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Relapsing polychondritis (RP) is a chronic multisystemic disease characterized by recurrent episodes of cartilage inflammation throughout the body. The lower respiratory tract is involved in 20% to 50% of patients and results in significant morbidity. Effective medical therapies and airway interventions are available in experienced centers; however, no single treatment is curative, and the prognosis of RP with airway disease remains overall guarded.

OBJECTIVE: Between 1940 and 1970, 1.5 million female fetuses were exposed to diethylstilbestrol in utero. Numerous deleterious effects on reproductive anatomic and physiologic characteristics have been documented in these women. However, the effects of this exposure on nonreproductive systems, which may have lifelong consequences as this cohort of women progresses beyond the childbearing years, have received little attention. On the basis of an earlier preliminary observation of altered immune reponse, we hypothesized that diethylstilbestrol-exposed women may show abnormalities in T-cell-mediated immune response. STUDY DESIGN: Thirteen women exposed to diethylstilbestrol in utero were compared with 13 age- and menstrual cycle phase-matched control subjects with respect to the in vitro T-cell response to the mitogens phytohemagglutinin, concanavalin A, and interleukin 2. RESULTS: As compared with controls, tritiated thymidine incorporation by T cells harvested from diethylstilbestrol-exposed women was increased 3-fold over a range of concentrations in response to concanavalin A (P

Objective Oral administration of cartilage-derived type II collagen (CII) has been shown to ameliorate arthritis in animal models of joint inflammation, and preliminary studies have suggested that this novel therapy is clinically beneficial and safe in patients with rheumatoid arthritis (RA). The present study was undertaken to test the safety and efficacy of 4 different dosages of orally administered CII in patients with RA. Methods Two hundred seventy-four patients with active RA were enrolled at 6 different sites and randomized to receive placebo or 1 of 4 dosages (20, 100, 500, or 2,500 µg/day) of oral CII for 24 weeks. Efficacy parameters were assessed monthly. Cumulative response rates (percentage of patients meeting the criteria for response at any time during the study) were analyzed utilizing 3 sets of composite criteria: the Paulus criteria, the American College of Rheumatology criteria for improvement in RA, and a requirement for ≥30% reduction in both swollen and tender joint counts. Results Eighty-three percent of patients completed 24 weeks of treatment. Numeric trends in favor of the 20 µg/day treatment group were seen with all 3 cumulative composite measures. However, a statistically significant increase (P = 0.035) in response rate for the 20 µg/day group versus placebo was detected using only the Paulus criteria. The presence of serum antibodies to CII at baseline was significantly associated with an increased likelihood of responding to treatment. No treatment-related adverse events were detected. The efficacy seen with the lowest dosage is consistent with the findings of animal studies and with known mechanisms of oral tolerance in which lower doses of orally administered autoantigens preferentially induce disease-suppressing regulatory cells. Conclusion Positive effects were observed with CII at the lowest dosage tested, and the presence of serum antibodies to CII at baseline may predict response to therapy. No side effects were associated with this novel therapeutic agent. Further controlled studies are required to assess the efficacy of this treatment approach.

Objective. To compare 3 sets of criteria for meaningful improvement in a rheumatoid arthritis (RA) clinical trial, and to evaluate the implications of these criteria sets for RA trial design. Methods. Data were obtained from the Minocycline in Rheumatoid Arthritis (MIRA) trial (primary outcome measures: 50% improvement in joint tenderness and 50% improvement in joint swelling, based on joint scores). These MIRA data were evaluated against 1) the Paulus criteria (20% improvement in 4 of 6 measures: joint tenderness scores, joint swelling scores, physician's and patient's global assessments, erythrocyte sedimentation rate [ESR], and morning stiffness); and 2) the American College of Rheumatology (ACR) criteria (20% improvement in joint tenderness and joint swelling counts, and in 3 of 5 other measures: physician's and patient's global assessments, ESR, modified Health Assessment Questionnaire, and patient's pain assessment). The ACR criteria were modified using 3 of 4 remaining measures, since baseline pain assessment data were not available. Results. Percentages of minocycline-treated patients versus placebo-treated patients showing meaningful improvement were as follows: by MIRA criteria, for joint tenderness, 56% versus 41% (P = 0.021), and for joint swelling, 54% versus 39% (P = 0.023); by Paulus criteria, 41% versus 28% (P = 0.040); and by ACR criteria, 44% versus 26% (P = 0.004). Both the modified ACR criteria and the Paulus criteria demonstrated a reduced placebo response rate. Compared with the MIRA criteria, the ACR criteria increased, and the Paulus criteria decreased, absolute between-group differences in improvement; however, both criteria sets increased relative percentages of patients showing improvement in the minocycline group versus the placebo group. Study design considerations indicated that application of the ACR criteria would reduce the required sample size. Conclusion. Different placebo response rates and treatment group differences were found using the 3 RA improvement criteria sets. These findings support the use of the ACR criteria for defining improvement in RA clinical trials.

Objective. This pilot phase II, double-blind, placebo-controlled trial of 1 month duration, with a 2–3-month open-label extension, evaluated the safety, tolerability, biologic effects, and efficacy of interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis (RA). Methods. Forty-five RA patients were enrolled in the trial, and were randomized, after a 3–4-week diseasemodifying antirheumatic drug washout, to receive a daily intravenous dose of either DAB486-IL-2 or placebo (saline) for 5 days. A blinded, third-party observer evaluated arthritis activity. Clinical response was defined as ≥25% improvement in swollen and tender joints and ≥25% improvement in at least 2 of 6 additional parameters. The double-blind phase was 4 weeks; placebo patients could cross over to receive open-label treatment for a maximum of 3 monthly DAB486IL-2 cycles. Results. In the double-blind phase, 4 of 22 patients (18%) in the treated group and none in the placebo group (P = 0.05) met the criteria for clinical response. During the open-label treatment phase, 11 of 36 patients (31%) and 11 of 33 patients (33%) had a clinical response after completing 2 and 3 courses of DAB486IL-2, respectively. Adverse events included transient fever/chills (45%), nause/vomiting (50%), elevated (≥13x normal) transaminases (55%), and increased joint pain (45%). Twelve patients (8 placebo, 4 DAB486IL-2) did not complete 3 treatment cycles. No apparent differences were noted in CD4+ CD25+ cells of responders versus nonresponders, or of DAB486IL-2-treated versus placebo-treated patients. Conclusion. Clinical responses were noted in patients treated with DAB486IL-2 (18%) compared with placebo (0%) in the double-blind phase. In the open-label phase, 33% of patients completing 3 monthly DAB486IL-2 cycles had improvement in arthritis activity. Further studies of IL-2 diphtheria fusion proteins are warranted to elucidate factors that may predict clinical response and define mechanism(s) of action.

Minocycline is arguably the most interesting new drug for rheumatoid arthritis since the development of methotrexate. Tetracycline compounds have long been used by rheumatologists who were considered mavericks by their peers, and recent controlled studies have demonstrated their antirheumatic activity. The reason that minocycline works is unclear, and their niche in the treatment of rheumatoid arthritis remains to be established. Nonetheless, it is clear that some patients with rheumatoid arthritis respond favorably to this form of treatment.

Rheumatoid arthritis is an inflammatory synovial disease thought to involve T cells reacting to an antigen within the joint. Type II collagen is the major protein in articular cartilage and is a potential autoantigen in this disease. Oral tolerization to autoantigens suppresses animal models of T cell-mediated autoimmune disease, including two models of rheumatoid arthritis. In this randomized, double-blind trial involving 60 patients with severe, active rheumatoid arthritis, a decrease in the number of swollen joints and tender joints occurred in subjects fed chicken type II collagen for 3 months but not in those that received a placebo. Four patients in the collagen group had complete remission of the disease. No side effects were evident. These data demonstrate clinical efficacy of an oral tolerization approach for rheumatoid arthritis.

DAB486IL-2 is an interleukin-2 receptor-specific cytotoxin which selectively targets and kills cells which bear the high-affinity form of the IL-2 receptor. Since elimination of activated T lymphocytes may be useful in the treatment of rheumatoid arthritis, the effect of DAB486IL-2 treatment in an animal model of arthritis was investigated. We demonstrated that rats treated with DAB486IL-2 during the induction phase of disease have delayed onset of symptoms and significantly reduced severity of inflammation as well as a depressed proliferative response to mycobacterial stimulation in vitro. In addition, the presence of preexisting antibodies to the molecule had no impact on the anti-arthritic effects observed in this model. These data suggest that DAB486IL-2 may have therapeutic potential in the treatment of rheumatoid arthritis.

The intent of this study was to compare, in a monotherapy framework, an optimal dose of the synthetic hexose sugar, amiprilose hydrochloride (HCl), to a placebo in the treatment of rheumatoid arthritis. In this double-blind, randomized, multi-center study, patients first underwent a washout period from disease-modifying antirheumatic drugs. Those who subsequently met flare criteria within 14 days of discontinuing previously stable doses of nonsteroidal anti-inflammatory drugs were randomized to amiprilose HCl (103 patients) or a placebo (115 patients) for the subsequent 20 weeks. Glucocorticoid or nonsteroidal anti-inflammatory drugs use was not permitted. At the baseline, demographic and disease characteristics were similar in both groups. Of patients completing the course of therapy, 73% were in the amiprilose HCl group and 66% were in the placebo group. Using an intent-to-treat analysis, numeric trends favoring amiprilose HCl treatment were found for clinical and laboratory parameters of disease activity. Compared with the placebo group, statistically significant degrees of improvement were achieved for the number of swollen joints (p/= 0.04), number of patients who experienced a/= \50% reduction in swollen joints (p/= 0.04), number who improved by the Paulus composite score criteria (p/= 0.02), improvement in the frequency distribution in Functional Class (p/= 0.01), and improvement in the mean erythrocyte sedimentation rate (p/= 0.03). Significant worsening in the duration of morning stiffness (p/= 0.05) and in 4 of the 5 items in the clinical health assessment questionnaire (p/= 0.004) occurred in the placebo but not in the amiprilose HCl group. No side effects clearly attributable to the drug were noted. This study provides an independent confirmation that the novel and nontoxic carbohydrate, amiprilose HCl, provides an effective approach to the treatment of rheumatoid arthritis. The Food and Drug Administration will now consider whether it should be approved for this indication.

Objective To assess the prevalence and characteristics of airway involvement in relapsing polychondritis (RP). Methods Retrospective chart review and data analysis of RP patients seen in the Rheumatology Clinic and the Complex Airway Center at Beth Israel Deaconess Medical Center from January 2004 through February 2008. Results RP was diagnosed in 145 patients. Thirty-one patients had airway involvement, a prevalence of 21%. Twenty-two patients were women (70%), and they were between 11 and 61 years of age (median age, 42 years) at the time of first symptoms. Airway symptoms were the first manifestation of disease in 17 patients (54%). Dyspnea was the most common symptom in 20 patients (64%), followed by cough, stridor, and hoarseness. Airway problems included the following: subglottic stenosis (n = 8; 26%); focal and diffuse malacia (n = 15; 48%); and focal stenosis in different areas of the bronchial tree in the rest of the patients. Twelve patients (40%) required and underwent intervention including balloon dilatation, stent placement, tracheotomy, or a combination of the above with good success. The majority of patients experienced improvement in airway symptoms after intervention. One patient died during the follow-up period from the progression of airway disease. The rest of the patients continue to undergo periodic evaluation and intervention. Conclusion In this largest cohort described in the English language literature, we found symptomatic airway involvement in RP to be common and at times severe. The nature of airway problems is diverse, with tracheomalacia being the most common. Airway intervention is frequently required and in experienced hands results in symptom improvement.

To retrospectively determine the prevalence of expiratory computed tomographic (CT) abnormalities, including malacia and air trapping, in patients with relapsing polychondritis and to retrospectively determine the frequency with which expiratory abnormalities are accompanied by inspiratory abnormalities on CT scans.Institutional review board approval was obtained, and informed consent was not required for this retrospective HIPAA-compliant study. A computerized hospital information system was used to identify all patients with clinically diagnosed or biopsy-proved relapsing polychondritis who were referred for CT airway imaging during a 17-month period. The study cohort comprised 18 patients (15 women, three men; mean age, 47 years; age range, 20-71 years). Multidetector helical CT was performed in all patients by using a standard protocol, which included end-inspiratory and dynamic expiratory volumetric imaging. Two observers who were blinded to the original scan interpretations simultaneously reviewed CT scans. Findings were recorded in consensus. Dynamic expiratory CT scans were assessed for malacia that involved the trachea and main bronchi (reduction in cross-sectional area of more than 50%) and for air trapping (failure of lung parenchyma to increase in attenuation during expiration). Air trapping was visually classified according to pattern and extent (lobular, segmental, lobar, or whole lung). Inspiratory CT scans were evaluated for tracheal and bronchial stenosis (25% luminal diameter narrowing compared with a corresponding uninvolved segment), wall thickening (2 mm), and calcification.Expiratory CT abnormalities were present in 17 (94%) of 18 patients and included malacia in 13 patients (72%) and air trapping in 17 patients (94%). Inspiratory CT abnormalities were found in eight (47%) of 17 patients who had expiratory CT abnormalities. Calcification of the airway walls was present in seven (39%) of 18 patients. All patients who had inspiratory CT abnormalities demonstrated expiratory CT abnormalities.Expiratory CT abnormalities were present in the majority of patients with relapsing polychondritis who were referred for airway imaging, yet only half of these patients demonstrated abnormalities on routine inspiratory CT scans. Thus, dynamic expiratory CT should be a standard component of imaging assessment in patients with relapsing polychondritis.

During the past year, another disease possibly influenced by intravenous gammaglobulin was identified as dermatomyositis/polymyositis. Additional studies provided further information regarding the use of monoclonal anti-CD4 antibody and combination therapy in rheumatoid arthritis, antithymocyte globulin in scleroderma, and intravenous gammaglobulin in juvenile rheumatoid arthritis. New therapeutic horizons also emerged including the novel immunosuppressant FK-506, the removal of disease incitants by medical arthroscopy, antiarthritic T-cell receptor V beta-specific antibodies, and the potential of achieving tolerance via peroral administration of autoantigens.

The basic science immunology community is quite accepting of the phenomenon of oral tolerance induction in animals; however, in contradistinction, the clinical community is somewhat agnostic regarding oral tolerance. Progress in multiple sclerosis has not been definitive and outcomes in RA have been modest at best. Recent reports in animal models have suggested that oral ingestion of autoantigen can have deleterious effects on the host. Although those experiments have had a highly artificial framework, they are consistent with the possibility that oral antigen therapy in human disease may be: (1) beneficial; (2) of no consequence; or (3) detrimental. An extremely open mind will hopefully be applied to future research efforts.

Objective. To evaluate the efficacy of oral chicken type II collagen (CCII) in the treatment of juvenile rheumatoid arthritis (JRA). Methods. Ten patients with active JRA were treated with CCII for 12 weeks. Efficacy parameters, which included swollen and tender joint count and score, grip strength, 50-foot walking time, duration of morning stiffness, and patient and physician global scores of disease severity, were assessed monthly. Results. All patients completed the full course of therapy. Eight patients had reductions in both swollen and tender joint counts after 3 months of CCII. The mean changes from baseline in swollen and tender joint counts for the 8 responders at the end of the study were –61% and –54%, respectively. Mean values for other efficacy parameters also showed improvement from baseline. There were no adverse events that were considered to be treatment related. Conclusion. Oral CCII may be a safe and effective therapy for JRA, and its use in this disease warrants further investigation.

Adjuvant and collagen arthritis in the rat are widely accepted T-cell-dependent counterparts of rheumatoid arthritis and were used to examine the antiinflammatory properties of minocycline. Administration of oral minocycline, a semisynthetic tetracycline, significantly decreased (P0.01) the incidence of arthritis in both models. In vivo exposure to minocycline also significantly increased the percentage of splenocytes exhibiting a rise in free intracellular calcium concentration ([Ca2+]i) following concanavalin A stimulation (P0.05 in adjuvant and P0.01 in collagen). This enhancement was mitogen dose-dependent and supported exclusively by extracellular Ca2+. Resting [Ca2+]i levels were unaffected by minocycline and predominantly the CD4+ subset was involved. No changes were observed in weight, IgG antibodies to collagen, synoviocyte release of collagenase and prostaglandin E2, acute inflammation in an air-pouch system, or cell surface expression of activation markers (interleukin-2 and transferrin receptors) by splenocytes or lymph node cells. As a controlled [Ca2+]i rise is a critical event in normal T cell activation, minocycline's antiarthritic profile in vivo may relate to perturbed Ca2+ influx during T cell activation, an alteration that could promote the development of clinical tolerance to otherwise arthritogenic stimuli.

Objective. To evaluate the safety and antiarthritic effects of DAB486IL-2. This agent is a fusion toxin and the product of a synthetic gene, engineered by replacing the codons for the receptor-binding domain of diphtheria toxin (DT) with the codons for human interleukin-2 (IL-2). DAB486IL-2 targets cells expressing the 2-chain, high-affinity form of the IL-2 receptor (IL-2R), and achieves selective diphtheria toxin–mediated cytotoxicity of activated T cells by inhibition of protein synthesis. Methods. Nineteen patients with rheumatoid arthritis (RA) that had been refractory to methotrexate participated in an open-label, phase I/II trial evaluating 3 dose levels of intravenous DAB486IL-2 given for 5 or 7 consecutive days. Thirteen patients received additional courses, at higher doses if the original response had been inadequate or at an equivalent dose if the original course produced a response, for a total of 38 courses. Arthritis response was assessed at 28 days, with biweekly followup of patients with substantial response (⩾50% improved) or meaningful response (⩾25% improved). Laboratory monitoring included measurement of CD4+ cells and circulating shed IL-2R. Results. Nine of 19 patients treated with high- or medium-dose DAB486IL-2 had a substantial or meaningful response after 1 or 2 treatment courses. No significant responses occurred with the low-dose regimen. Clinical benefit was rapid, with full effect noted by 14 days following completion of infusions. Antibodies to DT developed in all patients, or levels of preexisting antibodies were boosted. Adverse effects included transient elevation of transaminase levels (55% of the patients), fever (40%), nausea or anorexia (30%), hypersensitivity (6%), and thrombocytopenia (5%). Repeat courses were associated with less transaminase elevation and were clinically effective despite induction of anti-DT antibodies. Conclusion. The results of this open trial provide preliminary evidence for a potential therapeutic effect of DAB486IL-2 in RA, with an acceptable safety profile. Reversible transaminase elevations limit escalation of the dosage beyond 0.1 mg/kg/day. A controlled study of DAB486IL-2 is required to determine the efficacy of this high-affinity IL-2R–targeted fusion toxin in the treatment of RA.

Although the pathogenesis of rheumatoid arthritis increasingly continues to be well understood, therapeutic approaches to the disease remain relatively unsophisticated and based more on anecdote than scientific reasoning. During the past year, additional supportive data regarding the usefulness of front-line agents such as methotrexate and hydroxychloroquine were acquired, and novel potential interventions, such as pulse gammaglobulin and OM-8980 were identified. Animal model studies still support the prospect that genuine remission-inducing strategies will be realized in the future.

A unique patient with type VIII Ehlers-Danlos syndrome and cutaneous vasculitis, resorptive osteolysis, and cardiac valvular disease is described. Collagen analyses identified morphologic and physical abnormalities of type I collagen. The patient's T lymphocytes could be propagated in vitro with type I collagen and produced a 60-kd lymphokine that bound this protein. Cellular autoimmunity to type I collagen may be responsible for this patient's intractable clinical condition.

Although no true breakthroughs occurred, publications during the 12-month period of this review added substantial definition to certain novel immunotherapies potentially applicable to the treatment of rheumatoid arthritis. Overall, this period witnessed maturation in the field of biologic interventions. Clinical trials provided further data needed to assess the efficacy of high-dose intravenous gamma-globulin therapy in patients with systemic juvenile rheumatoid arthritis, and extended uncontrolled experience with interferon-gamma in adult rheumatoid arthritis was obtained. An intriguing immunostimulant and antiviral drug, isoprinosine (inosine pranobex), failed in a scientifically rigorous trial in rheumatoid arthritis. Provocative insights into totally new approaches surfaced in additional reports from a variety of immunologic areas. Although seemingly distal to rheumatoid arthritis, these papers are cited because their further development or adaptations could reach a stage where clinical trials in rheumatoid arthritis are warranted.

Our aim was to assess whether "idiopathic" bilateral progressive sensorineural hearing loss (BPSHL) has an immunological cause in some patients; antibodies to native type II collagen were sought by an ELISA in eighteen patients with BPSHL, before and after corticosteroid treatment, and in twelve patients with Meniere's disease, fifteen with otosclerosis, eighteen with rheumatoid arthritis, nine with fibrositis, and nine healthy controls. A positive result was defined as a mean dilution titre of 2 or more. Eight of eighteen BPSHL patients had positive titres--significantly (p less than 0.005) more than in any other group (one Meniere's disease, two otosclerosis, and no others). The mean antibody titre was higher in the BPSHL group than in any other group (2.02 [SEM 0.62] vs 0.17 [0.17]) Meniere's disease, 0.44 [0.32] otosclerosis, 0 all others; p less than 0.005). The nine BPSHL patients who showed a clinical response to corticosteroids (improvement in at least one tone by audiogram or 25 db in speech discrimination score) had the highest mean antibody titre (3.46 [0.88] vs 0.59 [0.59] for the nine non-responsive patients; p less than 0.04). We suggest that in some patients with BPSHL, immunity to type II collagen, a major constituent of the inner ear, may be important in the pathogenesis of the disorder.

Extremely preliminary results from uncontrolled feasibility studies hint that minocycline and T-cell cytolitic strategies deserve further evaluation in RA, as does the use of high-dose intravenous gammaglobulin in chronic cutaneous vasculitis.

Studies in the collagen and rabbit models of arthritis have indicated that indium-111 chloride (111InCl3) scintigraphy objectively measures synovial inflammation. Indium-111 chloride scans, with imaging three days after 19 MBq intravenous injection, were performed on 21 patients with definite or classical rheumatoid arthritis (RA), all of whom were functional class II. Standard clinical indices of disease activity were recorded at the time of imaging by the same investigator, who was unaware of the results of joint scans. In addition, eight patients with severe osteoarthritis, four of whom were considered to need hip or knee joint replacement, were similarly scanned. In each patient 16 joints were graded as 0 to 5, based on increasing degrees of 111InCl3 uptake, by a single investigator blinded to the patient's diagnosis and clinical status. In the group with RA significant correlations were observed between individual joint uptake on scan and peripheral joints with swelling, joints reported to be painful, and joints with any abnormality on physical examination. In the group with osteoarthritis joints positive on scan correlated with the presence of pain. A total scan score (sum of individual joint scores) was calculated for each patient. In the patients with RA values ranged from 0 to 42 with a mean (SEM) of 20.7 (2.7) and correlated with the number of swollen joints and decreasing grip strength. In the group with osteoarthritis the mean total scan score (9.2 (1.5), range 3-14) was significantly lower than in the patients with RA. These data show that 111InCl3 scanning can measure joint involvement by RA.

Based on its efficacy in rheumatoid arthritis and anecdotal evidence, we did an open trial of minocycline in early diffuse scleroderma. Patients satisfied criteria for the diagnosis of scleroderma and did not have additional rheumatic disease. Inclusion criteria were clinical systemic sclerosis on the extremities proximal to the elbow and knee and on the trunk below the clavicles, and disease duration of 3 years or less from the onset of the first symptoms, including Raynaud’s phenomenon, as determined by the patient’s rheumatologist. Exclusion criteria included internal-organ damage. Patients were evaluated at 3-month intervals for 1 year. Medications for Raynaud’s and gastrointestinal-tract disturbances were continued. Patients on treatments that might modify scleroderma had a 1-month washout period. Minocycline was started at 50 mg twice daily, taken with water on an empty stomach; the dose was increased to 100 mg twice daily after 1 month. At each visit, a previously validated total skin score (TSS) was determined by palpation of the skin at 17 surface areas and was graded: 0=normal, 1=thickened skin, 2=thickened, unable to move, and 3=thickened, unable to pinch; maximum possible TSS was 51. Response in TSS was defined as a more than 35% decrease at 12 months. To measure overall well being, a patient and physician 10 cm visual analogue scale (VAS) was used: 0 cm=could not be better, 10 cm=could not be worse. Response in VAS was arbitrarily defined as more than 35% decreased at 12 months. Eleven patients, all diagnosed by at least one independent rheumatologist, were enrolled. Patients number 1, 4, and 11 washed off penicillamine and 2, methotrexate (table). A single observer (CHL) did the evaluations except for the final two visits of patient 11. At the end of 1 year, four patients had complete resolution of their skin disease and their final TSS was 0 (table). In three of these four patients, patient and physician VAS scores improved to 0. In two of the 11 patients, there was no improvement in TSS. In one of these two patients, there was a significant improvement in VAS scores. Five patients did not complete the study; two with renal crisis, one died of adenocarcinoma, and two were noncompliant. Adverse reactions included oral yeast infection in one patient and two episodes of vaginal yeast infection in another. One patient developed nausea and dizziness for the first two weeks. On initial testing, serum concentrations of the adhesion molecules, ICAM-1, VCAM-1, and E-selectin were elevated in patients 11, 10, and nine. Changes did not occur during the trial. No accepted reversal treatment for scleroderma exists. Although the mechanism of action is unknown, minocycline should undergo larger-scale study in scleroderma.

Objective: To determine whether an excess incidence of dermatomyositis or polymyositis or both exist in patients treated with injectable bovine collagen implants and to characterize the clinical pi...

In utero diethylstilbestrol (DES) exposure results in long term reproductive consequences. Preliminary evidence suggests a link between prenatal DES exposure and long term alterations in the immune system. To further test this hypothesis, we compared the phytohemaglutinin (PHA) and concavlin A (con A) induced blastogenic response of mononuclear cell in prenatally exposed women (n=13) to age matched non DES exposed women (n=9). 15 ml. of whole blood obtained during the early follicular phase of cycling women were heparinized, diluted 1:2, layered over ficoll-paqun density gradient. The mononuclear cells were washed X 3 (10%, R.P.M.I. 1640). Aliquots (final cone, of 5 × 105ml). Either PHA (7.5ug-1ug/ml) or Con-A were added to each well. After 48 hours of incubation at 37° C the cells were pulsed with 1 Cμ-thymidine(H-Td), reincubated for 18 hours, harvested, counted, and a geometric mean of 3 determinations obtained. Results: Decreasing H-Td proliferation responses paralleled declining mitogen concentrations both with PHA and Con-A. Con-A showed no significantly different response in cells from DES subjects compared to controls. In contrast, PHA responses were greater in DES subjects (p

Photochemotherapy in systemic sclerosis—remedy or nostrum? In this issue of theArchives, Rook et al 1 report on the results of a randomized, investigator-blind multicenter comparison of extracorporeal photochemotherapy (photophoresis) vs penicillamine in this disease. The study represents a herculean team effort involving a number of high-quality medical centers and, overall, was well performed. It obtained evidence suggesting that photochemotherapy was more effective than penicillamine in decreasing clinical skin involvement, ascertained by gross appearance, and that it was a safer approach as well. The cornerstone for this conclusion was a frequency of 21 (68%) of 31 patients exhibiting improvement in skin scores after 6 months of photochemotherapy that contrasted to only eight (32%) of 25 patients receiving penicillamine. Serious adverse events related to penicillamine required 24% of the patients to permanently discontinue this therapy before a 10-month treatment interval had transpired. Side effects were noted in nine patients receiving photochemotherapy.

To determine which synovial fluid tests are most useful, we prospectively analyzed the synovial fluid test results of 100 consecutive patients undergoing diagnostic arthrocentesis. Each patient's diagnosis was established independently of synovial fluid laboratory test results; in 69 patients a definite inflammatory or noninflammatory categorization could be made. Sensitivity and specificity were estimated for synovial fluid white blood cell count (sensitivity, 0.84; specificity, 0.84), percentage of polymorphonuclear cells (sensitivity, 0.75; specificity, 0.92), glucose (sensitivity, 0.20; specificity, 0.84), protein (sensitivity, 0.52; specificity, 0.56), and lactate dehydrogenase (sensitivity, 0.83; specificity, 0.71). Receiver operating characteristic regression analysis indicated that both white blood cell count and percentage of polymorphonuclear cells were found to contribute independent diagnostic information but lactate dehydrogenase did not. In a separate, retrospective analysis of 19 patients with definite septic arthritis, similar results were observed. We conclude that synovial fluid white blood cell count and percentage of polymorphonuclear cells perform well as discriminators between inflammatory and noninflammatory disease. Ordering chemistry studies of synovial fluid should be discouraged because they are likely to provide misleading or redundant information. ( JAMA . 1990;264:1009-1014)

A patient with a unique case of chronic episodic arthritis coincident with flares of acneform, pustular, nodular and ulcerating skin lesions was observed over a five-year period. This patient and a review of the literature on arthritis associated with the inflammatory dermatoses provide evidence which may interrelate several of these nosologically confusing skin conditions, e.g., the family of leukocytoclastic angiitides with the newly posited acute febrile neutrophilic dermatosis of Sweet. Systemic manifestations and a variety of acneform, pustular, nodular and ulcerating cutaneous lesions in the inflammatory dermatoses are best explained by small vessel involvement, with individual syndromes being determined by the type and degree of vascular change. Perivascular neutrophilic infiltration is the unifying histologic feature of these small vessel diseases. Neutrophil infiltration differentiates these entities, and our patient, from the histologically nonspecific inflammations of the skin, e.g., Behcet's disease and pyoderma gangrenosum, which, although capable of causing identically appearing skin lesions, consist predominantly of lymphocytic dermal infiltrates even in the earlier stages. It appears important to recognize these morphologically varied acute inflammatory dermatoses with perivascular neutrophilic infiltration in view of their systemic features and the dramatic efficacy of corticosteroid therapy.

This review will mainly highlight data from selected, independent studies which collectively implicate a primary role for T cells in the pathogenesis of collagen arthritis in rats. Conferring insusceptibility to this experimental disease with the use of polyclonal, T cell specific antiserum provided direct initial evidence for this conclusion. Substantiation for the theory of a dominant T cell role in collagen arthritis was afforded by T cell line vaccination; scrutiny showed that the mechanism accounting for this protection was a specific down-regulation of the cellular response to collagen. Additional support came from experiments which showed that as few as 10(3) type II collagen specific T line cells were capable of provoking a sustained proliferative synovitis when instilled into the knee joint cavity of syngeneic naive rats. Further analysis of this phenomenon revealed that the arthritogenic capacity of various collagen-reactive line cells correlated with their ability to release a 65-Kd, collagen-binding lymphokine. This antigen-specific lymphokine was designated arthritogenic factor, based on an arthritogenic activity in the knee joint bioassay similar to that of the cells. A functional and physicochemically identical rat arthritogenic factor has also been identified in the adjuvant model of arthritis. These data support the premise that a major effector mechanism in experimental rat arthritis is the release of arthritogenic factor by expanded clones of autoreactive T cells; they also indicate that substantive efforts should be undertaken to seek to identify arthritogenic factor-like lymphokines in patients with chronic inflammatory synovial disease. As an equally plausible alternative hypothesis, the review will close with a brief discussion of recent findings supporting the possible involvement of cartilage-binding, complement-fixing anti-type II collagen antibodies in the pathogenesis of rheumatoid arthritis.

Twenty-six patients with severe rheumatoid arthritis who had completed a randomized crossover trial of methotrexate elected to continue to receive the drug in a long-term prospective study. At 36 months, 16 patients remained in the study. Over this period of time, significant improvement was noted in the number of painful and swollen joints, physician and patient global assessments, erythrocyte sedimentation rate, and prednisone dose. Adverse reactions occurred in 16 patients (62%), including nausea, alopecia, headache, stomatitis, herpes zoster, and diarrhea. Mild leukopenia (3 patients), thrombocytopenia (3 patients), and elevated transaminase levels (8 patients) resolved with temporary drug discontinuation. No patient withdrew due to drug toxicity. Liver biopsy specimens in 17 patients after 24 months of treatment showed no evidence of fibrosis or cirrhosis. A significant increase in the percentage of T3 and T4 blood cells and increases in lymphocyte proliferation to concanavalin A and purified protein derivative of tuberculin were found after 2 years of therapy. Our findings indicate that methotrexate has remained effective over 36 months of therapy, with acceptable toxicity levels and no evidence of systemic immunosuppression.

All the findings discussed support the premise that animal experimentation is a pertinent endeavor for understanding chronic inflammatory synovitis in humans. Whether any of these data actually identify processes operative in RA or can be used to predict outcomes in the human disease is currently unclear. The review closes with an illustration of an area of controversy existing, in part, because of an absence of animal model research. The rationale for the use of gamma-interferon (IFN) in RA has been aptly described by S. H. Pincus as "curious". Evidence of deficient gamma-IFN production within the rheumatoid synovium has been acquired by several laboratories, suggesting that administration of this lymphokine might be helpful. This conclusion has been supported by news of short-term success in uncontrolled pilot trials. However, gamma-IFN is perhaps the most vigorous of the interleukins in terms of diversely activating the immune system. Thus, it would seem logical to envision that gamma-IFN would accelerate any process attributable to autoimmunity. The use of animal models to probe this dilemma, and others arising in the future, could provide a more convincing scientific cornerstone for clinical trials in RA. One caveat, however--animal models provide only clues or potential insights, not final answers, for human disease.

ConclusionsStudies of the immunologic properties of native type II collagen in the past decade have delineated a new field in connective-tissue disease. The opinion that cartilage injury may not be merely the result of pannus but that the origin of synovial hyperplasia could, in some way, be related to cartilage is no longer iconoclastic. The recent advances in the field of collagen immunology have provided data which are clear cut, but the proper interpretation of the experimental results is, at present, only partially evident. In the near future, additional work may answer the questions posed in this review; out of controversy could come certainty.

Rat lymph node cells (LNC) produce a mediator which exhibits functional and physicochemical similarities to human leukocyte inhibitory factor (LIF). Measurement of LIF can be used to quantify cellular sensitivity in rats to foreign protein antigens or to a heterologous antigen in vitro . Concanavalin A-induced rat LIF has a molecular weight of 100,000-60,000 daltons and retains activity after heating to 56 °C for 30 min. Rat LIF is not synthesized in the presence of puromycin and appears to be a protein, since it is inactivated by treatment with chymotrypsin. Moreover, the activity of rat LIF is susceptible to the serine esterase inhibitor, diisopropylphosphofluoridate, but it is resistant to neuraminidase treatment. Finally, rat LIF preferentially inhibits the migration of rat and human polymorphonuclear leukocytes but not that of rat or guinea pig peritoneal exudate cells enriched for macrophages. Except for the more dispersed size of rat LIF, these properties are analogous to those described for human LIF. LIF activity is generated, in an antigen-specific manner, by LNC sensitized to ovalbumin or purified protein derivative of tuberculin when cultured with the antigen used for sensitization. LNC from rats rendered arthritic by prior intradermal (id) injection of native chick type II collagen in incomplete Freund's adjuvant produce LIF in response to this heterologous antigen. These studies delineate a new assay for cellular sensitivity in rats and provide additional evidence that cellular reactivity to type II collagen is present in this animal model of arthritis.

The 1980s was a decade of immunologic, biochemical, and pharmaceutical advances in the treatment of patients with rheumatic diseases. The therapeutic revolution will continue into the 1990s, and this article reviews several areas of change and controversy that have developed.

Thirty-one patients with seronegative psoriatic arthritis, 27 patients with rheumatoid arthritis, 10 with psoriasis alone, and 20 normal volunteers were studied for autoimmunity to human collagens. Cellular and humoral responses were frequently observed in the 2 groups with arthritis, but the subjects without arthritis did not display reactivity to native collagens. These data demonstrate that collagens function as autoantigens in both psoriatic and rheumatoid arthritis.

Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.

Ten patients with refractory rheumatoid arthritis were given 3000 rad of fractionated total lymphoid irradiation in an uncontrolled therapeutic trial. Total lymphoid irradiation was associated with objective evidence of considerable clinical improvement in eight patients and with reduced blood lymphocyte counts in all 10. On completion of irradiation, there was an abrogation of lymphocyte reactivity in vitro in the patients with clinical responses, but abnormal antibody activities characteristic of rheumatoid arthritis and normal components of humoral immunity were not suppressed. Partial recrudescence of arthritis occurred shortly after a year after the completion of irradiation and was paralleled by a restitution of lymphocyte concentrations and responsiveness to mitogens to levels similar to those observed before irradiation. These data provide further evidence of T-cell involvement in the pathogenesis of rheumatoid arthritis and demonstrate that total lymphoid irradiation can induce temporary relief, but they do not ascertain whether the natural history of this disease was altered.