Effects of Teriparatide on Joint Erosions in Rheumatoid Arthritis: A Randomized Controlled Trial.

OBJECTIVE: Articular erosions correlate with disability in rheumatoid arthritis (RA). Biologic agents reduce erosion progression in RA, but erosion healing occurs infrequently. This study was undertaken to assess the effects of the anabolic agent teriparatide on joint erosion volume in RA patients treated with a tumor necrosis factor inhibitor (TNFi). METHODS: We conducted a randomized controlled trial in 24 patients with erosive RA, osteopenia, and disease activity controlled by TNFi treatment for at least 3 months. Half were randomized to receive teriparatide for 1 year and the others constituted a wait-list control group. Subjects and primary rheumatologists were not blinded with regard to treatment assignment, but all outcomes were assessed in a blinded manner. The primary outcome measure was change in erosion volume determined by computed tomography at 6 anatomic sites. Significance within each hand and anatomic site was based on a 2-tailed test, with P values less than 0.05 considered significant. RESULTS: Baseline characteristics of the treatment groups were well balanced. After 52 weeks, the median change in erosion volume in the teriparatide group was -0.4 mm3 (interquartile range [IQR] -34.5, 29.6) and did not differ significantly from that in controls (median change +9.1 mm3 [IQR -29.6, 26.4]) (P = 0.28). No significant difference in change in erosion volume was noted at the radius, ulna, or metacarpophalangeal joints. Bone mineral density improved at the femoral neck and lumbar spine in the teriparatide group. CONCLUSION: Our findings indicate that teriparatide treatment for 1 year does not significantly reduce erosion volume in the hands or wrists of patients with established RA with disease activity controlled by TNFi treatment.

Pulmonary hypertension and interstitial lung disease within PHAROS: impact of extent of fibrosis and pulmonary physiology on cardiac haemodynamic parameters.

OBJECTIVES: We sought to examine the relationship between measures of ILD severity and PH in patients with SSc. METHODS: We identified 55 subjects from 12 PHAROS sites with RHC-proven PH and HRCT evidence of ILD. Subjects with PH due to left heart disease were excluded. Baseline HRCT scans were scored by a standardised system that graded severity of ILD. Summary statistics were generated for baseline characteristics. Spearman correlation and linear regression were used to examine relationships between ILD and PH severity variables. RESULTS: The majority of subjects were white women; nearly half had limited cutaneous SSc. Most subjects were New York Heart Association functional class II or III. Pulmonary function testing revealed moderate restriction (mean FVC 64.3 ± 17.2% predicted) with severe reduction in diffusing capacity (mean DLco 34.2 ± 13.3% predicted). RHC demonstrated mild to moderate PH (mean PAP 35 ± 9 mmHg, mean PVR 5.1 ± 3.7 WU). There was no correlation between severity of ILD (by either HRCT or PFT) and cardiac haemodynamic parameters of PH. CONCLUSIONS: No association between severity of ILD and cardiac haemodynamic profiles were identified in this cohort. We believe this underscores the complex nature of PH and ILD in individuals with SSc. We do suspect that some individuals with SSc-ILD will also have concomitant pulmonary vascular disease but simple assessments to grade severity of ILD - by PFT or HRCT estimates of ILD extent - are likely not enough to reliably distinguish between PAH versus PH-ILD. Further research into how to distinguish and manage these subsets is warranted.

Scleroderma renal crisis in pregnancy associated with massive proteinuria.

Scleroderma renal crisis is a well-recognized complication of systemic sclerosis (SSc) usually occurring early in the course of the disease in patients with diffuse skin involvement. We report the diagnostic challenge of a case of scleroderma renal crisis associated with massive proteinuria at approximately 20 weeks gestation in a pregnant patient with diffuse cutaneous systemic sclerosis.

Carpal tunnel syndrome in sarcoidosis.

Sarcoidosis is a systemic disease that may affect the musculoskeletal system. An association between carpal tunnel syndrome (CTS) and sarcoidosis has not been demonstrated. Consecutive patients from the sarcoidosis clinic at our institution were questioned about history and symptoms of carpal tunnel syndrome: hand numbness and nocturnal paresthesias with relief of symptoms by shaking of the hands (flick sign). A physical exam was performed to evaluate for Tinel's and Phalen's signs. A comparison of the presence of arthritis, prednisone treatment, spirometry, and number of organs involved with sarcoidosis was made in patients with a history or clinical findings of CTS versus those without. Eighty-nine patients were evaluated. Thirty-five patients (39%) had nocturnal paresthesias with a positive flick sign. Fourteen patients (16%) had physical findings of CTS. A history of CTS was present in 14 (16%) of the patients, four of which were documented by EMG. There was no significant difference between the frequency of prednisone treatment in patients with or without CTS history, nocturnal paresthesias, or Phalen's sign. There were significantly fewer patients with a positive Tinel's sign who were receiving prednisone. There was a trend toward an increased frequency of wrist arthritis in patients with a history or clinical findings of CTS. There was no significant difference in disease severity, assessed by spirometry or organ involvement, when comparing sarcoidosis patients with or without a history or clinical findings of CTS. Thirty-nine (44%) had symptoms and/or signs of CTS. Even when we adjusted our sarcoidosis population for other factors associated with CTS, the prevalence of symptoms and signs of CTS was much higher in our patient population than in studies of the general population. Our findings suggest that CTS is common in sarcoidosis.

Assessment and management of scleroderma lung disease.

Lung disease is a major cause of morbidity and is the leading cause of mortality in patients with systemic sclerosis, most commonly occurring as interstitial lung disease or as pulmonary hypertension. Cyclophosphamide has been used to treat the interstitial lung disease and a placebo-controlled trial is planned. Potent pulmonary vasodilators, many of which have been studied in primary pulmonary hypertension, are now undergoing study in patients with systemic sclerosis.

Cytokine concentrations in bronchoalveolar lavage fluid of patients with systemic sclerosis.

OBJECTIVE: The pathophysiology of pulmonary fibrosis in patients with systemic sclerosis (SSc) is poorly understood, but a number of recent studies have demonstrated an inflammatory process involving the lower respiratory tract. The objective of the present study was to determine the concentrations of several cytokines in the bronchoalveolar lavage (BAL) fluid of patients with SSc and to assess whether the enhanced expression of certain cytokines is associated with the presence of alveolitis. METHODS: BAL was performed on patients with SSc (with or without alveolitis) and on normal control subjects. Lyophilized BAL fluid samples were assayed by enzyme-linked immunosorbent assay for tumor necrosis factor alpha (TNF alpha), interleukin-1alpha (IL-1alpha), IL-4, IL-6, IL-8, macrophage inflammatory protein 1alpha (MIP-1alpha), and RANTES. RESULTS: There were significant differences between groups in the BAL fluid concentrations of TNF alpha (P = 0.0005, with levels in SSc patients with alveolitis higher than those in normal controls), IL-8 (P = 0.006, with levels in both SSc groups higher than those in normal controls), MIP-1alpha (P = 0.009, with levels in SSc patients with alveolitis higher than those in SSc patients without alveolitis and than those in normal controls), and RANTES (P = 0.03, with levels in SSc patients without alveolitis higher than those in normal controls). With the exception of RANTES, the highest levels were detected in SSc patients with alveolitis. CONCLUSION: Each of these cytokines, either alone or in combination, may play an important role in the pathogenesis of pulmonary fibrosis in SSc.

Scleroderma and related conditions.

Systemic sclerosis is a generalized disorder characterized by fibrosis and microvascular injury in affected organs. Despite being recognized nearly 250 years ago, knowledge regarding pathogenesis remains limited, and treatment remains directed at symptomatic improvement. Early recognition of systemic sclerosis, however, is important in order to monitor for specific disease complications (i.e., fibrosing alveolitis, scleroderma renal crisis) as well as initiate manifestation specific therapies that improve quality of life.

Cognitive deficits in a murine model of the eosinophilia-myalgia syndrome: a preliminary report.

The described study was to determine the effects of chronic exposure to 1,1'-ethylidenebis[L-tryptophan] (EBT), a tryptophan contaminant, on cognitive behavior of female C57BL/6 (C57) mice. EBT (also designated as "peak E" or "peak 97") is one of several compounds that are suspect in the eosinophilia-myalgia syndrome (EMS). Groups of female C57 mice (12/group) were injected IP with saline (SAL), tryptophan (TRY), EBT, or an EBT + tryptophan combination (EBT + TRY) over a 6-week period. Previous experiments established that the dosing conditions produce several characteristics of EMS, including dermal inflammation and fibrosis, increased dermal mast cells, and increased levels of quinolinic acid. The mice exposed to EBT + TRY were abnormal during the solution of a Morris water maze problem. First, they had a shorter latency to locate the submerged platform goal during the initial day of training compared to SAL or TRY mice; secondly, they did not show the systematic reduction in latency to locate the platform goal across days of training noted for SAL or TRY mice. These abnormalities occurred in the absence of altered body weight or gross motor activity during the treatment procedure, or in the animal's swim speeds at the time of testing, 3 days after termination of treatment. The results suggest that prolonged exposure to EBT + TRY can alter the reaction to a stressful environment and can alter cognitive behavior.

Office evaluation and treatment of Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon, an episodic vascular disorder induced by cold temperatures or stress and characterized by white, blue, and red discoloration of the fingers and toes, may affect up to 20% of the general population. KEY POINTS: Raynaud's phenomenon may exist independently (primary) or in association with an underlying disease (secondary), most commonly systemic sclerosis. The pathophysiologic features include vasospasm, endothelial cell changes, vessel obstructive features, and hemorrheologic factors. Raynaud's phenomenon is the initial manifestation of disease in 70% of patients with systemic sclerosis, in whom it may be present for many years before the development of the connective tissue disease. Patients with primary Raynaud's phenomenon need only conservative management and should be reassured that digital ischemia and loss of tissue occur extremely rarely. Pharmacologic agents that have been studied include vasodilators, platelet inhibitors, serotonin antagonists, and fibrinolytics. CONCLUSIONS: For prognostic and therapeutic reasons, it is important to determine if Raynaud's phenomenon is associated with an underlying condition and if the patient may develop a connective tissue disease.

Eosinophilia-myalgia syndrome, toxic-oil syndrome, and diffuse fasciitis with eosinophilia.

Eosinophilia-myalgia syndrome, a recently described illness, reached epidemic proportions in 1989 and was linked to the ingestion of L-tryptophan containing trace amounts of several contaminants. Eosinophilia-myalgia syndrome shares many clinical and pathologic similarities with toxic-oil syndrome, an epidemic linked to the ingestion of adulterated cooking oil that occurred in Spain in 1981, and to diffuse fasciitis with eosinophilia, a condition first described in 1974. Over the past year, much work has been done in understanding the etiology and pathogenesis of eosinophilia-myalgia syndrome and toxic-oil syndrome. Follow-up data detailing the long-term sequelae and mortality rates for these two conditions are becoming available. The results from these studies are reviewed in this paper.

Lung disease in systemic sclerosis (scleroderma).

Scleroderma (SSc) is a disease characterized by skin fibrosis but it is the end-organ effect of microvascular injury and fibrosis that is important prognostically. Pulmonary involvement in SSc patients, either of parenchymal fibrosis and/or pulmonary hypertension, is a major cause of morbidity and mortality. Interstitial lung disease occurs more commonly in patients with diffuse SSc and is associated with a loss of lung volume, as well as a defect of gas exchange. Parenchymal fibrosis may also cause pulmonary hypertension. Isolated pulmonary hypertension occurs exclusively in patients with limited SSc and is detectable by a reduced DCO. The early identification of either manifestation is difficult. Patients may have minimal symptoms, unremarkable physical findings, normal chest radiographs and/or minimally abnormal pulmonary function tests at a time when significant lung pathology is present. It is essential to attempt to identify pulmonary disease early, at a potentially reversible stage. Multiple therapeutic endeavours have yielded only short-term or minimal benefits in symptoms and pulmonary function, and thus a major alteration in SSc pulmonary prognosis has not been achieved. Further study of the pathogenesis of this disease manifestation will be helpful in its earlier identification and intervention.