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Theresa Gillis,Megan Crane,Carly Hinkle,Nathan Wei Arthritis Treatment Center, Frederick, MD, USA Objective: Many types of treatment are available for patients with rheumatoid arthritis (RA), however, some patients fail to achieve remission. This report aims to determine the safety and efficacy of using repository corticotropin injection (RCI) as an adjunctive therapy in patients with RA refractory to at least three therapeutics with different mechanisms of action. Method: In this open-label, interventional, single-group study, patients received 80 U RCI twice weekly via subcutaneous injection over 12 weeks. Changes in the Ritchie–Camp Articular Index and health assessment questionnaire scores were monitored for changes from baseline measures. Results: Eight patients were enrolled and consisted of seven females and one male with an average age of 64.6 years and disease duration of 20.9 years. Use of RCI resulted in significant improvement in swollen and tender joint counts. The disease activity score 28 and the physician and patient visual analog scale scores were significantly reduced at treatment week 12. The reduction in health assessment questionnaire scores did not reach statistical significance after RCI treatment. Once RCI therapy was discontinued, all improvements in disease activity score 28, physician and patient visual analog scale, and tender and swollen joint counts achieved during treatment were lost by the week 16 follow-up visit. Conclusion: While larger clinical trials are necessary to further confirm the efficacy of RCI in patients with refractory RA, the response of patients with refractory RA in this study suggests that RCI can be an effective add-on therapy for patients who have exhausted several classes of treatments. Furthermore, this study suggests that RCI has an alternative mode of action, compared to other available antirheumatic drugs. Keywords: refractory rheumatoid arthritis, rheumatoid arthritis, adrenocorticotropic hormone, repository corticotropin injection

Psoriatic arthritis (PsA) is a heterogeneous and inflammatory disease with diverse clinical manifestations, including psoriasis, nail psoriasis, peripheral joint disease, axial joint disease, enthesitis, and dactylitis. Typically, this varied clinical presentation complicates the clinician’s ability to distinguish PsA from other forms of arthritis. In the synovium of individuals with PsA, upregulation of the genes WNT3A, BMPR2, and TGFBR1 results in bone erosion and new bone formation, a pattern unique to the disease. Additionally, genes associated with angiogenesis and vascularization such as VEGF and TGFB1 facilitate inflammation and joint damage. Gross pathogenesis of PsA is driven by proinflammatory cytokines, and key cytokines affecting joint structures include tumor necrosis factor-α, interleukin (IL)-6, IL-17A, IL-21, IL-22, and IL-23. Early diagnosis is critical for providing treatment that prevents irreversible disease progression and function loss. This narrative review discusses differentiation of PsA from other forms of arthritis. Additionally, we detail the role of cytokines at the joint in mediating PsA pathogenesis. Funding: Novartis Pharmaceuticals Corporation.

Purpose The thread carpal tunnel release (TCTR) technique has been improved and offers more precise control in dissecting thread placement. The purpose of this cadaveric study was to test the procedure operationally and verify the modified TCTR anatomically. Methods Eleven unembalmed cadaver wrists underwent the transverse carpal ligament (TCL) release by using the modified TCTR technique. An experienced observer dissected each specimen and assessed for completeness of release under direct visual assessment. Injury to the superficial palmar aponeurosis (SupPA), the Berrettini and common digital nerve branches were also recorded as a secondary outcome. Results Eleven out of 11 wrists (100%) underwent the modified TCTR with complete release of the TCL. All 11 wrists were released without damage to any vital neurovascular structure including the Berrettini branch and the common digital nerves. The SupPA remained intact in all 5 wrists performed with the preservation steps. Conclusions The modified TCTR technique demonstrated complete division of the TCL while protecting the SupPA as well as the Berrettini and common digital nerve branches. Clinical relevance The modified TCTR has the potential to offer a clinically safe and effective minimally invasive procedure for complete carpal tunnel release.

Summary Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. Methods ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than −13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. Findings 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI −6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (−6 [−14 to 3]) or tofacitinib and methotrexate (−8 [−16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Interpretation Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Funding Pfizer Inc.

Tumor necrosis factor-superfamily (TNF-SF) members, lymphotoxin (LT)-alpha and LTbeta, are proinflammatory cytokines associated with pathology in rheumatoid arthritis. LTalpha3 homotrimers are secreted, whereas LTalpha(1)beta(2) heterotrimers are expressed on the surface of activated lymphocytes. As many TNF-SF members are actively cleaved from cell membranes, we determined whether LTalphabeta heterotrimers are also cleaved, and are biologically active in rheumatoid arthritis (RA) patients. LTalphabeta heterotrimers were detected in culture supernatants from activated human T-helper (Th) 0, Th1, and Th17 cells, together with LTalpha3 and TNFalpha. The heterotimers were actively cleaved from the cell surface by ADAM17 metalloproteinase (MMP) and MMP-8, and cleavage was inhibited by TAPI-1, a TNF-alpha converting enzyme (TACE) inhibitor. Soluble LTalphabeta was detected in serum from both normal donors and RA patients, and was elevated in synovial fluid from RA patients compared to osteoarthritis (OA) patients. Levels of LTalphabeta in RA patient synovial fluid correlated with increased TNFalpha, IL-8, IL-12, IL-1beta, IFN-gamma, and IL-6 cytokines. Moreover, recombinant LTalpha1beta2-induced CXCL1, CXCL2, IL-6, IL-8, VCAM-1, and ICAM-1 from primary synovial fibroblasts isolated from RA patients. Therefore, soluble LTalphabeta in synovial fluid is associated with a proinflammatory cytokine milieu that contributes to synovitis in RA.

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated.MethodsA randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699).ResultsTofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (pConclusionsTofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response.Trial registration numberNCT00976599.

Symptomatic osteoarthritis of the base of the thumb is a common malady and is responsible for significant morbidity. This report describes a minimally invasive technique combining arthroscopic debridement and intraarticular visco-supplementation in patients who do not respond to more conservative measures. Eleven patients with symptomatic osteoarthritis of the carpometacarpal joint not responding to antiinflammatory medications, injections, and splinting underwent arthroscopic debridement and intraarticular visco-supplementation. Using pain relief as a measure of success, 5 patients had excellent results, 4 patients had good results, and 2 patients had poor results. There were no complications. This procedure may provide a bridge between more conservative palliative therapies and the much more invasive open hand procedures currently being performed for this problem.

Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Up to 30% of patients with psoriasis develop PsA (1). The pathogeneses of both the skin disease and the joint inflammation of PsA are not well defined. Early studies designated psoriasis and PsA as Th1-mediated diseases with a focus on interferon-γ (IFNγ) and interleukin-2 (IL-2) (2). More recent studies identify IL-17 as the most critical cytokine for sustaining skin disease, with important interactions between IL-17 and tumor necrosis factor (TNF) within skin cells (3,4). IL-17 has also been implicated in PsA, with an increased number of Th17 cells in the peripheral blood, synovial fluid, and synovial tissue of PsA patients (5–7). In addition, synoviocytes of PsA patients show increased expression of IL-17 receptor (IL-17R) compared with the synoviocytes of patients with osteoarthritis (OA) (7). There is little understanding of the relative levels of cytokines and chemokines within skin and synovium in PsA. Moreover, to our knowledge, there is no broad genomic analysis comparing skin and synovium in PsA. The purpose of this study was to better define the inflammatory pathways of PsA in both skin and joint pathogenesis in matched lesional skin and affected synovial tissue specimens in patients with PsA. We conducted a comprehensive analysis of the cytokine and chemokine activation that defines Th1, Th2, Th9, Th22, and Th17 T cell subsets as well as genes representative of the inflammatory processes that are seen in psoriatic skin and joint disease. Our results establish marked within-patient differences in gene expression between lesional skin and affected synovium in PsA patients. Specifically, IL-17 expression is significantly higher in skin than in synovium, while IL-6 expression is higher in synovium.

Objective.To evaluate efficacy and safety of CE-224,535, a selective P2X7receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX).Methods.In our phase IIA study (ClinicalTrials.govno.NCT00628095; A6341009), patients aged ≥ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of ≥ 7.5 mg MTX.Results.The American College of Rheumatology 20% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0% vs 36.2%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3% (CE-224,535) and 55.3% (placebo) of patients; the most common AE were nausea (11.3%, CE-224,535; 4.3%, placebo) and diarrhea (7.5%, CE-224,535; 4.3%, placebo). The proportion of patients discontinuing due to an AE was 9.4% (CE-224,535) and 6.4% (placebo); no deaths were reported. Serious AE occurred in 3.8% (CE-224,535) and 2.1% (placebo) of patients; none was considered treatment-related.Conclusion.CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.

The B-cell chemokine, CXCL13, is a proposed serum biomarker of synovitis in RA. Its behaviour in the context of B-cell depletion therapy and reconstitution was studied during treatment of RA with rituximab.Serum samples from 20 RA patients were analysed for CXCL13, RF-IgM and anti-CCP by ELISA before and 2 and 6 months following rituximab treatment. B cells were monitored by flow cytometry. Gene expression in blood and synovial biopsies was determined by qPCR.Patients with detectable B cells at 6 months had significantly higher levels of CXCL13 and RF-IgM and slightly higher levels of anti-CCP throughout the study, including at baseline, compared with patients with undetectable B cells at 6 months. Conversely, 10 of 12 patients with high baseline CXCL13 had detectable circulating B cells at 6 months, whereas no B cells could be detected at 6 months in patients with low baseline CXCL13. Synovial CXCL13 expression at baseline correlated significantly with serum CXCL13 levels, and the synovium of patients with high serum CXCL13 expressed elevated levels of IL-1β, IL-8, MMP1 and MMP3. In addition, synovial CXCL13 expression correlated significantly with several synovial inflammatory markers.Serum CXCL13 is predictive of the rate of B-cell repopulation following a course of rituximab in RA. Serum CXCL13 correlates with synovial CXCL13 measured at a single joint, suggesting synovitis as an important source of circulating CXCL13. Within the synovium, CXCL13 expression is highly correlated with markers of synovitis.ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00147966.

IL-17AA, IL-17FF, and IL-17AF are proinflammatory cytokines that have been implicated in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). In order to measure the levels of these cytokines in synovial fluid and serum samples from RA patients, immunoassays specific for IL-17AA, FF, and AF were developed. Although these assays could tolerate up to 50% pooled normal human serum, false positive reactivity was problematic in patient samples suggesting interference from heterophilic antibodies. We therefore evaluated the ability of several commercially available heterophilic antibody blocking agents to reduce false positive reactivity by testing them against samples that were confirmed as false positives in the IL-17AA, FF, and AF assays. Several of the blockers performed well, including HBR-1, HBR-9, HBR-11, HBR-Plus, Serum Cytokine Assay Diluent, and IIR. We chose to move forward using IIR blocker for sample analysis and verified that IIR had no effect on the assay standard curves and did not affect IL-17 quantitation in plasma from ex vivo stimulated human whole blood. IL-17FF and IL-17AF were below the limits of quantitation of the assays (12.3 and 10.5pg/ml, respectively) in synovial fluid and serum samples from patients with RA and osteoarthritis (OA). For the more sensitive IL-17AA assay (1.6pg/ml limit of quantitation), low levels of IL-17AA were measurable in 48% of RA synovial fluid samples (mean, 7.9pg/ml; median

Objective.To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene.Methods.In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 × 1011, 1 × 1012, or 1 × 1013DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12–30 weeks later, depending on when the target joint met predetermined criteria for reinjection.Results.127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14).Conclusion.IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.

A review of the results of the second 100 cases of office-based arthroscopy is presented. The major difference between the first 100 cases and the present group has been the change from a diagnostic mode to an interventional mode. This transition has been facilitated by the use of a 2.7-mm, 30-degree oblique arthroscope along with a computerized fluid management system. The indications included knee pain refractory to conservative measures that included rest, exercise, physical therapy, anti-inflammatory medication, monoarticular arthritis of uncertain etiology, and the abrupt onset of locking suggestive of an acute mechanical problem. The pathology found at the time of arthroscopy for the most part confirmed the clinical impression; however, there were several instances in which the diagnosis was changed and the subsequent medical therapy was changed accordingly. The clinical response to arthroscopic intervention generally paralleled what has been reported by others, with important and prolonged relief of pain in most cases. Three major complications (septic joint, cellulitis, and thrombophlebitis) were seen. Strategies are suggested to avoid these. Arthroscopy is valuable in establishing, confirming, or possibly negating previous diagnostic impressions. More importantly, the ability to perform arthroscopic intervention in the office in patients with arthritis adds another therapeutic weapon to the armamentarium of clinical rheumatologists.

Symptomatic osteoarthritis of the base of the thumb is a common malady and is responsible for significant morbidity. This report describes a minimally invasive technique combining arthroscopic debridement and intraarticular visco-supplementation in patients who do not respond to more conservative measures. Eleven patients with symptomatic osteoarthritis of the carpometacarpal joint not responding to antiinflammatory medications, injections, and splinting underwent arthroscopic debridement and intraarticular visco-supplementation. Using pain relief as a measure of success, 5 patients had excellent results, 4 patients had good results, and 2 patients had poor results. There were no complications. This procedure may provide a bridge between more conservative palliative therapies and the much more invasive open hand procedures currently being performed for this problem.

Human cartilage glycoprotein 39 (HC gp-39) appears to be a relevant autoantigen in patients with rheumatoid arthritis (RA). Administration of major histocompatibility complex (MHC) Class II complexed antigens without requisite costimulatory signals can induce immunologic tolerance. We evaluated the safety, pharmacokinetics, and preliminary efficacy of AG4263 in patients with RA. AG4263 is a soluble complex of native HLA-DR4 (beta*0401) complexed to Org 36601, a 13-mer peptide derived from HC gp-39 (also referred to as CDP263).Thirty-one HLA-DRB1*0401 positive patients with persistent RA disease activity despite concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or placebo (n = 7) over 6 weeks. The initial dose of 0.5 micro g/kg was escalated in subsequent cohorts to a maximum of 150 micro g/kg. Safety analyses included recording of adverse events and measurement of CD4/CD8 counts, reactivity to recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed using the Paulus 20 criteria.Treatment was well tolerated, with injection site reaction the most common adverse event. There was no loss of reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR. The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263.AG4263 was safe, well tolerated, and without evidence of generalized immune suppression. Along with the observed trend toward clinical efficacy, the results suggest that this therapeutic approach warrants further investigation in patients with RA.

We present an office-based technique for performing arthroscopic synovectomy of the wrist in patients with rheumatoid arthritis. Intra-articular anesthesia as well as subcutaneous portal anesthesia are used. Standard portals are used in the radial carpal and midcarpal joints. Standard instrumentation is used and the synovectomy is accomplished using a motorized shaver. We performed 30 procedures in 21 patients: 15 complete synovectomies, 3 radioulnar carpal synovectomies because of only limited disease, and 12 limited synovectomies because these patients were participants in a clinical trial and required only limited synovectomy for investigational purposes. There were no complications. Office-based arthroscopic synovectomy of the wrist in patients with refractory rheumatoid arthritis can be performed safety and effectively. This technique is useful in both a clinical as well as a research setting.

Although small joint arthroscopy has become commonplace over the past decade, relatively little attention has been paid to the investigation and clinical utility of metacarpophalangeal (MP) joint arthroscopy. The literature is scant in this area and consists of only a handful of case reports. In addition, the arthroscopic anatomy of the MP joint has not as yet been reported. Six cadaveric hands (24 joints) were rigorously studied in the laboratory using standard 2.5-mm small joint arthroscopic instrumentation and 5 lb of overhead traction. Radial and ulnar portals were used with care not to injure the extensor tendons. Arthroscopic anatomic landmarks include: (1) A consistent tripartite configuration of the main radial and ulnar collateral ligaments with characteristic changes in relative fiber orientation as the digit goes from extension to flexion, (2) nonvisualization of the accessory collateral ligament from inside the joint, (3) transitional amorphous capsular fibers connecting the collateral ligaments to the volar plate and dorsal capsule, (4) four synovial recesses (radial, ulnar, volar, and dorsal-proximal), (5) metacarpal head and proximal phalanx, (6) a consistent circumferential meniscal equivalent around the margin of the proximal phalanx articular surface, and (7) the sesamoid-metacarpal articulation in the thumb MPjoint. There are published case reports on the utility of MP joint arthroscopy for synovectomy in rheumatoid arthritis and hemachromatosis and realigning Stener lesions in gamekeepers' thumbs. The current clinical series reveals preliminary experience with the technique. MP joint arthroscopy was useful in relieving a locked MP joint from a loose osteochondral body and sagittal tear in the volar plate that enfolded into the joint surface. Intra-articular release of post-traumatic volar plate and dorsal capsular contracture were readily accomplished using this technique. Juxta-articular bone lesions such as osteoid osteomas can be removed with careful preoperative planning. Gamekeeper's thumbs that are unstable on stress radiographs can undergo arthroscopy with excellent sensitivity to determine the presence of a Stener lesion before an open or arthroscopic repair. The advantages of arthroscopic versus open techniques are similar to those experienced in larger joints. With time, more indications will emerge.

Vesnarinone is an experimental drug that has been used successfully in the treatment of congestive heart failure patients. In this report we investigate the effect of vesnarinone on the cytokine secretory products of mononuclear phagocytes. In a concentration-dependent manner, the drug inhibits the endotoxin(LPS)-stimulated release of tumor necrosis factor (TNF) alpha and suppresses interleukin(IL)-6 release, but does not affect the release of IL-1 alpha, IL-10 and leukemia inhibitory factor (LIF) by mouse peritoneal macrophages. Using competitive polymerase chain reaction (PCR) analyses, we find that vesnarinone significantly reduces TNF(alpha), but not IL-10 mRNA. In addition to LPS, the drug inhibits TNF(alpha) release induced by several other stimuli. The inhibitory effect of the drug on the TNF(alpha) biosynthesis can be observed in differentiated human monocytes, in macrophage cell lines, and in synovial adherent cells from rheumatoid arthritis patients. Although the precise mode of action of vesnarinone in the signal transduction pathway leading to the selective inhibition of TNF(alpha) is not known, the drug might be useful in the treatment of diseases involving that cytokine.

Excerpt To the Editor:Nonsteroidal, anti-inflammatory drugs are among the most frequently prescribed medications. Many of the serious side effects of these drugs that have been documented involve v...

The effects of intensive plasma exchange on the serological and clinical manifestations of mildly active systemic lupus erythematosus were evaluated in a controlled, double-blind trial. Twenty patients were randomised to receive either six 4-litre plasma exchanges or a seemingly identical control procedure over a 2-week period. Plasma exchange produced significant reductions in serum levels of IgG, IgM, IgA, and circulating immune complexes measured by an 125 I-C1q binding assay. These serological measures returned to baseline 4 weeks after plasma exchange without a rebound above baseline values. Antibodies to DNA were reduced immediately after plasma exchange; however, they often returned to pre-treatment levels before the next procedure. No changes in any of the serological measures were observed in the control group. In sixteen of the eighteen patients who completed the clinical trial activity had either remained stable or improved; the frequency and degree of clinical improvement was the same in both plasma exchange and control groups.

A 44-year-old man had mycosis fungoides and generalized plaque disease involving 80% of his skin surface with diffuse lymphadenopathy and alopecia of the scalp and groin. In addition, distal to the wrist, there were sclerodermatous changes involving the skin of the hands with associated sclerodactyly of all digits with loss of normal palmar creases. There were no subungual telangiectasis or digital ulcers. The changes in the hand that occurred in this case, no doubt arose as a result of the patient's neoplasm. Abnormalities of collagen biosynthesis and degradation probably occur with mycosis fungoides as a result of the extensive infiltration of the epidermis and dermis with malignant cells. To our knowledge, the association of sclerodactyly with mycosis fungoides has not been previously reported.

Excerpt To the editor: Second generation nonsteroidal anti-inflammatory agents have been associated with a relative lack of serious adverse reactions. Although many minor side effects have been doc...