James J. Curran

Knee laxity in symptomatic osteoarthritis

Twenty-two patients with primary osteoarthritis (OA) of the knee were studied to determine the effects of OA on laxity of the knee joint. Laxity was measured with a Genucom Knee Analysis System. Ten knees had mild OA (> 50% preservation of joint space). Fifteen knees had moderate OA (some preservation of joint space, but < 50%). Eighteen knees had severe OA (no joint space). A group of 18 knees from 9 healthy (asymptomatic) subjects of ages similar to those of the OA patients were used as controls. Compared to control knees, severe OA knees had less total anteroposterior (AP) translation (12.2 versus 6.6 mm, p < 0.025) and less total tibial rotation (79 versus 59 degrees, p < 0.01). Compared to early OA knees, knees with severe OA had 57% less average total AP translation (15.2 versus 6.6 mm, p < 0.01), 31% less total varus/valgus rotation (15 degrees versus 10.4 degrees, p < 0.016), and 26% less total internal/external tibial rotation (80.1 degrees versus 59 degrees, p < 0.007). These data indicate that osteoarthritic knees tend to have less laxity than normal knees, probably because of a combination of contracture of the ligaments and pressure of osteophytes against ligaments and other capsular structures.

Wegener's granulomatosis in pregnancy

This report describes a case of severe limited Wegeners granulomatosis (WG) presenting in the third trimester of pregnancy with pansinusitis and necrotizing pneumonitis. The patient was treated successfully with a combination of corticosteroids and cyclophosphamide (CYC). The outcomes in the mother and the newborn were excellent. In a review of the English-language literature, we found 10 similar cases of WG with 13 pregnancies. WG occurring during pregnancy may have a more aggressive course and may require more aggressive treatment compared with WG occurring at other times. The treatment options for WG in pregnancy are discussed.

Clinical characteristics of patients with anti-Jo-1 antibodies: a single center experience.

The idiopathic inflammatory myopathies (IIM) are a group of autoimmune disorders, including polymyositis (PM), dermatomyositis (DM), inclusion body myositis, and myositis associated with malignancy and other connective tissue diseases. Both DM and PM can have associated interstitial lung disease (ILD).1,2 A number of autoantibodies, called myositis-specific autoantibodies, have been described. These include antibodies to aminoacyl-tRNA synthetases, to signal recognition particle, and to the nuclear helicase Mi-2. The most common of these is the anti Jo-1 antibody directed against the antihistidyl–tRNA synthetase. It is detectable in approximately 15% to 30% of myositis patients overall, and is more common in PM.3 The presence of these antibodies has been associated with a clinical subset characterized by myositis, ILD, arthritis, fever, Raynaud phenomenon and mechanic’s hands, referred to as the antisynthetase syndrome.2 There is a well-established association of antisynthetase antibodies and the presence of ILD. Patients may present first with ILD and then later develop myositis. One series reported 10 patients with antisynthetase antibodies and ILD with no clinical evidence of myositis. Of these patients, 2 had anti Jo-1 antibodies. In patients with the antisynthetase syndrome, the lung involvement usually determines the prognosis of the disease.3 In another series, 3 patients with Jo-1 antibodies developed fatal acute respiratory distress syndrome.4 While not all patients develop rapidly progressive fatal lung disease, the presence of antisynthetase antibodies has been associated with a poor prognostic outcome.2– 4 Despite the limited number of randomized controlled studies, the mainstay of therapy for PM and DM is corticosteroids plus either methotrexate or azathioprine.5 Other agents such as cyclosporine, tacrolimus, cyclophosphamide, intravenous immunoglobins, and rituximab have been used with some success.5– 8 Frequently, weakness improves more than pulmonary symptoms following treatment.2,9 The clinical characteristics of African American (AA) patients with anti-Jo-1 antibody ILD and/or myositis have not been well described in the literature. We describe the clinical characteristics of our patients with anti-Jo-1 antibody disease, more than half of whom are AA reflecting the demographics of our medical center.

Critical appraisal of tocilizumab in the treatment of moderate to severe rheumatoid arthritis

Recent advances in our understanding of the role of interleukin (IL)-6 in autoimmunity and in particular rheumatoid arthritis (RA) have brought about important changes in the way we think about autoimmune diseases. Encouraging data from several phase III clinical trials of tocilizumab, a humanized monoclonal antibody against IL-6R, have led to its approval in Europe for the treatment of moderate to severe RA. Data on clinical efficacy, patient-reported outcomes, safety, and cost-effectiveness with the use of tocilizumab in patients with RA will be summarized in this review, with particular emphasis on phase III clinical trials. Furthermore, adverse events associated with the use of tocilizumab will be reviewed. Future clinical trials will evaluate the role of tocilizumab in other autoimmune diseases. The goal of this review is to describe the current understanding of the role of IL-6 in mediating the inflammatory response in RA, as well as the role of tocilizumab in the treatment of RA and the evolving role of this agent in other autoimmune diseases.

Nephrogenic systemic fibrosis associated with stromal and vascular calcification, report of two cases

Nephrogenic systemic fibrosis (NSF) is a systemic fibrosing disorder characterized by the development of large indurated plaques on the skin, primarily in patients with end‐stage renal disease (ESRD). Skin biopsy reveals an increased frequency of CD34+ and Factor XIIa+ cells. Microscopic calcification has been reported in the skin biopsies of rare cases of NSF. The etiology and significance of this calcification is not clear. We present two cases of typical NSF, for which marked stromal and vascular calcification was identified on skin biopsy. In both cases, the calcification was within typical NSF lesions and was intimately associated with aggregates of CD34+, Factor XIIIa+ spindle and stellate cells. This particular pattern of calcification strongly argues against either nonspecific dystrophic calcification or coincidental metastatic calcification. These findings suggest that calcification may be intrinsic to the pathophysiology of NSF, at least in a subset of NSF patients. In addition, the vascular calcification involving small arteries and arterioles in these two cases morphologically resembled calciphylaxis, which is another poorly understood complication of ESRD. This resemblance raises the possibility that NSF may predispose to or develop in the vicinity of indolent lesions of early‐stage calciphylaxis. We propose that skin biopsies performed as part of a diagnostic workup for suspected NSF should preferably include the deep dermis and subcutis, in order to assess possible vascular calcification.

Underuse of intra-articular and periarticular corticosteroid injections by primary care physicians: discomfort with the technique.

Musculoskeletal disorders account for 11% to 13% of office visits in ambulatory care clinics and 9% of all physician visits in the United States. Intra-articular or periarticular aspiration or injections are an integral part of the management of arthritis or periarthritis. Our aim was to determine the use and level of comfort of administering intra-articular and periarticular injections by primary care physicians (PCPs) practicing in a university setting.A self-administered questionnaire with 20 questions querying experience and training in local injection therapy was mailed to 82 physicians (junior residents, senior residents, and faculty) offering primary care at the University of Chicago. Comfort scores were measured with a scale of 1 to 10 (1 = minimum and 10 = maximum). The response rate to the questionnaire was 67% (36 residents and 19 faculty).Seventy-one percent of PCPs routinely suggested the procedure for severe arthritis and bursitis, but only 19% had (self-administered) performed it themselves. Eighty-nine percent of the PCPs referred their patients to specialty clinics. Forty-eight percent referred their patients to rheumatology, 11.5% to orthopedics, and 29% to both. Other PCPs were consulted for the procedure by 9.6%. Discomfort with the performance of the technique was the predominant reason for 83% of the referrals. The mean comfort score for intra-articular or periarticular injections was 3.10 ± 2.14 in general and 4.45 ± 2.92 for knee joint. The mean comfort score for other joints and bursae ranged from 1.20 to 2.15. Ninety-five percent of PCPs regarded themselves to be inadequately trained. Regarding the training, 41% had received a lecture during medical school and residency, while 40% had received demonstration of the techniques during residency. Of the faculty, 26% had never received any formal lecture, and 5.2% had never received formal demonstration of the techniques during their training.Joint injections observed ranged from 89% for knee to 59% for shoulder and 22% for wrist joints. Only 11% of faculty had performed more than 5 intra-articular injections during their training. A need for formal training inthese techniques was identified by 95% of the subjects, of whom 65% thought the residency period was the best time to do so. Performing 5 to 10 intra-articular injections during residency was considered optimal training by 60%. On subanalysis, the mean comfort scores were higher in the residents in general (3.60 ± 2.29 versus 2.18 ± 1.47;P = 0.01) as compared with faculty. The residents’ scores were also higher across different joints as compared with those of faculty but assumed statistical significance only for olecranon bursa injection (2.32 ± 2.76 versus 1.27 ± 0.67;P = 0.04) and subacromial bursa injection (2.08 ± 2.27 versus 1.27± 0.75;P = 0.06). The mean comfort scores were lower by 1.74 (P = 0.007) for women physicians.There is underuse of self-administered intra-articular and periarticular injection techniques by PCPs in the management of arthritis or periarthritis. The reasons include inadequate training and low comfort in performing these procedures. Eighty-nine percent of PCPs would refer their patients to subspecialty clinics for these “routine” injections. There is a clear need for a training in these procedures during residency.

Benefit of adjunctive tacrolimus in connective tissue disease-interstitial lung disease.

We evaluated the safety and effectiveness of adjunctive tacrolimus therapy with conventional immunosuppression in patients with severe connective tissue disease-related interstitial lung disease (CTD-ILD). We included patients from our interstitial lung disease (ILD) registry with CTD-ILD, in whom tacrolimus was added to corticosteroids and an additional immunosuppressive agent. Demographic data, clinical features, lung function, radiographic images, and pathologic findings were reviewed. Effectiveness was assessed by comparing pulmonary function tests (PFTs) closest to tacrolimus initiation to PFTs approximately 6-12 months later. Corticosteroid dose at these time points was also evaluated. We report adverse events attributed to tacrolimus. Seventeen patients with CTD-ILD were included in adverse event analysis; twelve were included in efficacy analysis. Length of tacrolimus therapy ranged from 6 to 110 months (mean 38.8 months ± 31.4). The mean improvement in percent predicted total lung capacity was 7.5% ± 11.7 (p = 0.02). Forced vital capacity mean improvement was 7.4% ± 12.5 (p = 0.06). The average decrease in corticosteroid dose at follow-up was 20.3 mg ± 25.2 (p = 0.02) with complete discontinuation in six patients. No patients experienced a life-threatening adverse event attributed to tacrolimus. Tacrolimus can be effective and is well tolerated as an adjunctive therapy and allows tapering of corticosteroids.

Lenalidomide for the Treatment of Cryoglobulinemia and Undifferentiated Spondyloarthropathy in a Patient With Multiple Myeloma

Cryoglobulinemia refers to the presence of one or more immunoglobulins that precipitate at temperatures below 37°C and redissolve on rewarming. It is classified into 3 types based on immunochemical characteristics of the paraprotein. Type I is a monoclonal immunoglobulin that is most often associated with Waldenstrom macroglobulinemia, lymphoma, multiple myeloma (MM), and monoclonal gammopathy of unknown significance (MGUS).1 The cutaneous manifestations of cryoglobulinemia include palpable purpura, livedo reticularis, ischemic necrosis, and cutaneous ulcerations.1 Here, we report a case of cryoglobulinemia in a patient with undifferentiated spondyloarthropathy and multiple myeloma, who was successfully treated with lenalidomide. A 43-year-old white man presented with history of recurrent episodes of anterior uveitis and progressive limping secondary to lower back and buttock pain. His physical examination showed only mild tenderness and swelling of the right midfoot. Erythrocyte sedimentation rate (ESR) was 54 (<15), human leukocyte antigen B27 was positive, and magnetic resonance imaging of the lumbosacral spine was consistent with left sacroiliitis (Fig. 1). A diagnosis of undifferentiated spondyloarthropathy was made and he was managed conservatively with nonsteroidal anti-inflammatory medications.2 FIGURE 1 Magnetic resonance imaging of the sacroiliac joints, T2-FLAIR sequence showing edema in the left SI joint (arrow). One year later, he developed recurrent sinopulmonary infections. Extensive workup revealed elevated serum monoclonal IgG to 2.82 g/dL ( 13), calcium level was 9.0 mg/dL (<10.4), and no overt lytic lesions were detected on the skeletal survey. Therapy was deferred given the absence of end organ damage.3 Three months later, he developed a flare of the inflammatory arthritis manifested by worsening right foot and left hip pain and new rashes. Physical examination noted limited left hip range of motion secondary to pain, right foot swelling, and livedo reticular type of rashes associated with necrotic plaques and ulcerations on the bilateral lower extremities. ESR was now 134 and hepatitis C viral antibody was negative. Type I cryoglobulinemia was diagnosed with a cryocrit of 8% (<0.5% volume) and pathologic findings of ischemic and thrombotic vasculopathy with extensive fibrin deposition and red blood cell extravasations on skin biopsy (Fig. 2). FIGURE 2 Skin biopsy showing fibrin deposition and red blood cell extravasations (arrows). Low dose prednisone therapy was first attempted without significant clinical improvement in several weeks and his cryocrit was now 25%. Plasmapheresis was initiated and his cutaneous symptoms partially improved. Lenalidomide, 25 mg by mouth once a day 3 weeks on and 1 week off, and weekly dexamethasone pulse, 40 mg by mouth, were then started and continued for 4 cycles. The skin ulcers healed, his livedo reticular rash resolved, and his cryocrit became negative. Interestingly, his hip and foot pain also resolved; physical examination revealed diminished right foot swelling; and the ESR post-treatment became undetectable. The serum monoclonal IgG was now is 0.76 g/dL and repeat bone marrow biopsy showed 3% plasma cells. He subsequently underwent consolidative bone marrow transplantation and remained symptom free 8 months after treatment with lenalidomide. Treatment options for patients with Type I cryoglobulinemia occurring in the setting of MM or MGUS include systemic corticosteroid therapy with or without alkylating agents.1 Plasmapheresis has been used in severe or life threatening cases of cryoprecipitation or serum hyperviscosity syndrome. However, it is inconvenient and produces only transient decrease in cryoglobulin level.4 Lenalidomide is a new generation antiangiogenic and immunomodulatory drug related to thalidomide, an inhibitor of the tumor necrosis factor (TNF) alpha pathway.5 It has enhanced TNF-alpha inhibitory activity and tumor cytotoxicity, and fewer side effects of deep vein thrombosis and peripheral neuropathy than thalidomide. It is now used as a first-line treatment for MM and myelodysplastic syndrome.3 This is the first reported case of human leukocyte antigen B27 spondyloarthropathy and Type I cryoglobulinemia treated successfully with lenalidomide. Review of the literature revealed only 2 other cases of paraproteinemia-associated Type I cryoglobulinemia treated with thalidomide. Neither of these 2 cases had associated inflammatory arthritis.6,7 The first unique feature of our case is that lenalidomide appears to have activity in both HLA B27 spondyloarthropathy as well as Type I cryoglobulinemia. This could be explained mechanistically by the involvement of TNF-alpha pathway in both disease processes, and supported by clinical observations that inflammatory arthritis can be associated with MGUS and MM.8 The second unique feature is that the exacerbation of his inflammatory spondyloarthropathy was temporally associated with the development of cryoglobulinemia. It is possible that cryoglobulin crystals may be contributing to the worsening of arthropathy as suggested by a recent report.9 The arthropathy in that patient responded to oral and intra-articular corticosteroids, and MM was subsequently diagnosed and treated with lenalidomide.9 In summary, on the basis of our limited experience and literature review, lenalidomide may have a potential role in the treatment of inflammatory spondyloarthropathy as well as Type I cryoglobulinemia associated with paraproteinemia.

Chlamydial infection preceding the development of rheumatoid arthritis: a brief report

Chlamydia trachomatis-triggered reactive arthritis is a well-documented entity that has been extensively described. We do not have a clear understanding about the inflammatory oligoarthritis associated with the presence of this organism. It is rarely cultured from the synovial fluid, but is usually detectable by molecular biological techniques. Typically, Chlamydia trachomatis causes a sterile but inflammatory oligoarthritis. We report an unusual case of inflammatory monoarthritis in a young woman in whom Chlamydia was isolated from the synovial fluid. This is the first case of documented isolation of Chlamydia from synovial fluid, which subseqently was diagnosed as rheumatoid arthritis.

The Diagnosis and Treatment of Antisynthetase Syndrome.

Antisynthetase syndrome is an autoimmune condition, characterized by antibodies directed against an aminoacycl transfer RNA synthetase along with clinical features that can include interstitial lung disease (ILD), myositis, Raynaud’s phenomenon, and arthritis. There is a higher prevalence and increased severity of ILD in patients with antisynthetase syndrome, as compared with dermatomyositis and polymyositis, inflammatory myopathies with which it may overlap phenotypically. The diagnosis is made by a multidisciplinary approach, synthesizing rheumatology and pulmonary evaluations, along with serologic, radiographic, and occasionally muscle and/or lung biopsy results. Patients with antisynthetase syndrome often require multimodality immunosuppressive therapy to control the muscle and/or pulmonary manifestations of their disease. The long-term care of these patients mandates careful attention to the adverse effects and complications of chronic immunosuppressive therapy, and disease-related sequelae that can include progressive ILD necessitating lung transplantation, pulmonary hypertension, malignancy, and a decreased survival. It is expected that a greater awareness of the clinical features of this syndrome will allow for an earlier diagnosis and appropriate treatment to improve outcomes in patients with antisynthetase syndrome.