Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.

OBJECTIVE: To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA). METHODS: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008-9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed. RESULTS: A total of 39,756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA. CONCLUSIONS: Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use.

Prevention of anticardiolipin antibody-related pregnancy losses with prednisone and aspirin.

PURPOSE: Prevention and treatment of pregnancy loss associated with the antiphospholipid syndrome (APS) are controversial. Successful pregnancies have been reported with prednisone and low-dose aspirin in patients with lupus anticoagulant and anticardiolipin antibodies (aCL), but failure has also been reported. The purpose of this prospective study was to define the efficacy of such combination therapy in the prevention of pregnancy loss related to aCL. PATIENTS AND METHODS: Consecutive pregnant patients with a minimum of one pregnancy loss and at least two positive aCL determinations more than 3 months apart, and in whom other causes of pregnancy loss were ruled out, were included in the study. aCL concentrations were determined by enzyme-linked immunosorbent assay before and during therapy. Patients received prednisone, at a dosage of 40 mg/d, for 4 weeks. The dose was then tapered down 10 mg every 4 weeks, and then to a maintenance dose of 5 mg/d. They also received aspirin, 81 mg/d, throughout the pregnancy. Babies were evaluated during the pregnancy by measurement of fetal heart rate and ultrasonography, and after the delivery by measurement of weight and Apgar scores, and, in some cases, by arterial gasometry. RESULTS: Eleven patients with a mean (+/- SD) age of 33.2 +/- 5.01 years were included. Prior to therapy, the rate of live-born babies was 15.6% (32 previous fetal losses and 5 live-born babies), and, after therapy, it was 100% (12 pregnancies and 12 live-born babies). There were no significant adverse effects to either mothers or babies. All the patients had positive aCL determinations. Nine patients had positive IgG aCL. The levels of the antibodies decreased during treatment in these nine patients. IgM aCL determinations were positive in nine patients. The levels of this isotype decreased in eight patients (90%) during treatment. CONCLUSIONS: Treatment with prednisone and aspirin appears to be efficacious, safe, and economic in the prevention of pregnancy loss and fetal growth retardation in patients with aCL.

Anticardiolipin antibodies in polymyalgia rheumatica-giant cell arteritis: association with severe vascular complications.

PURPOSE: We studied a group of patients with polymyalgia rheumatica (PMR) with or without biopsy-proven giant cell arteritis (GCA) in order to determine the prevalence of anticardiolipin antibodies (aCL) in these disorders and their association with vascular complications. PATIENTS AND METHODS: The study consisted of 50 patients, 30 with PMR alone and 20 with associated GCA. Determinations of IgG and IgM aCL by enzyme-linked immunosorbent assay were done in the patients and in 50 age- and sex-matched healthy control subjects. We also measured von Willebrand factor (vWF) antigen, C-reactive protein, and erythrocyte sedimentation rate. RESULTS: Twenty-four (48%) of the 50 patients had aCL. Eleven were positive for IgG and five for IgM, whereas eight were positive for both. In the group of patients with PMR alone, only eight (26.6%) had aCL, while 16 of 20 patients (80%) with GCA had these antibodies (p less than 0.01). In the control group, 10 of 50 patients (20%) had positive aCL, a finding that was statistically significantly different only when compared with the finding in patients with GCA (p less than 0.01). Both isotypes of aCL were seen mainly in patients with GCA, and five of these patients had severe vascular complications. Levels of vWF antigen were significantly higher in patients with GCA as compared with patients with PMR alone; however, the highest titers did not correlate with vascular complications. Erythrocyte sedimentation rate and C-reactive protein were increased but comparable in both groups. CONCLUSION: This study demonstrates that aCL are prevalent in patients with GCA. These antibodies might imply severe vascular damage and could play an important role in the pathogenesis of the vasculopathy observed in this disease.

Treatment of the eosinophilia-myalgia syndrome.

The eosinophilia-myalgia syndrome (EMS) is a unique entity associated with products that contain L-tryptophan (L-trp). Studies of the underlying etiopathogenic processes are underway. EMS is a distinct syndrome, but shares features with eosinophilic fasciitis and other variants of systemic sclerosis. A wide spectrum of clinical manifestations has been described, but there is no consensus regarding treatment. We report the clinical and laboratory features of 12 patients. All were treated with nonsteroidal antiinflammatory drugs (NSAIDs) and analgesics with transient or minimal effect. Two received D-penicillamine (DP) and colchicine, with minimal improvement; one had no response to azathioprine (AZA). Eleven received corticosteroids and had improvement of general symptoms, arthralgias, arthritis, myalgias, skin changes, eosinophilia, and leukocytosis. Nevertheless, all but the latter two findings recurred when corticosteroids were tapered. Seven patients who were unresponsive to the former treatments received low-dose pulse oral methotrexate. Six exhibited continued improvement after a mean follow-up of 4.5 months, with good drug tolerance. Corticosteroids were tapered and, in some instances, discontinued without relapse or complications. One patient improved but later died of aspiration pneumonia. We conclude that methotrexate (MTX) is a therapeutic alternative for patients with severe or refractory EMS.

Prolactin, immunoregulation, and autoimmune diseases.

Cells of the immune system synthesize prolactin and express mRNA and receptors for that hormone. Interleukin 1, interleukin 6, gamma interferon, tumor necrosis factor, platelet activator factor, and substance P participate in the release of prolactin. This hormone is involved in the pathogenesis of adjuvant arthritis and restores immunocompetence in experimental models. In vitro studies suggest that lymphocytes are an important target tissue for circulating prolactin. Prolactin antibodies inhibit lymphocyte proliferation. Prolactin is comitogenic with concanavalin A and induces interleukin 2 receptors on the surface of lymphocytes. Prolactin stimulates ornithine decarboxylase and activates protein kinase C, which are pivotal enzymes in the differentiation, proliferation, and function of lymphocytes. Cyclosporine A interferes with prolactin binding to its receptors on lymphocytes. Hyperprolactinemia has been found in patients with systemic lupus erythematosus. Fibromyalgia, rheumatoid arthritis, and low back pain patients present a hyperprolactinemic response to thyrotropin-releasing hormone. Experimental autoimmune uveitis, as well as patients with uveitis whether or not associated with spondyloarthropathies, and patients with psoriatic arthritis may respond to bromocriptine treatment. Suppression of circulating prolactin by bromocriptine appears to improve the immunosuppressive effect of cyclosporine A with significantly less toxicity. Prolactin may also be a new marker of rejection in heart-transplant patients. This body of evidence may have an impact in the study of rheumatic disorders, especially connective tissue diseases. A role for prolactin in autoimmune diseases remains to be demonstrated.

Clinical findings in symptomatic women with silicone breast implants.

We report the clinical findings in a series of women with silicone breast implants (SBI) and rheumatic disease. These findings represent the first 50 patients seen at the University of South Florida Medical Clinic between March 1977 and January 1991. The average age was 44 years with a range of 30 to 66 years. The most common clinical findings included chronic fatigue, muscle pain, joint pain, joint swelling, and lymphadenopathy. Seventeen women with an average Steinbrocker functional class of 1.8 decided not to remove the implants. An average of 14 months later, follow-up showed no change in their condition. Thirty-three women, with an average functional class of 2.5 underwent implant removal. Twelve of the 33 had documented implant rupture. During an average follow-up of 22 months after implant removal, 24 women improved clinically, 8 did not change, and 1 worsened. We believe this series supports a relationship between silicone breast implants and rheumatic disease signs and symptoms. Although this report is not a definitive epidemiological study, findings suggest that physicians should inform women about the possible benefit of implant removal.

Gonococcal arthritis.

Disseminated gonococcal infection is a preventable communicable disease. It is an important cause of arthritis in sexually active adults. Prompt recognition and treatment of this common disease results in cure and eliminates unnecessary diagnostic procedures and prolonged hospitalization.

There is an association between human immunodeficiency virus infection and spondyloarthropathies.

The presence of inflammatory musculoskeletal manifestations during the course of human immunodeficiency virus (HIV) infection is well established. A wide spectrum of rheumatic disorders have been reported since the first reports of Reiter's syndrome with HIV infection. Other reported associations include forms of arthropathies, psoriatic arthritis, Sjögren's syndrome, polymyositis-dermatomyositis, vasculitis, and septic arthritis.

Characteristics and pathogenesis of myositis in human immunodeficiency virus infection--distinction from azidothymidine-induced myopathy.

Inflammatory muscle involvement during the course of human immunodeficiency virus (HIV) infection is described and guidelines are suggested for its differentiation from the myopathy associated with azidothymidine (AZT) therapy. Six patients infected with HIV presented with proximal muscle weakness, biochemical and electromyographic abnormalities consistent with myositis. One patient had a skin rash characteristic of dermatomyositis. Muscle biopsy findings demonstrated the presence of an inflammatory cell infiltrate and HIV-p24 antigen. All patients developed their clinical picture prior to AZT therapy and responded to steroids with or without coadministration of AZT.

Does serum rheumatoid factor have an influence on the clinical picture of ankylosing spondylitis?

OBJECTIVE: To describe the influence of serum rheumatoid factor (RF) on the clinical and radiological picture of definite ankylosing spondylitis (AS). METHODS: In a retrospective chart review of 281 AS patients typed for RF, the clinical picture of RF positive patients (Group 1) was compared with RF negative patients (Group 2); mode of onset, disease duration, and treatment were recorded. All patients were examined to determine their clinical status; the blood cell count. HLA-B27, serum IgG, IgM, IgA, and erythrocyte sedimentation rate (ESR) were determined, and radiological studies of the entire spine, pelvis and affected peripheral joints were carried out. In patients from Group 1 the HLA-DR was also determined. RESULTS: Fifteen of 281 patients (8 men, 7 women) with AS were RF+ (1:64 to 1:1024) (5.3%) and 11 were HLA-B27+. Seven patients in Group 1 had spine involvement and chronic arthritis of the knees. Four out of these 7 were tested for DR, and none was positive; in 6, AS and rheumatoid arthritis (RA) coexisted, 2 were DR1 and 2 were DR4 (test not carried out in 2). In two others we found spinal involvement only, and one of them had both DR1 and DR4. The onset of AS was similar in both groups. Group 1 was characterized by a chronic disease of moderate intensity with chronic arthritis of the metacarpophalangeal and proximal interphalangeal joints (p = 0.0008 and p = 0.04, respectively), no valvulopathy (p = 0.04) and fewer uveitis sequelae (p = 0.007) than Group 2. The ESR (p = 0.01), IgG (p = 0.008) and IgM (p = 0.0001) were higher in Group 1 than in Group 2. CONCLUSIONS: The presence of RF in AS is associated with a chronic disease of moderate intensity with chronic peripheral arthritis and fewer extra-articular manifestations. The presence of RF, not always associated with HLA-DR, seems to affect the course of AS and does not necessarily indicate an association with RA.

Lack of immunosuppressive effect of low-dose oral methotrexate on lymphocytes in rheumatoid arthritis.

Whether methotrexate (MTX) is effective in rheumatoid arthritis (RA) because of immunosuppressive and/or anti-inflammatory mechanisms of action is controversial. Many lines of investigation point to the latter. We evaluated DNA synthesis in peripheral blood lymphocytes (PBL) from 33 RA patients on oral MTX (7.5-15 mg/wk) and in 30 healthy controls by flow cytometric cell cycle analysis (CCA). DNA synthesis was also evaluated with a thymidilate synthetase activity assay (TSA) (3H-deoxyuridine incorporation) in 12 patients and 21 controls (12 on MTX and NSAID, and 9 healthy subjects). The patients had taken MTX for at least 3 months and were in different stages of clinical activity. There were no significant differences in TSA or in the cell cycle phase distributions (especially the S phase) between treated RA patients and controls. These data suggest that low-dose oral MTX does not inhibit DNA synthesis and therefore does not have an immunosuppressive effect on lymphocytes from patients with RA.

Hyperprolactinemia in systemic lupus erythematosus: association with disease activity.

This study was designed to determine the prevalence and clinical significance of hyperprolactinemia in systemic lupus erythematosus (SLE) and other rheumatic diseases. Basal levels of prolactin were determined in 130 nonselected sera from patients with rheumatic diseases including 45 with SLE, 31 with rheumatoid arthritis, 23 with osteoarthritis, 18 with fibromyalgia, and 13 with polymyalgia rheumatica. Serum samples of 28 healthy subjects were used as normal controls. Serum prolactin was measured by radioimmunoassay. ANA, anti-DNA, RNP, Sm, Ro, La, and anticardiolipin antibodies were determined by standard techniques. Elevated serum levels of prolactin (PRL greater than 20 ng/ml) were found in a subset of SLE patients. In addition, a direct correlation with clinical disease and serological (ANA) activity was also found. These findings suggest a potential role for this immunoregulatory hormone in SLE pathogenesis.

Eosinophilic hepatitis: a new feature of the clinical spectrum of the eosinophilia-myalgia syndrome.

The eosinophilia-myalgia syndrome associated with L-tryptophan-containing products is highlighted by eosinophilia, incapacitating myalgias, and diverse multisystemic manifestations. In addition to involvement of the skin, skeletal muscle, and peripheral nerves, visceral damage has been quite prominent, particularly affecting the lungs, the heart, and the liver. Hepatic involvement has been manifested by altered liver tests but is clinically silent. We report the unique case of a woman with this syndrome who developed abdominal pain, a clinical picture of hepatitis and chronically abnormal liver tests. Histologic examination of the liver disclosed eosinophilic hepatitis with piecemeal necrosis. The occurrence of clinically overt hepatic involvement has not been reported previously. Potential mechanisms of liver damage in eosinophilia-myalgia syndromes are discussed.

Ultraviolet-A1 (340-400 nm) irradiation therapy in systemic lupus erythematosus.

Ultraviolet-A1 (UV-A1) wavelengths have been found effective in mitigating signs and symptoms of disease activity in systemic lupus erythematosus (SLE) but studies have been uncontrolled. To rigorously assess the effectiveness and safety of daily low-dose UV-A1 irradiation as a therapeutic agent in this disorder we enrolled 26 women with SLE in an 18-week two-phase study. During the initial six-week prospective, double-blind, placebo-controlled phase, the patients were divided into two groups; Group A was exposed to 60kJ/m2 of UV-A1 (340-400 nm) irradiation within a sunbed five days a week for three weeks and Group B was exposed for an equal amount of time to visible light of greater than > 430 nm (placebo). Each group was then crossed over for exposure to the other source for three weeks. During the second phase-2 weeks-patients and physicians were unblinded and patients were irradiated with progressively decreasing levels of UV-A1 only. Twenty-five patients completed the six-week placebo-controlled phase of the study and eighteen patients participated for the entire 18 weeks. In Group A the systemic lupus activity measure (SLAM) score improved significantly after three weeks of five-day-a-week UV-A1 irradiation (P < 0.05), regressing to baseline during the three weeks of placebo irradiation. Improvement recurred and progressed with six weeks of three-day-a-week UV-A1 irradiation (P < 0.05). Group B patients responded negligibly to the three weeks of visible light, more sharply to UV-A1, and as with Group A, maximally to the six weeks of three-day-a-week UV-A1 (P < 0.01). With twice- and then once-weekly UV-A1 irradiation the SLAM scores worsened slightly. All patients decreased their drug use. Anti-double-stranded DNA antibodies (anti-dsDNA) decreased significantly (P < 0.05) and anti-nuclear antibodies non-significantly. Side effects were negligible. Visible light had no significant effect. In conclusion, low-dose UV-A1 irradiation effectively, comfortably, and without apparent toxicity diminished signs and symptoms of disease activity in SLE.

Is silicone associated with connective tissue disease?

Connective tissue diseases have been described in patients who have had silicone augmentation mammoplasty. Several possible mechanisms of pathogenesis are postulated. Although otherwise indistinguishable from other connective tissue disease, these patients may experience improvement or remission following implant removal. Current data suggest that the risk of disease after silicone breast augmentation is less than one percent. A large well-designed epidemiologic study will be needed to confirm this association.

Intravenous cyclophosphamide pulses in the treatment of pyoderma gangrenosum associated with rheumatoid arthritis: report of 2 cases and review of the literature.

Pyoderma gangrenosum is a chronic ulceronecrotic inflammatory cutaneous disorder that can be associated with diseases such as rheumatoid arthritis (RA). No definitive treatment exists for this condition; steroids have been the mainstay of therapy, and the addition of immunosuppressives has been advocated. We describe 2 patients with pyoderma gangrenosum occurring in the setting of RA who, in addition to steroids, received pulse intravenous cyclophosphamide and had a remarkably good and lasting response. This is the first report of such a therapeutic approach. The pertinent literature is discussed. We conclude that pulse cyclophosphamide is another possible therapy for pyoderma gangrenosum.