Immunoglobulin (Ig)M antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3-ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.

Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Glycosylation of proteinase 3 (PR3) is not required for its reactivity with antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis.

OBJECTIVE: The glycosylation status of autoantigens appears to be crucial for the pathogenesis of some autoimmune diseases, since carbohydrates play a crucial role in the distinction of self from non-self. Proteinase 3 (PR3), the main target antigen for anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG), contains two Asn-linked glycosylation sites. The present study explores the influence of the glycosylation status of PR3 on the PR3 recognition by ANCA in a well characterized population of patients with WG. METHODS: Forty-four patients with WG (459 serum samples) who participated in a multicenter randomized trial, were tested by capture ELISA for ANCA against PR3 and deglycosylated recombinant variants of PR3. RESULTS: The patients were followed for a median of 27 months, and the median number of serum samples per patient was 10. At baseline, the correlation between the levels of ANCA against PR3 and against all the deglycosylated recombinant variants of PR3 were greater than 0.94 (?<0.001 for all the comparisons). Longitudinal analyses comparing the levels of ANCA against PR3 versus all the deglycosylated recombinant variants of PR3, using linear mixed models, showed no significant statistical differences (rho >or=0.90 in all cases). CONCLUSION: The glycosylation status of PR3 has no impact on its recognition by ANCA in WG.

Life-threatening reaction to vancomycin given for noninfectious fever.

OBJECTIVE: To report a case of vancomycin-induced anaphylaxis (or anaphylactoid reaction) in a patient with a fever of unrecognized noninfectious origin. CASE SUMMARY: An 83-year-old white man, who was a patient of the Veterans Affairs Medical Center, developed a serious anaphylactic (or anaphylactoid) reaction while receiving intravenous vancomycin as empiric therapy for a nosocomial fever of unknown origin. The fever was subsequently proved to have been due to acute polyarticular gout rather than an infection. DISCUSSION: This patient developed respiratory distress and an increased serum troponin concentration, suggestive of a myocardial enzymatic leak as a result of vancomycin therapy. Vancomycin was given before the noninfectious cause of his fever was recognized. CONCLUSIONS: Even with cautious slow infusion, intravenous vancomycin can precipitate life-threatening infusion-related reactions in some patients. Because of this, and to reduce selective pressure for vancomycin resistance, sources of fever that do not require treatment with vancomycin should be diligently investigated prior to the institution of empiric vancomycin therapy in febrile patients, particularly when the past medical history is suggestive of an alternative diagnosis.

Viral arthritis.

Identifying viral infections related to rheumatic syndromes and understanding the pathophysiologic mechanisms by which they cause disease are crucial steps to furthering our understanding of the pathogenesis of rheumatic disease. Many common viral infections can induce autoantibody formation. Parvovirus B19 (B19) can cause acute arthritis, and occasionally chronic arthropathy, in infected adults. Persistent B19 infection can be found in synovium of some patients. Antibodies reactive with B19 epitopes can cross react with some autoantigens. Studies of rheumatic syndromes associated with other viral infections, including alphaviruses, rubella, hepatitis C, and retroviruses, suggest differing mechanisms of host interaction with the infectious agents to cause disease.

Codeine and oxycodone use in patients with chronic rheumatic disease pain.

OBJECTIVE: Opioid treatment of chronic rheumatic disease pain is controversial because of concerns regarding efficacy, toxicity, tolerance, dependence, and abuse. This study examined opioid use in a cohort of patients with pain due to defined rheumatic diseases. METHODS: Opioid use was studied retrospectively in a cohort of 644 rheumatology clinic patients. Computerized pharmacy records identified patients who had been prescribed opioids during the previous 3 years. Medical records were reviewed to determine reasons for opioid dosage escalations. Patients were interviewed to determine efficacy, frequency and types of side effects, and history of alcohol or street-drug abuse. RESULTS: Opioid prescriptions were found in the 3-year pharmacy database for 290 of 644 clinic patients: 153 for <3 consecutive months and 137 for > or =3 months. All opioid-treated patients received codeine and/or oxycodone. In this cohort, 133 patients in each opioid-treated group and 76 of the 354 non-opioid-treated control patients were studied. Opioids significantly reduced rheumatic disease pain severity scores from 8.2 to 3.6 (on a 0-10 scale) (P < 0.001). Mild side effects were reported in 38%; nausea, dyspepsia, constipation, and sedation were the most common. The mean +/-SD initial dosage was 2.1+/-1.7 30-mg codeine equivalents/day, the mean peak was 3.4+/-3.3 per day, and the mean current dose was 2.7+/-2.0 per day. Dosage escalations occurred in 32 patients and were attributable to worsening of the underlying painful condition or a medical complication thereof in all but 4 patients, who also displayed other abuse behaviors. Abuse behaviors were not more frequent in those with or without a history of abuse/ addiction. CONCLUSION: Prolonged treatment of rheumatic disease pain with codeine or oxycodone was effective in reducing pain severity and was associated with only mild toxicity. Doses were stable for prolonged periods of time, with escalations of the opioid dose almost always related to worsening of the painful condition or a complication thereof, rather than the development of tolerance to opioids. Doubts or concerns about opioid efficacy, toxicity, tolerance, and abuse or addiction should no longer be used to justify withholding opioids from patients with well-defined rheumatic disease pain.

Neoprene splinting: dermatological issues.

Occupational therapists are expanding their use of custom and commercial soft splints fabricated from neoprene (polychloroprene), but little has been written regarding dermatological issues associated with this material. Skin contact with neoprene poses two dermatological risks: allergic contact dermatitis (ACD) and miliaria rubra (i.e., prickly heat). Allergic reaction to neoprene is generally ascribed to the accelerants used to manufacture the man-made rubber, specifically thiourea compounds and mercaptobenzothiazole (MBT). Symptoms of neoprene-related ACD include itching, skin eruptions, swelling, and hemorrhages into the skin. Miliaria rubra creates small, red, elevated, inflammatory papules and a tingling, burning sensation. Although neoprene hypersensitivity is rare, its incidence may grow as neoprene becomes a more commonly used material. It is recommended that therapists screen patients for a history of dermatological reactions to neoprene or other materials containing thiourea compounds or MBT and educate patients to discontinue splint use if dermatological symptoms develop. Therapists are also encouraged to notify splint manufacturers regarding all ACD reactions.

Commercial wrist extensor orthoses: a descriptive study of use and preference in patients with rheumatoid arthritis.

OBJECTIVE: To describe patients' functional uses of 3 commercial wrist orthoses, to describe patients' preference patterns for the orthoses, and to clarify orthotic attributes that are viewed positively and negatively. METHODS: Using a cross-over design, 42 patients with definite rheumatoid arthritis used each of 3 commercial orthoses for one week. There was a one-week wash-out between each week of use. At the end of the study, private semi-structured interviews were conducted with each participant. Data from close-ended questions were tabulated. Open-ended data were analyzed using qualitative methods. RESULTS: Patients reported that the 3 commercial wrist orthoses reduced wrist pain similarly, but that comfort and a sense of security during functional tasks were only found if the orthoses were comfortable and well-fitting. Most subjects preferred the padded, short forearm orthosis, though a small number found it uncomfortably warm, and many complained that it was difficult to use when wearing long-sleeved garments. Common complaints about the two elastic orthoses included chafing at the thumb webspace and chafing at the proximal closures. Longer forearm length was often perceived as providing unnecessarily high levels of wrist support. CONCLUSIONS: No single orthosis suited all subjects. Satisfaction with an orthosis appears to be based not only on its therapeutic effect, but also the comfort and ease of its use. To maximize patient satisfaction and improve the likelihood of appropriate fit and comfort, several styles of commercial orthoses should be available. The current trend toward restricted clinic stocks appears contrary to both therapeutic goals and patient satisfaction.

Murine progressive ankylosis is not immunologically mediated.

OBJECTIVE: Murine progressive ankylosis is an autosomal recessive disorder in mice similar to the human spondyloarthropathies. The gene responsible for progressive ankylosis, ank, has not been identified and its product is unknown. We investigated whether the immune system plays a role in the pathogenesis of progressive ankylosis. METHODS: Reciprocal transfers of spleen or bone marrow cells or serum between ank/ank and normal mice were performed. CD4 T cells were depleted in vivo by injection with monoclonal antibody. Ank/ank; nu/nu mice were bred from double heterozygote offspring of homozygote parents. RESULTS: Disease was neither ameliorated nor induced by these immune system manipulations. CONCLUSION: We conclude that progressive ankylosis is not immune mediated. The similarities between ankylosing spondylitis and murine progressive ankylosis may be due to mechanisms producing osteogenesis in nonosseous tissues.

Infectious agents associated with myopathies.

Several infectious agents can cause chronic or acute myopathy. Most current investigations into possible infectious causes of the idiopathic inflammatory myopathies have focused on retroviruses, including HIV and human T-cell leukemia-lymphoma virus type I. In both cases, viruses likely do not directly infect muscle fibers but instead induce an immunologically mediated myositis. Other interest has focused on enteroviruses as potential etiologic agents of idiopathic inflammatory myopathy, but their relationship to human myositis is less clear. In addition to chronic muscle disease, several infectious agents can cause acute myositis, including pyomyositis, which is being recognized in temperate climates with increasing frequency, and rhabdomyolysis.

Finger dexterity and hand function: effect of three commercial wrist extensor orthoses on patients with rheumatoid arthritis.

OBJECTIVE: To investigate the effect of 3 commercial wrist orthoses on finger dexterity and hand function of patients with rheumatoid arthritis (RA). METHODS: Forty-two patients with definite RA participated in the cross-over study comparing 3 styles of commercial wrist orthoses. Finger dexterity and hand function of the dominant hand were assessed while splinted and unsplinted, at the initial session and after 1 week of intermittent orthosis use. Finger dexterity was assessed using two subtests from the Purdue Pegboard Test (Purdue) and hand function was assessed using the Jebsen-Taylor Hand Function Test (Jebsen-Taylor). RESULTS: Both finger dexterity and hand function were reduced by splinting; men and women were affected similarly. There was no difference in finger dexterity or hand function afforded by the 3 orthoses. Results on both the Purdue and Jebsen-Taylor tests showed a significant learning effect across time. CONCLUSIONS: The 3 commercial wrist orthoses studied reduce dexterity similarly and significantly. When commercial wrist orthoses are to be used during tasks that require maximum dexterity, this reduction should be weighed against the known benefits of splinting.

Immediate and short-term effects of three commercial wrist extensor orthoses on grip strength and function in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the immediate and short-term effects of 3 commercial wrist orthoses on grip strength and function. METHODS: Thirty-six patients with definite rheumatoid arthritis participated in the randomized, controlled, cross-over design study of 3 commercial wrist extensor orthoses. Dominant-hand dynamometric grip strength was assessed at both initial and followup sessions while splinted and nonsplinted. Functional impact was assessed using a written questionnaire. RESULTS: All 3 commercial orthoses reduced grip strength when first donned. After a 1-week adjustment period, one orthosis, the Smith and Nephew Roylan D-Ring (Roylan), afforded splinted grip strength equal to that of the nonsplinted grip strength. The other 2 orthoses continued to reduce grip strength, and afforded splinted grip strength significantly below that of the Roylan. The Roylan was deemed comfortable by more subjects than the other orthoses. CONCLUSIONS: The belief that commercial orthotic use increases grip strength, either immediately or after 1 week, is not supported by this study's data. Different styles of commercial wrist orthoses appear to have differing influence on splinted grip strength.

Lack of detection of enteroviral RNA or bacterial DNA in magnetic resonance imaging-directed muscle biopsies from twenty children with active untreated juvenile dermatomyositis.

OBJECTIVE: To investigate for the presence of increased titers of circulating antibody to putative infectious agents and for detectable viral RNA or bacterial DNA in children with active recent-onset juvenile dermatomyositis (DM). METHODS: Magnetic resonance imaging-directed muscle biopsies were performed in 20 children with active, untreated, recent-onset juvenile DM and in age-matched children with neurologic disease. Sera were tested for complement-fixing antibody to Coxsackievirus B (CVB), influenza A and B, parainfluenza 1 and 3, Mycoplasma pneumoniae, mumps, respiratory syncytial virus, and Reovirus; and by immunofluorescence for IgG antibody to Toxoplasma gondii cytomegalovirus and IgM antibody to Epstein-Barr virus. Muscle from juvenile DM patients and control children, CD-1 Swiss mice with and without CVB1 infection, and viral stock positive for CVB1-6 were tested using reverse-transcriptase polymerase chain reaction with 5 primer sets, 4 probes (1 Coxsackievirus, 3 Enterovirus), and universal primers for DNA. RESULTS: No increased antibody, viral RNA, or bacterial DNA was present in the juvenile DM patients or the control children. CONCLUSION: Juvenile DM may be triggered by unidentified agent(s) in the genetically susceptible host.