American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015: recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.(AU)

Ophthalmologic manifestations of rheumatic diseases.

OBJECTIVES: Detailed review of the manifestations of eye involvement in the context of rheumatic diseases. METHODS: An OVID Medline search of the rheumatology and ophthalmology English literature related to the eye manifestations of human rheumatic diseases from 1966 to the present was conducted by the authors. RESULTS: Analysis of 300 recent and consecutive rheumatology consultations from a large Veterans Administration Healthcare System shows that 4% are referred for eye manifestations of suspected rheumatic diseases, most commonly, anterior uveitis and keratoconjunctivitis sicca (KCS). Ocular involvement is common in the rheumatic diseases but varies among the different disorders. A literature review indicated that the most common ocular manifestations of rheumatic diseases include keratoconjunctivitis sicca, anterior uveitis, and scleritis. The most serious eye complications of the inherited connective tissue disorders are lens involvement with cataract formation or subluxation. The most significant side effects of the drugs used to treat rheumatic diseases are the maculopathy associated with anti-malarial agents and cataracts and glaucoma associated with corticosteroid use. Although many of the eye manifestations are easily recognizable, consultation with an ophthalmologist is usually necessary for optimal treatment and prevention of complications. CONCLUSIONS: The rheumatologist, in coordination with the ophthalmologist, can play a major role in detecting and managing the eye involvement in his patients to save this important sense. Understanding the varied manifestations of eye disease will permit the rheumatologist to better evaluate the activity of the rheumatic disease.

Systemic lupus erythematosus in men: a retrospective analysis in a Veterans Administration Healthcare System population.

Systemic lupus erythematosus (SLE), a connective tissue disease of unknown etiology, is generally considered to occur in women of child-bearing age and to be uncommon among men . Because of the female predominance in most studies, less is known about the disease in men. To begin to better understand lupus in men, we retrospectively analyzed all the SLE patients from all the hospitals in the Department of Veterans Affairs (VA) system, a population that is predominantly male. Between 1987 and 1996, 2614 SLE patients were retrieved from the VA databank; 2144 were male, making this the largest group of male patients with SLE reported in United States of America. Age, racial and geographic distribution, comorbidities, and mortality of the SLE patients are reported. This study suggests that SLE men in this population are older at onset of disease, have different comorbidities, and have a higher mortality at 1 year than women with SLE. These findings suggest that men with SLE have a more complex clinical course than women, although the data do not illuminate whether the comorbidities are due to or coincident with SLE. On the basis of these data, practitioners are reminded to consider SLE in the differential diagnosis for older men and be attentive to the frequent presence of comorbidities such as cardiac ischemia and neoplasms. Because of the identified regional variations in demographics, comorbidities, and mortality, this study suggests the need for future SLE studies to include data from multiple geographic areas.

Growth effects of Phaenicia sericata larval extracts on fibroblasts: mechanism for wound healing by maggot therapy.

The potential growth stimulating effects of the blow fly, Phaenicia sericata, on mammalian tissue were assessed by exposing human fibroblast tissue culture to maggot extracts. The growth effects of these extracts were compared to those of epidermal growth factor (EGF), recombinant interleukin 6 (IL6), and the insect hormone 20-hydroxyecdysone (EC). Results of dose-response experiments revealed that EGF had a maximum fibroblast stimulation at 66078 +/- 1979 counts per minute (cpm), with peak counts on day 6 of culture, as measured by [3H]-thymidine incorporation. P. sericata hemolymph (HL) and alimentary secretions (AS) and EC were also demonstrated to stimulate resting fibroblast tissue cultures, but the maximal stimulations only achieved 12% of EGF. Their growth rates plateaued between days 4 and 6. Addition of both HL and AS, as well as EC, significantly increased the growth rate of EGF-stimulated fibroblasts; AS increased the maximal stimulation of IL6-stimulated fibroblasts. These studies suggest the existence of intrinsic factors within the maggot which may be responsible for the growth-stimulating effects seen in maggot-infested wounds.

The contribution of synovial fluid lipoproteins to the chronic synovitis of rheumatoid arthritis.

Lipids in the synovial fluid of patients with active rheumatoid arthritis are elevated compared to normal synovial fluid and that of other inflammatory arthropathies. Various assumptions about the role of these lipids have been made. This study offers evidence that these lipids may contribute to the synovitis in rheumatoid arthritis through participation in the arachidonic pathway within the joint space. Phospholipase A2 activity, phospholipids, prostaglandin E2, and leukotriene B4 have been correlated in the synovial fluid and plasma of untreated rheumatoid patients and compared with that of patients with osteoarthritis.

Musculoskeletal disease in very elderly nursing home patients: does under-reporting exist?

To determine the extent of under-reporting of musculoskeletal disease among very elderly nursing home patients, 50 Veterans Affairs Nursing Home patients were evaluated by means of retrospective medical chart review. The primary caregivers' charted musculoskeletal examinations were scored objectively; then the patients completed an arthritis questionnaire, a short-form Geriatric Depression Scale assessment, and the Katz Activities of Daily Living Scale assessment. Finally, each patient underwent an objectively scored musculoskeletal examination by a rheumatologist. The results indicated that musculoskeletal disease in the very elderly nursing home patient is more prevalent than self-report or examination by the primary caregiver suggested. Brief but directed arthritis symptom questioning followed by a specialized examination were necessary to diagnose treatable musculoskeletal disease in this population.

Synovial fluid lipids and apolipoproteins: a contemporary perspective.

Normal human synovial fluid contains extremely low concentrations of lipoproteins and apolipoproteins, in sharp contrast to those found in plasma. Increased amounts of cholesterol and other lipids have been found in the synovial fluid of a chronic inflammatory joint disorder, rheumatoid arthritis (RA). More recently, apolipoproteins AI, B and E have also been found in increased amounts in RA synovial fluid. Theories have been proposed to account for this increase in the amount of apolipoproteins and for the source of lipids and lipoproteins in normal synovial fluid; however, the mechanisms have not yet been established. Lipoproteins may play dual roles in synovial fluid: A functional one in normal synovial fluid and, as some suggest, a pathologic one in the abnormal synovial fluid of certain arthritic diseases. The recent data prompt the need to define synovial fluid lipids, lipoprotein particle subfractions and their constituent apolipoproteins, as well as their respective roles in synovial fluid.

Randomized trial of switching rheumatoid arthritis patients in remission with injectable gold to auranofin.

This prospective unblinded 24-month-study compared the therapeutic value of oral gold with injectable gold to maintain rheumatoid arthritis (RA) patients in clinical remission and prevent the progression of erosive disease. Forty-six patients with definite RA in remission with injectable gold were randomized into two groups: a control group, continued on maintenance injectable gold (Solganal, aurothioglucose, 50-100 mg, intramuscularly, 2 to 4 weeks); and an experimental group, switched to oral gold (6-9 mg auranofin by mouth daily). Only 29% of the original 24 oral gold patients remained on assigned treatment at 24 months compared with 64% of the injectable gold group. By six months, over one-half of the oral gold patients had electively stopped their randomized therapy. Sixty-seven percent of the oral gold patients had adverse reactions, mostly gastrointestinal complaints, compared with one proteinuria in the injectable gold group. The oral gold group experienced significantly more deterioration in all the primary measures of treatment effect over the follow-up period. At the termination of the trial, 88% of the group had increases of 5 or more points in radiographic scores suggesting progression of erosive disease compared with only 29% of the control group. These data suggest that oral gold is not an effective substitute for injectable gold in maintaining remission in rheumatoid arthritis.

Synovial fluid lipoproteins: review of current concepts and new directions.

Recent developments in plasma lipoprotein and apolipoprotein research have been striking, but few studies have focused on the analysis of lipoproteins in synovial fluid (SF). SF contains small amounts of lipoproteins and apolipoproteins. The lipid concentration of normal human SF is extremely low and is in sharp contrast to the concentrations found in plasma. Little is known about the lipids in pathological SF, but studies have noted increased cholesterol and lipoprotein content in rheumatoid arthritis (RA) SF ranging from 40% to 60% of the total plasma lipoproteins. Recently apolipoproteins AI, B and E have also been found to be in increased amounts in RA SF. Several theories have been proposed to account for the increased presence of SF lipids in RA. Animal and human studies indicate the SF cholesterol, lipoproteins, and apolipoproteins may aggravate the inflammatory reaction within the synovial space. Research suggests an immunologic role for plasma lipoproteins on lymphocyte and monocytes in the blood and lymph. SF lipoproteins and apolipoproteins should be studied to define their actions within the synovial space.

Apolipoproteins A-I and B and cholesterol in synovial fluid of patients with rheumatoid arthritis.

Synovial fluid (SF) of patients with rheumatoid arthritis (RA) has been noted to contain cholesterol crystals and increased amounts of cholesterol compared with normal SF. SF, plasma apolipoproteins (apos) A-I and B, and cholesterol in 12 untreated classic RA patients (inflammatory arthritis) and eight untreated degenerative joint disease ([DJD] noninflammatory arthritis) patients were analyzed. Results showed that mean apo A-I, apo B, and cholesterol levels of RA SF were significantly higher than those of DJD SF (apo A-I, P = .004; apo B, P = .0008; cholesterol, P = .0004). Regression analyses of plasma and SF apo A-I and apo B (r = .72, P = .008 and r = .63, P = .02, respectively) suggested an increased permeability for these lipoprotein constituents across RA synovial membrane that was not observed in DJD synovial membrane. These data suggest that RA synovium but not DJD synovium is more permeable to major apoproteins of low- and high-density lipoproteins (LDL and HDL). These apolipoproteins have been shown to influence the immune response and may therefore be involved in the pathogenesis of RA.

Membrane surface properties of lymphocytes of normal (DBA/2) and autoimmune (NZB/NZW)F1 mice: effects of L-canavanine and a proposed mechanism for diet-induced autoimmune disease.

Partitioning cells in a dextran polyethylene glycol aqueous two-phase system (countercurrent distribution, CCD) is a sensitive method for learning about cell surface membrane properties and for subfractionating cell populations. In this study, we subjected lymphocytes from normal DBA/2 mice and autoimmune F1 New Zealand black/New Zealand white [NZB/NZW)F1) mice to countercurrent distribution and found that T cells partition to the right and B cells partition to the left of the CCD curve. We found no difference between the CCD patterns of normal and autoimmune mice. When the murine lymphocytes were exposed to a cationic dietary amino acid (L-canavanine) in vitro, L-canavanine selectively affected the CCD pattern of autoimmune B cells, reflecting an alteration in surface membrane properties. We separated these lymphocytes with altered surface membrane properties by CCD. Impaired B-cell immune responses associated with L-canavanine were isolated to this lymphocyte fraction. This study provides the first evidence that alterations in the charged surface membrane properties are associated with abnormal (auto) immune response.

Palmar fasciitis and arthritis with ovarian and non-ovarian carcinomas. New syndrome.

Paraneoplastic syndromes affect a variety of organ systems and often suggest occult malignancy. Recently, a distinct syndrome of palmar fasciitis and arthritis has been associated with ovarian carcinomas. The two cases presented illustrate the fasciitis-arthritis association with other non-ovarian malignancies and suggest an immunologic cause for this disorder.

Effects of L-canavanine on immune function in normal and autoimmune mice: disordered B-cell function by a dietary amino acid in the immunoregulation of autoimmune disease.

This study reports the effects in vitro and in vivo of L-canavanine (LCN), an amino acid found in commonly consumed legumes, on immune function in normal and autoimmune mice. L-Canavanine in high doses effectively blocks all DNA synthesis in vitro within 24 h. At lower doses, LCN affects B-cell function of autoimmune New Zealand Black/New Zealand White (NZB/NZW)F1 mice, inhibiting [3H]thymidine incorporation in response to B-cell mitogens, and pokeweed-induced intracytoplasmic immunoglobulin synthesis. LCN stimulates intracytoplasmic immunoglobulin (IgG greater than IgM). T-cell functions such as lymphoproliferation in response to concanavalin A or phytohemagglutinin and T-cell cytotoxicity are not affected. Suppression of the lipopolysaccharide response by LCN is removed by the addition of fresh B cells. Addition of the amino acid to mouse diet resulted in a decrease in the life-span of the autoimmune NZB and (NZB X NZW)F1 mice and abolished the protective effect of male sex on their survival. The decrease in survival in LCN-treated autoimmune mice correlated with an increase in spontaneous immunoglobulin-secreting cells (IgG greater than IgM) and antinuclear and double-stranded DNA antibodies. The histopathological analyses revealed increased glomerular damage and immunoglobulin deposition in the kidneys of the LCN-treated autoimmune and normal (DBA/2) mice. Ten percent of normal mice developed high titers of autoantibodies after 24 weeks of the diet. These data suggest a dietary amino acid, L-canavanine, affects B-cell function resulting in autoimmune phenomena and providing a new animal model of autoimmunity, a diet-induced systemic lupus erythematosus.

The nature of arthritis pain.

A modified version of the McGill Pain Questionnaire in visual analogue format was used to evaluate the sensory, affective and evaluative intensities of pain experienced by 40 patients with rheumatoid arthritis and 20 patients with degenerative arthritis. The affective component of the pain was found to be more intense than the sensory component in all patients indicating the importance of emotional factors in the pain experience. The sensory aspects of the pain were more complex than the affective ones reflecting the varied sources and combinations of somatic pathology. There were no significant differences found in the overall pain experience between rheumatoid and degenerative arthritis. No differences were noted in the evaluative category of pain. Overall pain intensity increased with disease duration in both rheumatoid and degenerative arthritis. The relationship of affective and sensory components of the pain experience did not alter with duration of disease.