Leflunomide-associated weight loss in rheumatoid arthritis

OBJECTIVE: To determine the frequency of weight loss in patients treated with leflunomide for rheumatoid arthritis at an arthritis referral center. METHODS: We queried 35 rheumatologists at the Robert Breck Brigham Arthritis Center to determine if weight loss had occurred as an adverse event in patients treated with leflunomide between November 1998 and January 2000. Five such patients were identified and their clinical course was reviewed. RESULTS: Five of 70 patients who had begun leflunomide therapy had significant weight loss that could not be linked to other identifiable etiologies. The amount of weight loss was substantial in this group of patients, ranging from 19 pounds to 53 pounds. All patients had normal levels of thyroid-stimulating hormone and no other gastrointestinal complaints; evaluation revealed no other cause for the weight loss. Despite the significant weight loss, 4 of the 5 patients continued to take the drug due to its efficacy. CONCLUSION: Significant weight loss is a potential adverse event in patients with rheumatoid arthritis treated with leflunomide. Awareness of this may obviate the need for extensive medical evaluations.     

Leflunomide‐induced nodulosis in a case of Rheumatoid arthritis

We herein report accelerated nodulosis in a 49‐year‐old woman with rheumatoid arthritis who was treated with methotrexate and leflunomide. She developed multiple pulmonary and subcutaneous nodules 2 years after the addition of leflunomide to methotrexate. The nodules developed when the rheumatoid arthritis was in remission. The pulmonary nodules regressed following the institution of hydroxychloroquine after stopping leflunomide.     

HO‐1 promoter polymorphism associated with rheumatoid arthritis

Objective

To investigate the role of the HO‐1 gene as a novel functional candidate gene for rheumatoid arthritis (RA).

Methods

We performed a case–control study including 736 RA patients and 846 healthy controls of Spanish Caucasian origin. Two putative functional HO‐1 promoter polymorphisms, a (GT)_n microsatellite and a −413 A/T single‐nucleotide polymorphism (SNP), were selected as genetic markers and genotyped using polymerase chain reaction–based methods. In addition, the intracellular expression of heme oxygenase 1 (HO‐1) was determined in healthy individuals with different (GT)_n genotypes.

Results

The distribution of HO‐1 (GT)_n short (S) alleles (≤25 GT repeats) and long (L) alleles (>25 GT repeats) revealed a significant protective effect of S (GT)_n alleles (P = 0.019) (odds ratio [OR] 0.8, 95% confidence interval [95% CI] 0.7–0.9) and the SS (GT)_n genotype (P = 0.002) (OR 0.6, 95% CI 0.4–0.9). In contrast, the −413 HO‐1 promoter SNP did not yield any statistically significant deviation between RA patients and controls, considering either allele or genotype frequencies. The haplotype analysis showed a strong protective effect of the S/A haplotype (P = 7 × 10⁻⁷, corrected P [P_corr] = 3 × 10⁻⁶) (OR 0.4, 95% CI 0.3–0.6), whereas the L/A haplotype showed the opposite tendency (P = 0.008, P_corr = 0.03) (OR 1.2, 95% CI 1.0–1.4). In addition, we demonstrated that monocytes from individuals carrying the SS (GT)_n genotype showed a significantly higher percentage of HO‐1 expression than did cells from LL homozygous individuals (P = 0.0003).

Conclusion

In this study, we identified the HO‐1 (GT)_n microsatellite as a new genetic marker involved in RA genetics in our population.

     

Microbiome‐based mechanisms hypothesized to initiate obesity‐associated rheumatoid arthritis

Worldwide, the growing obesity pandemic contributes to a range of chronic diseases. Recent epidemiological studies have suggested an association between obesity and the development of rheumatoid arthritis (RA), particularly among young women, whereby pro‐inflammatory effects of adipokines provide one explanatory hypothesis. Yet, recent clinical and laboratory‐based studies provide emerging evidence indicating microbiome involvement in RA initiation and development, including anti‐citrullinated antibody formation and Th17 cell activation. Obesity and RA‐associated microbiome alteration might provide a plausible link to address the impact of obesity to RA pathogenesis. The microbiome's influence on RA development – at mucosal as well as articular sites – and relevant pathophysiological mechanisms regarding obesity's association with RA are presented herein to discuss this hypothesis and aid understanding of obesity's role in RA development.     

An unusual case of weight loss in a patient with refractory rheumatoid arthritis

We describe a case of metastatic malignant melanoma with no primary cutaneous lesion presenting as weight loss in a man with refractory, seropositive rheumatoid arthritis (RA). The patient had undergone multiple investigations previously and the case highlights the importance of repeat assessment in elderly patients presenting with unexplained weight loss.     

Sensorineural hearing loss in rheumatoid arthritis

Hearing function was tested in 20 patients affected by rheumatoid arthritis. Audiological examination was performed by pure tone audiometry thresholds, tympanometry, a stapedial reflex threshold test and auditory brainstem responses (ABR). Hearing impairment was observed in 55% of patients. Conductive hearing loss and the absence of stapedius reflex were never recorded. Five patients with abnormal audiograms had normal ABR and normal stapedial reflex thresholds while 6 patients showed abnormalities in their audiograms, stapedial reflex thresholds test and ABR. Abnormal audiometric results associated with normal ABR are compatible with cochlea involvement, while abnormal audiometric results associated with an altered ABR and stapedial reflex test may be due to retrocochlear involvement. Sensorineural hearing loss appeared to significantly correlate with active disease and with the presence of rheumatoid factor.     

Mechanisms of bone loss in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease in which destruction of bone in the joints causes major morbidity. Recent research has shed light on the cell and molecular mechanisms that lead to this osteolysis, all due directly or indirectly to the chronic inflammation. The aspects of this research covered in this review include the alteration of cell proliferation and survival that results in growth of the RA synovium. This process depends upon an increase in angiogenesis and local blood flow, which is also a feature of increased bone turnover. In addition, the inflammatory environment increases expression of chemokines, which are involved in the recruitment of monocytic osteoclast precursors. Chronic inflammation also promotes an overall catabolic state, with increased osteoclast differentiation and resorptive activity, driven by disregulation of receptor activator of NF-κB ligand (RANKL) and the synergistic activity of inflammatory cytokines such as tumor necrosis factor-α and interleukin-1. Osteoclast survival is increased in this environment, but osteoblast differentiation and survival are decreased, with a consequent reduction in bone formation and a net loss of bone. Recognition of these processes and the factors involved will enable more effective and targeted treatments for RA.     

Rapid periarticular bone loss in rheumatoid arthritis

For approximately 2 years, bone loss was measured in women with early stages of rheumatoid arthritis (RA) and in control subjects, using serial computed tomography and dual photon absorptiometry. Rapid trabecular bone loss from the distal radius was observed in the RA patients but not the controls. The bone loss correlated with initial plasma levels of parathyroid hormone and 1,25-dihydroxyvitamin D₃ (calcitriol) concentrations. It has been suggested that these humoral factors may interact with cytokines or other mediators produced in the adjacent wrist joint. Losses of the cortical bone of the radial midshaft and the lumbar spine were modest and were comparable in the 2 groups. Indices relating to both bone formation and bone resorption predicted bone loss at these 2 sites, but changes in the parathyroid hormone and calcitriol concentrations did not.     

Mechanisms of bone loss in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease in which destruction of bone in the joints causes major morbidity. Recent research has shed light on the cell and molecular mechanisms that lead to this osteolysis, all due directly or indirectly to the chronic inflammation. The aspects of this research covered in this review include the alteration of cell proliferation and survival that results in growth of the RA synovium. This process depends upon an increase in angiogenesis and local blood flow, which is also a feature of increased bone turnover. In addition, the inflammatory environment increases expression of chemokines, which are involved in the recruitment of monocytic osteoclast precursors. Chronic inflammation also promotes an overall catabolic state, with increased osteoclast differentiation and resorptive activity, driven by disregulation of receptor activator of NF-κB ligand (RANKL) and the synergistic activity of inflammatory cytokines such as tumor necrosis factor-α and interleukin-1. Osteoclast survival is increased in this environment, but osteoblast differentiation and survival are decreased, with a consequent reduction in bone formation and a net loss of bone. Recognition of these processes and the factors involved will enable more effective and targeted treatments for RA.     

Measures of bone loss in rheumatoid arthritis

Patients with rheumatoid arthritis (RA) are prone to develop osteoporosis, especially women receiving steroid hormone therapy. Inhibition of bone formation and/or excessive bone resorption may be responsible. Bone gamma-carboxyglutamic acid-containing protein (BGP), the major noncollagen protein of bone and a plasma marker of bone formation, was measured in 81 consecutive RA patients and 79 age- and sex-matched control subjects, in addition to the hormone regulators of bone metabolism, calcitonin, parathyroid hormone, and 1,25-dihydroxyvitamin D. Mean (+/- SE) BGP levels (picomoles per milliliter) were lower for RA men (1.46 +/- 0.14) and women (1.52 +/- 0.2) compared with their respective controls (2.05 +/- 0.17 for men, 2.47 +/- 0.22 for women). Women taking steroids had the lowest levels (1.13 +/- 0.22) and, in contrast to men, this value was lower than the nonsteroid-treated group. Steroid treatment appears to be a major determinant of low BGP levels; the effect of RA itself is suspected but not proved in this study. Calcitonin levels were lower in RA men as well as in all women. Diminution of BGP in these subjects supports the view that "low-dose" corticosteroid treatment may suppress bone formation, especially in women. Prevention or remediation of osteopenia may be monitored by BGP, if further studies validate this hypothesis with other measures of skeletal mass.     

Long‐term weight loss and weight‐loss maintenance strategies

It has been suggested that about 20% of subjects undergoing weight‐loss programmes can achieve a certain degree of long‐term success. At present, surgery remains the only method resulting in long‐term sustained weight loss, but access remains restricted. Hence it is important to analyse, in addition to pharmacotherapy, the methods to improve the effects of diet, exercise and behavioural modification. Since these techniques are less spectacular than others, there is a risk that their potential will be overlooked, in spite of the fact that they remain the main alternative for most subjects undergoing weight‐loss therapy. This review summarizes realistic treatment alternatives and also provides data from a day care treatment, a strategy not much reported in the literature. This is a standard treatment modality for diabetes but less common in obesity treatment.     

Vasculitis associated with rheumatoid arthritis

Vasculitis may accompany rheumatoid arthritis. One must distinguish between vascular involvement associated with the pathogenesis of rheumatoid arthritis, isolated digital vasculitis, and the syndrome of clinical rheumatoid vasculitis. The cause of clinical rheumatoid vasculitis is unknown. High titers of rheumatoid factor, cryoglobulins, diminished circulating complement, an increased prevalence of HLA-DR4, and the pathologic findings suggest an immune etiology. However, similar, but perhaps less pronounced, abnormalities occur in uncomplicated rheumatoid arthritis, and these findings are not universal in complicating vasculitis. Classic cutaneous clinical manifestations include ischemic ulcers, digital gangrene, and palpable purpura. Mononeuritis multiplex is another classic presentation of rheumatoid vasculitis. Small digital infarctions may accompany other manifestations in clinical vasculitis or may occur alone as isolated digital arteritis, in which case the prognosis is relatively favorable. Weight loss, pleuritis, pericarditis, ocular inflammation, splenomegaly, hepatomegaly, and Felty's syndrome have also been reported in association with rheumatoid vasculitis. Although renal involvement has been considered unusual in rheumatoid vasculitis, several studies suggest that this may be more common than previously recognized. Ideally, a biopsy or an angiogram confirms the diagnosis of rheumatoid vasculitis, but often the diagnosis rests upon the clinical picture. In general, blind biopsies are not helpful, although one series indicated that a blind rectal biopsy may be an exception to this rule. An elevated erythrocyte sedimentation rate, increased C-reactive protein level, anemia, thrombocytosis, hypoalbuminemia, and a positive rheumatoid factor are common laboratory findings. Leukocytosis, hypergammaglobinemia, leukocytopenia, an elevated creatinine level, and minimal abnormalities of the urinary sediment also occur in patients with rheumatoid vasculitis. However, these abnormalities overlap in patients with uncomplicated rheumatoid arthritis, and their role in distinguishing rheumatoid vasculitis from uncomplicated rheumatoid arthritis is limited. Other immunologic tests have no established clinical role in diagnosing rheumatoid vasculitis. Therapy depends upon the clinical manifestation of rheumatoid vasculitis. Uncomplicated rheumatoid arthritis deserves appropriate therapy, and general attention to nutrition, cessation of tobacco, and control of blood pressure are indicated for all patients. Isolated digital vasculitis generally requires no more than the usual treatment for uncomplicated rheumatoid arthritis. Appropriate dermatologic management is indicated for ischemic ulcers. Most clinical experience in managing more symptomatic rheumatoid vasculitis has focused on glucocorticosteroids, D-penicillamine, and cytotoxic immunosuppressive drugs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Determinants of axial bone loss in rheumatoid arthritis

To assess mechanisms that cause generalized osteoporosis in rheumatoid arthritis (RA), we measured bone mineral density (BMD) by dual photon absorptiometry in the lumbar spine and femoral neck of 111 patients with RA. BMD was significantly reduced at both sites in these patients. Physical activity correlated significantly with BMD in patients with RA, and was found, by multiple regression analysis, to be a significant predictor of femoral bone density in female patients. Multiparity exerted a protective effect on lumbar bone density. Prednisolone (mean dosage 8 mg/day) was not associated with significantly increased bone loss in women, whereas higher dosages in men (mean 10.3 mg/day) were associated with increased lumbar bone loss. Reduced physical activity leading to a form of disuse osteoporosis appears to be an important factor in axial bone loss in RA.     

Risk factors associated with bone loss and occurrence of fragility fractures in rheumatoid arthritis patients

Aim of the work

To investigate the bone mineral density (BMD) in rheumatoid arthritis (RA) Tunisian patients, to identify the risk factors associated with its decrease and to assess the fracture risk.