azathiaprine whenanti-TNF was added [7]. On the basis of these two cases cautionneeds to be extended to those with pre-existing lung disease, takingmethotrexate when etanercept is added, particularly if the lungdisease is due to rheumatoid involvement. Extra caution should betaken in patients with rheumatoid lung and poor respiratoryreserve. Patients should be prompted to contact the rheumatologydepartment if symptoms of acute breathlessness occur, especiallysoon after the introduction of etanercept.The authors have declared no conflict of interest.K. L

Remission in Rheumatoid Arthritis: Wishful Thinking or Clinical Reality?

To review the concept of remission in rheumatoid arthritis (RA), as defined by the Food and Drug Administration (FDA), the American College of Rheumatology (ACR), and the European League Against Rheumatism (EULAR). To delineate differences between significant clinical improvements, very low disease activity, and the achievement of true remission. To evaluate the prevalence of these outcomes with biologic therapy and traditional disease-modifying antirheumatic drugs (DMARD) regimens. The MEDLINE database was searched for the key words "remission" and "rheumatoid arthritis." Efficacy data of RA clinical trials from 1985 to 2004 are based on a literature review of medical journals and abstracts from rheumatology meetings. We review 3 well-defined sets of criteria established by the ACR, EULAR, and the FDA for measuring remission. Defining remissions in clinical trials and clinical practice requires appropriate standardized and objective outcome measures, such as the ACR and EULAR remission criteria. Traditional DMARDs often provide symptom relief, improvements in physical function, and the slowing of radiographic progression in patients with RA, but rarely lead to the complete cessation of RA activity. Remission, as defined by the ACR criteria, has been observed in 7 to 22% of patients treated with traditional DMARD monotherapy (ie, gold, penicillamine, methotrexate [MTX], cyclosporine A, or sulfasalazine), but these remissions have often been short-lived. Treatments with DMARD combinations, biologic monotherapy, and biologic combination therapy with MTX offer greater hope and may facilitate the higher rates of remission. Clinical trial results have shown that newer DMARDs such as leflunomide or the combination of multiple DMARDs can generally elicit greater EULAR remission rates (ranging from 13 to 42%) than monotherapies. Biologic combinations with MTX have also been shown to induce significant remission (as defined by the EULAR criteria) in RA patients, with a 31% rate observed with infliximab plus MTX at 54 weeks, a 50% rate observed for adalimumab plus MTX after 2 years of therapy, and a 41% rate observed for etanercept plus MTX after 2 years of therapy. In the era of biologics and combination therapy, identifying remission or at least very low disease activity as the ultimate goal in RA therapy should become the new standard for the outcome of all RA trials. The criteria established by the FDA, the ACR, and the EULAR represent an important step toward achieving this goal.

Increased Spontaneous Apoptosis of CD4+CD25+T Cells in Patients with Active Rheumatoid Arthritis Is Reduced by Infliximab

Increased secretion of tumor necrosis factor-alpha (TNF-alpha), along with interleukin-1 (IL-1) and interleukin-6 (IL-6), is important in the pathogenesis of rheumatoid arthritis (RA). T regulatory CD4(+)CD25(+) cells play a role in maintaining self-tolerance by downregulating Th1-induced proinflammation. This function has been found to be altered in active RA, whereas anti-TNF-alpha therapy has been found to improve the suppressive abilities of these cells. Our objectives were to investigate whether T regulatory cells in patients with active RA display a higher sensitivity to spontaneous apoptosis than in normals, and to look into the potential of infliximab (anti-TNF-alpha therapy) to reduce the sensitivity of these cells to spontaneous apoptosis. Seventeen patients suffering from active RA, having failed multiple disease-modifying antirheumatic drug (DMARD) therapies, were treated with infliximab. Spontaneous apoptosis (as detected by annexin V binding) was determined in all patients and compared with a group of normal individuals at baseline and after three months on infliximab treatment. Peripheral blood mononuclear cells were incubated in 24-well plates at 1 x 10(6) cells/mL for 48 hours. Annexin V binding on CD4(+)CD25(+) was assessed using three-color assay by flow cytometry. Prior to infliximab initiation, spontaneous apoptosis of T regulatory cells from active RA patients was found to be increased in comparison with controls (26 +/- 4.2% vs. 19.8 +/- 4.8%, respectively; P = 0.01). Three months later (while still on infliximab) spontaneous apoptosis was comparable in the two groups (20.7 +/- 5.2% vs. 20.9 +/- 3.4%; P 5 0.8). The absolute number of CD4(+)CD25(+) cells/mL in the peripheral blood at baseline was reduced in 11 out of 17 active RA patients when compared with that of the control group (24 +/- 7 vs. 32 +/- 11, respectively; P = 0.02). Following anti-TNF-alpha therapy, CD4(+)CD25(+) cell counts of patients were equivalent to those of normals. The alteration and reversal in both spontaneous apoptosis and cell count of T regulatory cells was found to correlate with RA disease activity. CD4(+)CD25(+) T regulatory cells display increased proclivity to undergo spontaneous apoptosis in active RA. Alterations in CD4(+)CD25(+) cell apoptosis and cell count were found to correlate with RA disease activity. Reversal of these deviations from normal was documented in association with the beneficial outcome of infliximab therapy.

Successful Therapy of Rheumatoid Arthritis With Rituximab

Rheumatoid arthritis (RA) is often considered a T cell-mediated disease, yet recent studies describe benefit with rituximab, a monoclonal antibody directed against the B cell antigen CD20. We report our experience using rituximab for 5 patients with severe, disease-modifying antirheumatic drug (DMARD)-refractory RA. Five patients with seropositive, erosive RA received rituximab as 4 weekly doses of 375 mg/m. Four subjects experienced remission lasting 5 to 12 months after noting lack of efficacy with antitumor necrosis factor (TNF) therapy. All patients have relapsed, with signs and symptoms of RA returning a mean of 8 months after therapy. Rituximab appears to be a safe and potentially helpful treatment of refractory RA and, until U.S. Food and Drug Administration approval, could be considered for compassionate use in people who have failed multiple DMARDs. Individuals who do not respond to anti-TNF therapy could experience arthritis that is perpetuated by B cell more than T cell function; these patients could be most likely to respond to rituximab. Further studies are needed to clarify the optimal dose and frequency of rituximab therapy, and its role in combination therapy for individuals with RA.

Interleukin 6 receptor as a target for the treatment of rheumatoid arthritis

Chronic synovial inflammation and joint damage are cardinal features of rheumatoid arthritis (RA). Although the precise cause remains unknown, cytokines have a major pathogenic role. The therapeutic benefit of antagonists...

New Therapies for Rheumatoid Arthritis.

New Therapies for Rheumatoid Arthritis.

Successful treatment of a small cohort of patients with adult onset of Still's disease with infliximab: first experiences

OBJECTIVETo test the efficacy of infliximab in the treatment of patients with severe and active adult onset Still's syndrome (AOSD) despite conventional immunosuppressive therapy.PATIENTS AND METHODSSix patients with the diagnosis...

Overview of Combination Second-Line or Disease-Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis

This article discusses the use of combinations of disease-modifying antirheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA). Patients with RA have a disease that can be disabling and life threatening and current therapies do not prevent these complications. The need for more aggressive therapy is apparent. The rationale for combinations of DMARDs is explored and the efficacy and safety of reported combinations is summarized. The variables to be reviewed in selecting a combination of DMARDs are examined. Newer approaches employing multiple DMARDs will be considered.