Refractory Rheumatoid Arthritis Research Articles

Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid arthritis

Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid arthritis

Heparin-induced coagulopathy associated with staphylococcal protein A immunoadsorption treatment columns: an in vitro and in vivo analysis.

The staphylococcal protein A (SPA) column used to treat refractory autoimmune and alloimmune thrombocytopenia and rheumatoid arthritis patients is primed with heparin to prevent possible fibrin clot formation when the patient's plasma is passed through the column. A BMT patient with refractory alloimmune thrombocytopenia had prolonged activated partial thromboplastin times (aPTTs) at the end of SPA column treatments. This observation led to in vivo and in vitro analysis of the kinetics of heparin elution from the SPA column. Two patients with refractory rheumatoid arthritis, who were treated on five occasions with the SPA column (as a part of a national trial) primed with 5000 U of heparin, were monitored for aPTT and heparin in their plasma. In addition, two in vitro analyses were performed with FFP for heparin elution from the SPA column. The in vivo studies showed the presence of 0.3 to 1.5 U per mL of heparin in patients' plasma at the end of the SPA column treatments that corresponded with the prolonged aPTTs. The in vitro studies showed that 82 to 85 percent heparin (approx. 4400 U) was eluted from the SPA column during rather than before the procedure. Patients undergoing SPA column treatments, especially those with thrombocytopenia, may be at increased risk of bleeding as a result of the presence of a significant amount of heparin in their circulation during the entire period of SPA column treatment.

Additive combination of actarit and methotrexate in the treatment of refractory rheumatoid arthritis

The objective of this study was to evaluate the efficacy and safety of an additive combination of a disease-modifying antirheumatic drug (DMARD) actarit and low-dose methotrexate (MTX) in patients with active rheumatoid arthritis (RA) unresponsive to MTX. Thirty-four patients with active RA, who had been unsuccessfully treated with MTX for at least 3 months were enrolled on a 24-week course of actarit (300 mg/day) and MTX (2.5–10 mg/week). Disease activity was evaluated by physical global assessments using conventional measures (Japan Rheumatism Association), and the American College of Rheumatology (ACR) criteria of improvements in RA. Thirty-two patients completed this study. No severe adverse drug reactions were seen. Patients whose RA did not respond to MTX alone responded to the combination therapy, with a significant improvement in the duration of morning stiffness, grip strength, swollen joint counts, patient's articular pain score, modified health assessment questionnaire (M-HAQ) score, score of both patient's and physician's global assessments, and C-reactive proteins (CRP). Sixteen patients (50.0%) and 9 patients (31.0%) showed a significant improvement in overall conventional measures, and ACR response criteria, respectively, and 60.0% of RA patients who received MTX for more than 1 year showed improvement in ACR definition. Patients who responded to the combination treatment within the first 12 weeks showed persistent improvement for the remaining part of the 24 week period. Our results indicate that the additive combination of actarit and MTX is safe, and without serious adverse effects, and has an excellent efficacy in patients with active and refractory RA.

Management of the Patient with Severe Refractory Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease leading to joint destruction. It is the most common cause of potentially treatable disabilities. The outcome of the disease varies from very mild to a refractory, rapidly progressive type with a high mortality rate. In recent years, profound changes in the traditional paradigms of RA therapy have been introduced. Instead of a therapeutically progressive approach, aggressive therapy is recommended for aggressive forms of RA. It has forced us to remodel the traditional treatment pyramid, and to start new strategies such as saw-tooth or step-down-bridge schedules. The last 10 years have seen wide acceptance of immunosuppressive therapy. These agents hold much promise for the further treatment of RA. A few years ago it seemed that we would be unable to influence the long term outcome in RA, but today the development of new drugs and techniques has increased our chances of fighting RA, and prospects for the future are even more promising.

Methotrexate use in rheumatoid arthritis. A clinician's perspective

Aminopterine, a precursor of methotrexate (MTX), was first used for the treatment of rheumatoid arthritis (RA) in 1951 [Gubner, R., 1951. Therapeutic suppression of tissue reactivity: I. Comparison of the effects of cortisone and aminopterin. Am. J. Med. Sci. 221, 169–175; Gubner, R., August, S., Ginsberg, V., 1951. Therapeutic suppression of tissue reactivity: II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am. J. Med. Sci. 221, 176–182.]. Corticosteroids, and to some extent cyclophosphamide, took MTX out of the rheumatologist's armamentarium until the late 1970s–early 1980s when the toxic profile of these compounds became apparent. By the mid 1980s, four randomized clinical trials (RCTs) had proven beyond doubt the beneficial effects of MTX when administered to patients with established disease who had failed to respond to other compounds such as gold salts and d-penicillamine [Thompson, R.N., Watts, C., Edelman, J., Esdaile, J., and Russell, A.S., 1984. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J. Rheumatol. 11, 760–763; Andersen, P.A., West, S.G., O'Dell, J.R., Via, C.S., Claypool, R.G., and Kotzin, B.L., 1985. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann. Intern. Med. 103, 489–496; Weinblatt, M.E., Coblyn, J.S., Fox, D.A., Fraser, P.A., Holdsworth, D.E., Glass, D.N., and Trentham, D.E., 1985. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818–822; Williams, H.J., Willkens, R.F., Samuelson, C.O.J., Alarcón, G.S., Guttadauria, M., Yarboro, C., Polisson, R.P., Weiner, S.R., Luggen, M.E., Billingsley, L.M., Dahl, S.L., Egger, M.J., Reading, J.C., and Ward, J.R., 1985. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 28, 721–730.]. Subsequently, these four trials were included in a meta-analysis and the drug was approved by the Food and Drug Administration for use in RA [Health and Public Policy Committee, H.P.P.C. and American College Physicians, A.C.P., 1987. Methotrexate in rheumatoid arthritis. Ann. Intern. Med. 107, 418–419; Paulus, H.E., 1986. FDA Arthritis Advisory Committee meeting: Methotrexate; guidelines for the clinical evaluation of antiinflammatory drugs; DMSO in scleroderma. Arthritis Rheum. 29, 1289–1290; Tugwell, P., Bennett, K., and Gent, M., 1987. Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Ann. Intern. Med. 107, 358–366.]. Since then, rheumatologists have become aware of what Pincus et al. have called “the side effects” of RA comparing the morbidity and mortality caused by RA with that potentially caused by medications used to treat this disease [Pincus, T. and Callahan, L.F., 1993. The “side effects” of rheumatoid arthritis: joint destruction, disability and early mortality. Br. J. Rheumatol. 32, 28–37.]. Thus, during the 1990s the use of MTX for the treatment of RA became generalized [O'Dell, J.R., 1997. Methotrexate use in rheumatoid arthritis. Rheum. Dis. Clin. N Am. 23, 779–796 (a); Bannwarth, B., Vernhes, J., Schaeverbeke, T., and Dehais, J., 1995. The facts about methotrexate in rheumatoid arthritis. Rev. Rhum. 62, 471–473 (b); Bologna, C., Jorgensen, C., and Sany, J., 1997a. Methotrexate as the initial second-line disease modifying agent in the treatment of rheumatoid arthritis patients. Clin. Exp. Rheumatol. 15, 597–601; Bologna, C., Viu, P., Picot, M.C., Jorgensen, C., and Sany, J., 1997b. Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate an open, retrospective, observational study. Br. J. Rheumatol. 36, 535–540.]. By now, basic and clinical investigators have gathered a wealth of information covering many aspects related to this compound, ranging from its mechanism of action to how it can be administered in a much safer way to patients.This article highlights the way in which MTX is currently used by rheumatologists for the treatment of RA primarily, and to a lesser extent for the treatment of other rheumatic disorders. Other aspects of this compound have been covered elsewhere and will not be emphasized in this review.

Evaluation of a filtration lymphocytapheresis (LCP) device for use in the treatment of patients with rheumatoid arthritis. 1991.

Abstract: Guest Editor's Introduction: Cell adhesion on a material is caused by the interaction between them and related to the material characteristics including chemical structure, surface charge, wettability, smoothness, and microstructure such as microdomain structure. In addition, Nishimura of Asahi Medical Co. found that the size of the material is important particularly in the case of lymphocyte adhesion. Based upon this result Asahi Medical Co. developed lymphocyte removal filters by use of ultra fine fibers having a diameter of 1.7 μm. The filter was first used for leukocyte filters for blood transfusion, and then applied for therapeutic use in the treatment of patients with various hematological and autoimmune diseases. This paper describes the specification of the filter and clinical application for the treatment of rheumatoid arthritis. This paper was printed in Artificial Organs, vol. 15, page 180–188 (1991) and reprinted here with permission.A practical on‐line lymphocytapheresis (LCP) system using a leukapheresis filter (Cellsorba, Asahi Medical Co.) was evaluated in six patients with refractory rheumatoid arthritis. This filter consists of nonwoven fine polyester fiber wound around a porous cylinder. The blood was passed through the polyester fiber at a flow rate of 50 ml/min for 60 min. LCP was carried out once a week in the first month and biweekly in the next 2 months. An average of 98% of the leukocytes that entered the filter (1.27 × 1010 cells) and 100% of the lymphocytes that entered the filter (3.66 × 109 cells) were removed in the first LCP. A total of 96.6% of the platelets and 2.7% of the erythrocytes that entered the filter were also removed. All of the patients showed clinical improvement in morning stiffness, Lansbury articular index, and functional capacity, with no adverse reaction. The number of circulating lymphocytes erythrocytes, and platelets and the concentration of various serum components showed no significant change during the treatments. This LCP system required no fresh frozen plasma, albumin, or other blood transfusion. The number of circulating lymphocytes decreased to 65–70% of the pretreatment circulating lymphocyte count at the last procedure, with a decrease in the ratio of Leu3a positive cells to Leu2a positive cells. The proliferative response to phytohemagglutinin and concanavalin A was improved. These data suggest that LCP to remove ∼3 × 109 lymphocytes once a week or biweekly has an immunomodulatory effect.

Management of therapy-resistant rheumatoid arthritis.

During the last two decades, newly introduced therapeutic strategies have resulted in satisfactory modification of the disease course in the majority of the patients with rheumatoid arthritis (RA). Nevertheless, a definite number of RA patients remain therapy-resistant, and for this group more aggressive treatment may be required for preventing permanent disability and progressive joint damage necessitating surgical procedures. Therefore, management of therapy-resistant RA is one of the major challenges in modern rheumatology. RA patients who have not responded to conventional disease-modifying antirheumatic drug (DMARD) therapy are defined as refractory RA patients. However, a uniform description or definition for 'refractory' RA does not appear to be available. In this article we will deal with, and discuss, the term 'refractory RA' based on a MEDLINE database search using this term, currently available therapeutic options, data on therapy-resistant RA patients from an inception cohort of RA patients attending the Nijmegen University Hospital, management of extra-articular manifestations and future management strategies.

Clinical experience with soluble TNF p75 receptor in rheumatoid arthritis

Objectives: Managing rheumatoid arthritis (RA) can be difficult: the disease may follow an unpredictable course, and therapies are often ineffective or toxic. Etanercept, a bioengineered fusion protein derived from the human soluble tumor necrosis factor p75 receptor, recently has been approved for use in patients with refractory RA. Methods: Published data on clinical experience with etanercept in conjunctionwith case illustrations are presented. Results: Reports from clinical trials of patients with refractory RA indicate that etanercept significantly improves measures of disease activity, including swollen and tender joint counts, morning stiffness, pain, and erythrocyte sedimentation rate, compared with placebo. In the phase 3 trial, swollen joint counts improved by 47% in patients receiving etanercept 25 mg compared with a 7% worsening in patients receiving placebo. The drug is well tolerated; injection site reaction, the most frequent adverse event, was minor and manageable. In long-term studies, etanercept remains well tolerated and effective. Our clinical experience indicates that patients with refractory RA experience dramatic symptomatic relief, along with reduced fatigue and improved quality of life. One of 18 patients discontinued treatment; the rest have remained on therapy for up to 18 months. Conclusions: Etanercept diminishes disease activity in patients with refractoryRA. Its favorable safety profile provides symptom control without major toxicity. Etanercept is an important addition to RA therapeutic agents.

Open Trial of Thalidomide in the Treatment of Rheumatoid Arthritis

Reports on the use of thalidomide in the last 20 years have described favorable responses in a variety of inflammatory conditions. We have performed an open trial to begin to assess further its efficacy in rheumatoid arthritis (RA). During a 3-year-period, 31 patients with chronic active RA were enrolled into a 4-month open trial using thalidomide, to assess its efficacy and safety. Of these patients, 21 began the study taking 300 mg/day and the other 10 patients began at lesser doses that were increased gradually. Patients were evaluated at least 7 times during the 4-month study. Of the 31 patients, 17 (55%) withdrew from the study over the course of 12 weeks because of adverse events and no benefit was seen in any of these patients with a mean dose of 177 mg/day. There were 14 patients taking thalidomide for 4 months, and 4 of the 14 (29%) responded to therapy, satisfying at least 4 of the 6 Paulus criteria; 6 of 14 (43%) partially responded to therapy, satisfying 3 of the 6 Paulus criteria; and 4 of 14 (29%) did not respond, with each group taking average dosages, respectively, of 304 mg/day, 264 mg/day, and 303 mg/day. Of the 14 patients completing the 4-month study, 9 patients consented to participate in an extended trial of thalidomide treatment for at least 4 more months. Patients showing partial benefit within the first 4 months are more likely to show definite benefit later on.This study did not confirm the level of effect previously reported with thalidomide. However, some patients with previously refractory RA did improve. Although we had no comparison group, we believe that, as an investigational therapy, thalidomide should be considered in patients with RA for whom other conventional treatment approaches have failed. Thalidomide should be administered initially at 50 mg/hs for 1-2 weeks and then increased by 50 mg every 1-2 weeks as tolerated. The major obstacle to short term use of thalidomide is drowsiness and the major adverse effect to long term use is peripheral neuropathy.

Rheumatoid arthritis and primary care: the case for early diagnosis and treatment.

Rheumatoid arthritis is a chronic inflammatory disease that can cause severe pain and disability. Disease management historically was based on a "therapeutic pyramid" in which treatment escalated as symptoms worsened. However, the demonstration of early joint damage in patients with rheumatoid arthritis has emphasized the importance of early identification and treatment. Key features in establishing a diagnosis include joint examinations, assessments of extra-articular manifestations, laboratory tests, and radiologic examinations. Care must be taken to rule out other disorders with symptoms that overlap those of rheumatoid arthritis. Treatment of rheumatoid arthritis typically involves disease-modifying antirheumatic drugs, nonsteroidal anti-inflammatory drugs, and low-dose corticosteroids--often used in combination. A new class of therapeutic agents designed to neutralize inflammatory cytokines has added a new dimension to the therapeutic armamentarium against rheumatoid arthritis. Etanercept, a bioengineered soluble receptor fusion protein that blocks tumor necrosis factor activity, is the first compound in this class to be approved for treatment of patients with refractory rheumatoid arthritis. Therapeutic trials indicate that etanercept can reduce disease activity with relatively few drug-related adverse effects, thus helping persons with rheumatoid arthritis return to more normal, healthy lives.

Arthroscopic Synovectomy of the Metacarpophalangeal Joint in Refractory Rheumatoid Arthritis: A Technique

Summary: Arthroscopic synovectomy was performed on 29 metacarpophalangeal joints belonging to 21 patients with refractory rheumatoid arthritis. This article describes the method of anesthesia, landmarks, and operative technique. Short-term (12-month) results and patient satisfaction have been excellent. No complications were noted. We conclude that arthroscopic synovectomy of the metacarpophalangeal joints in patients with refractory rheumatoid arthritis can be performed safely and effectively. Possibilities for improvement of the technique as well as possible uses of the technique in research are discussed. Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 15, No 3 (April), 1999: pp 265–268

Anti-ICAM-1 Monoclonal Antibody R6.5 (Enlimomab) Promotes Activation of Neutrophils in Whole Blood

R6.5 (BIRR-1, Enlimomab), a murine IgG2a mAb to the human ICAM-1, inhibits leukocyte adhesion to the vascular endothelium, thereby decreasing leukocyte extravasation and inflammatory tissue injury. In initial clinical trials, R6.5 proved to be beneficial in reducing both disease activity in refractory rheumatoid arthritis and the incidence of acute rejection after kidney and liver allograft transplantations. However, adverse effects such as fever, leukopenia, or cutaneous reactions were not infrequent. We studied the effects of R6.5 on neutrophil function in whole blood samples ex vivo. Surprisingly, at the concentrations achieved in clinical trials, R6. 5 activated neutrophilic granulocytes, as indicated by a significant increase in expression of the adhesion molecule beta2-integrin CD11b, a concurrent decrease in L-selectin expression, and an enhancement of the oxidative burst activity. Neutrophil activation was not exerted by an anti-ICAM-1 mAb of the IgG1 isotype, by isotype-matched, irrelevant anti-2-phenyloxazolone mAb, or by F(ab')2 fragments of R6.5. Neutrophil activation was completely inhibited by soluble complement receptor type 1. We conclude that in whole blood, R6.5 activates resting neutrophils in a complement-dependent manner. This finding can explain, at least in part, the side effects associated with R6.5 therapy.

Etanercept: a review of its use in rheumatoid arthritis.

Etanercept, a fusion protein consisting of the extracellular ligand-binding domain of the 75kD receptor for tumour necrosis factor-alpha and the constant portion of human IgG1, is administered by subcutaneous injection and is the first specific anti-cytokine therapy approved for rheumatoid arthritis. In patients with active rheumatoid arthritis [American College of Rheumatology (ACR) functional class I to III] who had failed to respond to previous treatment with > or = 1 disease-modifying antirheumatic drug (DMARD), etanercept, alone or in combination with methotrexate, produced improvements in all components included in the ACR core set of disease activity measures. A dose-response effect was apparent with etanercept 0.25 to 16 mg/m2 twice weekly in a randomised, double-blind study in 180 patients. The mean number of swollen or tender joints at the end of the 12-week study decreased by >50% in patients treated with etanercept 16 mg/m2 twice weekly and by <25% in patients treated with placebo. In a 24-week multicentre, randomised, double-blind study in 234 patients who were not allowed to use DMARDs, etanercept 10 or 25mg twice weekly had a rapid onset of effect. Significantly more patients treated with etanercept 25mg twice weekly than placebo experienced 20 (ACR 20), 50 (ACR 50) or 70% (ACR 70) improvement in ACR criteria after 3 and 6 months. Limited evidence suggests that the therapeutic effects of etanercept are maintained for up to 2 years. Etanercept 25mg twice weekly produced significant improvement in patients receiving oral or subcutaneous methotrexate 10 to 25 mg/week in a multicentre, randomised, double-blind, placebo-controlled study. A significantly greater proportion of patients treated with etanercept plus methotrexate (71%) than placebo plus methotrexate (27%) achieved the ACR 20 criteria after 6 months. Moreover, 39 and 15% of patients treated with etanercept plus methotrexate, but no placebo plus methotrexate recipients, had achieved the ACR 50 and ACR 70 criteria at this time. Etanercept 0.4 mg/kg twice weekly reduced disease activity in a preliminary, noncomparative study in 69 children aged > or =4 years with refractory juvenile rheumatoid arthritis. Although the overall frequency of infections was similar in patients treated with etanercept or placebo, upper respiratory tract infections were more common in patients treated with etanercept (29%) than placebo (16%). Injection site reactions occurred more frequently in etanercept- than placebo-treated patients, but did not bias the results of any study. When etanercept is administered alone or in combination with methotrexate in patients with refractory rheumatoid arthritis, significant reductions in disease activity occur within 2 weeks and are sustained for at least 6 months. Thus, etanercept appears to be particularly well suited for use in patients who fail to respond to treatment with DMARDs.

SOLUBLE TUMOR NECROSIS FACTOR RECEPTOR (p75) FUSION PROTEIN (ENBREL) AS A THERAPY FOR RHEUMATOID ARTHRITIS

Soluble tumor necrosis factor (TNF) receptor fusion protein (p75) (Enbrel) is a reversible inhibitor of the biologic effects of TNF. Enbrel has been shown in placebo-controlled trials to significantly improve the signs and symptoms of rheumatoid arthritis. Clinical trials are now in progress to assess the safety and efficacy of Enbrel in combination with methotrexate in refractory rheumatoid arthritis along with trials to compare Enbrel to methotrexate in patients with early rheumatoid arthritis.

Treatment of refractory rheumatoid arthritis with low-dose cyclophosphamide. Long-term follow-up of 108 patients.

Although cyclophosphamide (CYC) is an effective drug in the treatment of refractory rheumatoid arthritis (RA), the application of this drug in RA has largely been abandoned, due to potentially life-threatening adverse events such as myelosuppression and cancer development. However, the question remains open, whether it is possible to balance the toxicity and the efficacy of CYC with low-dose therapy. 108 patients with refractory RA or with vasculitic organ involvement were treated with 50 mg CYC per day. Joint indices and laboratory parameters were gathered prospectively and the occurrence of serious side effects was monitored over a median of 10 years. The efficacy was surveyed in six months intervals. A 50% improvement of the swollen joint count was required to continue therapy. A long-term follow-up was performed to survey the incidence of malignancies. 85 patients dropped out within the first year. Only four patients were treated for longer than 4 years. In the total cohort, 50 patients were withdrawn due to the lack of efficacy, 34 patients had to discontinue because of adverse events, and 9 patients dropped out for both reasons. Gastrointestinal intolerance was the most frequent adverse event that led to the discontinuation of the drug, followed by myelosuppression. Five patients suffered from 6 malignancies occurring after a median of 4.5 years after cessation of treatment. Treatment of RA patients with 50 mg CYC per day resulted in a more favorable rate of serious adverse events and a markedly lower incidence of tumors compared to the treatment with 75 to 150 mg per day described in the literature. However, the long-term efficacy of this regimen was poor in our cohort.

Basic therapeutic combination therapy in chronic polyarthritis: an overview

Therapy of rheumatoid arthritis with a combination of several disease-modifying drugs aims towards better control of the disease than achievable by monotherapy. Based on a broad variety of clinical studies, revealing more or less positive results, several combinations have been suggested: the inclusion of cyclosporin into combinations with methotrexate, the inclusion of sulfasalazine into combinations with methotrexate, the combined use of two chemotherapeutic substances, including methotrexate, azathioprine and cyclophosphamide, the inclusion of chloroquine derivatives into such or other combinations, and the combination of methotrexate with injectable gold. The validity of some of the studies is affected by high drop out rates and by the unknown influence of concomitant therapy with corticosteroids. Our own beneficial experience with the triple combination of methotrexate with azathioprine and chloroquine in 21 patients with refractory rheumatoid arthritis is summarized.

Infliximab

Infliximab is a chimaeric monoclonal antibody which binds to and inhibits the activity of tumour necrosis factor-alpha (TNFalpha), a cytokine which is involved in the development of both Crohn's disease and rheumatoid arthritis. In patients with treatment-resistant Crohn's disease, infliximab was significantly more effective than placebo in the relief of symptoms. 50 to 89% of patients responded to infliximab and most of them also achieved remission. Patients showed signs of relapse 8 to 12 weeks after a single infusion but responded to additional infusions of the drug. Infliximab was also effective in closing the fistulae in 68% of patients with fistulising Crohn's disease; the response rate with placebo was 26%. Infliximab achieved a clinical response in 44 to 81% of patients with refractory rheumatoid arthritis. Following a single infusion, symptom recurrence was evident after 6 to 12 weeks, but subsequent infusions re-established a clinical response. Concurrent methotrexate appeared to prolong the effects of infliximab in this patient group. Anti-infliximab and anti-double-stranded DNA antibodies developed in some patients, particularly those who received multiple infusions of infliximab. Acute adverse events consistent with hypersensitivity occurred in some patients who received multiple infusions of infliximab. Infection occurred slightly more frequently with infliximab than with placebo. Infliximab appears to be an effective therapy for patients with treatment-resistant or fistulising Crohn's disease or refractory rheumatoid arthritis. The tolerability, long term efficacy and optimal dosage regimen need to be further defined in comparative trials before the full potential of infliximab is realised in these patients.

The Safety Profile of Low-dose Cladribine in Refractory Rheumatoid Arthritis

Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a newer purine analog with specific toxicity to lymphocytes. As lymphocytes play a major role in rheumatoid arthritis (RA), we assessed the safety profile of low-dose 2-CdA in patients who were refractory to more than three disease-modifying drugs. Five patients were given a subcutaneous dosage of 0.05 mg/kg 2-CdA weekly over a period of 8 weeks. Of the lymphocyte subsets, both T and B cells decreased below the normal range, whereas natural killer cells remained stable. These changes were the only side-effects noted during treatment and 4 weeks afterwards. In one patient a pacemaker was implanted for reasons unlikely to be related to 2-CdA administration.We conclude that even low-dose 2-CdA (0.05 mg/kg) can decrease T and B cell populations in patients with refractory RA, but other side-effects are unlikely. For assessing the possible clinical efficacy of low-dose 2-CdA further studies are warranted.

Recommendations for Drug Therapy of Rheumatoid Arthritis in Elderly Patients

Drug therapy of rheumatoid arthritis in the elderly depends on the severity of the disease. Mild cases, which are usually of late onset and seronegative for rheumatoid factor, may respond to nonsteroidal anti-inflammatory drugs (NSAIDs), low dosages of corticosteroids, or hydroxychloroquine. Patients with more severe disease usually need the addition of remittive agents such as methotrexate, gold or sulfasalazine. Patients with longer duration of the disease (earlier onset) frequently have refractory rheumatoid arthritis and may need combination therapy with multiple remittive agents. All medications for the treatment of rheumatoid arthritis are potentially toxic. The agents with the best efficacy/toxicity ratios appear to be methotrexate, hydroxychloroquine and sulfasalazine. The drug therapy of rheumatoid arthritis requires a delicate balance of risk and benefit. The treating physician should be familiar with the nature of the disease and with the currently available medications.

CAMPATH-1H in rheumatoid arthritis--an intravenous dose-ranging study.

Forty-one patients with active and refractory rheumatoid arthritis(RA) received a total of 100, 250 or 400 mg of CAMPATH-1H (CAMPATH is a trademark of Glaxo-Wellcome group companies, registered in the US Patent and Trademark Office) over 5 or 10 days in an open, uncontrolled study. Following therapy, patients were monitored for adverse effects and disease activity for 6 months. Therapy was associated with prolonged peripheral blood lymphopenia in all dosing cohorts. During the month immediately following therapy, lymphopenia was most profound in the 400 mg cohorts. The first dose of monoclonal antibody (Mab) was associated with a 'flu'-like syndrome, more pronounced at higher initial doses. One patient developed haemolytic-uraemic syndrome. There were a number of dose-related infections during the early post-treatment period and one fatal opportunistic infection which followed additional immunosuppressive therapy. Antiglobulin responses developed in 9 of 31 patients tested. The majority of patients showed symptomatic improvement following therapy and 20% of patients maintained a 50% Paulus response at 6 months, all of whom were in the 250 or 400 mg cohorts. CAMPATH-1H appears to be an effective treatment for RA. Allowing for the small number of patients treated, infections were more common with higher doses, although this was not true for adverse events overall, and therapeutic responses were more sustained at higher dosing levels. The broad specificity of CAMPATH-1H may be appropriate for the immunotherapy of RA and future studies should aim to define a dose with an optimal therapeutic ratio.