Rheumatoid nodulosis: report of two new cases and discussion of diagnostic criteria

Two patients with typical rheumatoid nodulosis are described and compared with 24 reported cases. Rheumatoid nodulosis is a particular variant of rheumatoid arthritis associated with palindromic rheumatism, subcutaneous rheumatoid nodules, mild or no systemic manifestation and a benign clinical course. Positive rheumatoid factor and radiologic subchondral bone cysts are usual, but their absence should not eliminate the diagnosis of rheumatoid nodulosis, particularly at the onset of the disease.     

Etanercept-related extensive pulmonary nodulosis in a patient with rheumatoid arthritis

OBJECTIVE: Although nodulosis is a common extraarticular manifestation of rheumatoid arthritis, accelerated pulmonary nodulosis is a rare event. The etiology of rheumatoid nodules is still unknown. Nodulosis is not necessarily associated with active joint inflammation, suggesting different pathogenic mechanisms for nodule formation and synovial tissue inflammation. We describe a patient with extensive pulmonary nodulosis, probably related to etanercept treatment. Our case emphasizes the need for careful monitoring for adverse events during treatment with biologicals, especially since the differential diagnosis often includes a broad spectrum of diseases.     

Palmar rheumatoid nodulosis associated with local pressure.

Rheumatoid nodulosis is a term used to describe adult patients with rheumatoid arthritis with little or no clinical joint inflammation who have numerous subcutaneous nodules indistinguishable from those of patients with active rheumatoid arthritis. This paper reports the case of a woman with quiescent rheumatoid arthritis who developed palmar nodulosis three weeks after the strenuous activity of painting her apartment. This case illustrates the direct association between the appearance of nodulosis and physical pressure despite inactive disease.     

Rheumatoid nodulosis: report of a case with evidence of intraosseous rheumatoid granuloma

We describe a patient who had multiple subcutaneous rheumatoid nodules associated with episodes of acute intermittent arthritis and subchondral cystic lesions of the small bones of the hands and feet; this condition is termed "rheumatoid nodulosis." The patient had a cystic lesion in communication with the joint cavity, rheumatoid granulomas, and evidence of a central zone of necrosis opening toward the joint space. His case is compared with 8 previously reported cases, and possible etiologies of the subchondral bone cyst formation in rheumatoid nodulosis are discussed.     

Methotrexate-associated appearance and rapid progression of rheumatoid nodules in systemic-onset juvenile rheumatoid arthritis

Rheumatoid nodules are a rare extraarticular manifestation of juvenile rheumatoid arthritis (JRA), usually detected in patients with polyarticular-onset disease and positive rheumatoid factor (RF). To date, there has not been a published report of rheumatoid nodules in systemic-onset JRA. Low-dose methotrexate (MTX) is generally considered to be the most useful second-line drug in the treatment of polyarticular JRA. In adult RA, MTX has been shown to be associated with appearance and progression of rheumatoid nodules. This report describes a 3-year-old girl with RF-negative, antinuclear antibody-negative systemic JRA who developed multiple rheumatoid nodules on the scalp and trunk during MTX therapy. The first nodule developed on the scalp 6 months after MTX treatment was initiated. Previous treatment with azathioprine was not associated with nodulosis. This represents an atypical case of MTX-associated accelerated nodulosis in systemic JRA, and raises the problem of treatment plan modification in the presence of this side effect.     

Accelerated nodulosis during low dose methotrexate therapy for rheumatoid arthritis. An analysis of ten cases.

OBJECTIVE. To obtain information on the occurrence of accelerated nodulosis during methotrexate (MTX) for rheumatoid arthritis (RA), localization, size and presence in heart and lungs of these nodules, predisposing factors, relationship with other extraarticular manifestations (EAM) and their histological features. METHODS. Ten patients with accelerated nodulosis were studied. Four participated in a double blind study of MTX and azathioprine. Patient characteristics, localization, size and histopathology of new nodules were determined. Echocardiography and chest roentgenograms were performed. RESULTS. Accelerated nodulosis occurred exclusively during treatment with MTX in our double blind study. The estimated incidence was 8%. One patient reported was rheumatoid factor negative. Newly developed nodules were small, and located in the fingers in all patients and in additional sites in 7. Pretreatment nodules were not found in the fingers. In one patient nodules on the mitral valve were found, but this was not likely to be associated with the use of MTX. No new pulmonary nodules were found. Other EAM developed concurrently in 4 patients. Histopathology revealed typical rheumatoid nodules. In 3 patients nodulosis regressed after MTX was stopped. In 2 of them they recurred after a rechallenge. CONCLUSIONS. Accelerated nodulosis during MTX for RA is not rare, and occurs despite good clinical response of polyarthritis. Rheumatoid factor positivity is not a prerequisite. New nodules are small and preferentially located in the fingers. Recurrence after rechallenge with MTX suggests causality.     

Successful treatment of methotrexate induced nodulosis with D-penicillamine.

Accelerated nodulosis is a recognized complication of methotrexate (MTX) therapy in rheumatoid arthritis (RA). We describe 3 patients with accelerated nodulosis treated with D-penicillamine (D-Pen) while continuing MTX. The combination of D-Pen with MTX therapy resulted in regression of subcutaneous nodules in all patients, disappearance of pulmonary nodules in one patient, and resolution of vasculitic lesions in 2 patients. Clinical response was observed within the first few weeks of therapy and usually required moderate doses (500 mg/day). Our observations suggest that addition of D-Pen to MTX therapy can be an alternative therapeutic option for accelerated nodulosis in patients with RA.     

Accelerated nodulosis and vasculitis during methotrexate therapy for rheumatoid arthritis

Three women with classic rheumatoid arthritis, who were receiving weekly doses of methotrexate (MTX), developed accelerated subcutaneous nodulosis, despite good response to the drug. In 2 of the patients, the onset of nodulosis occurred within 3 months and 5 months, respectively, after starting MTX; in the third patient, it was observed only after 4 years of MTX therapy. In all 3 patients, the onset was unusually abrupt, with extensive distribution and remarkable nodule size. Additional manifestations of cutaneous vasculitis in 2 of the patients and Raynaud's phenomenon in the third appeared concomitantly with the nodulosis. Physicians prescribing MTX therapy for patients with rheumatoid arthritis should be aware of these potential complications.     

Rheumatoid nodulosis an unusual variant of rheumatoid disease

A middle-aged man developed multiple subcutaneous nodules associated with palindromic rheumatism. There was little evidence of synovitis; however multiple cyst-like intraosseous radiolucencies were noted. Nodules from two sites were histologically typical rheumatoid nodules. Subjective and objective improvement occurred during penicillamine therapy. This clinical presentation seems sufficiently distinctive to warrant characterization as a variant of rheumatoid disease termed by us: rheumatoid nodulosis. .     

Coexistence of rheumatoid nodulosis and gout

The case of a 42-year-old white male with a 7-year history of multiple subcutaneous nodules and intermittent episodes of acute arthritis is presented. The patient was found to have monosodium urate crystals on joint aspiration and rheumatoid nodules on biopsy. Our patient, the first reported case of coexistent rheumatoid nodulosis and gout, emphasizes the importance of a thorough evaluation and the need to account for all available clinical and laboratory data. The classification system, differential diagnosis and clinical manifestations of patients presenting with rheumatoid nodules are briefly reviewed.     

Palmar rheumatoid nodulosis of the fingers

In conclusion the concept of rheumatoid nodulosis illustrates the multiplicity of the nosological pictures wich could be realized in rheumatoid arthritis by various combinations of constitutive clinical, biological and morphological features. The pathogenesis of this special variant provides a useful field of investigation, together with a long term follow-up of the articular as well as of the visceral evolution.     

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.     

Rheumatoid nodulosis: A puzzling variant of rheumatoid arthritis

Summary Four patients with rheumatoid nodulosis are here described, together with a review of cases reported to date in the literature. This particular variant of rheumatoid arthritis (RA) is characterized by the presence of subcutaneous rheumatoid nodules, scanty or absent systemic manifestations and a clinically benign course. Joint involvement appears more commonly as palindromic rheumatism, although patients with arthralgia episodes alone and others with chronic polyarthritis have been described. Seldom reported up to now, a consideration of this entity may help to avoid diagnostic pitfalls and the use of aggressive therapy.     

Juvenile rheumatoid arthritis and bronchiolitis obliterans organized pneumonia

Diverse pleuropulmonary manifestations, including pleural effusion, rheumatoid nodulosis, fibrosis, obliterans brochiolitis, bronchiectasias, vasculitis, drug-induced lung disease, and obliterans bronchiolitis with organized pneumonia, have been described in patients with rheumatoid arthritis (RA). Bronchiolitis obliterans organized pneumonia (BOOP) is an uncommon condition described in patients with RA but not in juvenile RA (JRA). We described a patient with JRA who developed a BOOP.     

2756GG genotype of methionine synthase reductase gene is more prevalent in rheumatoid arthritis patients treated with methotrexate and is associated with methotrexate-induced nodulosis

OBJECTIVE: To investigate the distribution of the A2756G polymorphism of the methionine synthase reductase (MTR) gene in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) compared with a healthy control group; and to examine the relationships among the A2756G polymorphism, plasma total homocysteine (tHcy), serum folate and vitamin B12 levels, disease activity, and MTX toxicity in patients with RA. METHODS: A cross-sectional study was performed on 86 MTX-treated RA patients, consisting of a clinical interview and physical examination to determine disease activity and MTX-related adverse reactions. Genotype analysis of the MTR gene was performed. Fasting plasma tHcy, serum folate, and vitamin B12 levels were measured. Allele and genotype distributions were compared to a healthy control group. RESULTS: The frequency of the 2756GG genotype (16.3%) in the RA study group was higher than that expected in the general population (3.6%; p < 0.000001). This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). No association of disease activity variables or plasma homocysteine with MTR A2756G polymorphisms was observed. The MTR 2756GG genotype, low plasma vitamin B12 levels, and the presence of rheumatoid nodules predicted MIARN. No association of nodulosis with any other indicator of disease activity or medical treatment was found. CONCLUSION: In our population of MTX-treated RA patients the 2756GG genotype of the MTR gene was more common than expected and was associated with MIARN.     

Complete reversal of rheumatoid nodulosis

A woman first seen in 1978 had a history of seropositive rheumatoid arthritis (RA) of 12 years' duration with attacks of palindromic rheumatism for 3 years. She was treated with D-penicillamine, pyridoxine and hydroxychloroquine and serial measurements of her grip strength and proximal interphalangeal joint circumference were taken. By 1987 all her nodules had resorbed completely. Hydroxychloroquine effects probably helped her improvement. Although spontaneous resorption of a rheumatoid nodule is not a rare event, to the best of our knowledge, this is the first instance of complete resolution of all nodules in a patient with RA with the nodulosis variant.     

Rheumatoid lung nodulosis and osteopathy associated with leflunomide therapy

Background Leflunomide (LEF) is indicated in adults for the treatment of active rheumatoid arthritis (RA). LEF inhibits dehydroorotate dehydrogenase, a key enzyme of the pyrimidine synthesis in activated lymphocytes. Among rare adverse effects, fatal interstitial lung disease has been recently reported during treatment of RA with LEF in Japan. Clinical trials outside Japan do not suggest that LEF causes an excess of pulmonary adverse effects. Development and increase of peripheral rheumatoid nodules in typical sites of RA patients following LEF therapy has been recently reported. Objectives Two cases with new and accelerated development of rheumatoid lung nodulosis during LEF therapy were described in this study. Methods LEF treatment was administered to two male patients (77 and 66 years old) with long-standing active seropositive nodular RA with failure of multiple second line drugs and without lung involvement. Clinical and laboratory assessment using the American College of Rheumatology response criteria, chest computed tomography (CT), quantification of serum rheumatoid factor (RF), and monocyte count of peripheral blood along with routine laboratory follow up were performed on both patients before and during therapy. In case 1, a bone scan was performed due to sustained limbs pain. Open lung biopsy was performed in case 1 and core lung biopsy in case 2. Results Both patients achieved full clinical remission during 2 months of LEF therapy. In case 1, the first complaints were limbs pain after 10 months of treatment associated with intensive bone uptake on a bone scan consistent with hypertrophic pulmonary osteopathy. Productive cough developed after 3 months of the therapy in case 2. Initially, these complaints were not attributed to therapy. New lung disease was present on CT with cherry-like progressive cavitary nodules, predominantly involving the basal segments of the right lung. The first lung lesions were found by CT 13 months (case 1) and 7 months (case 2) after the beginning of therapy and were erroneously related to bronchiectasia in case 2. In both cases, the lung biopsy showed necrosis surrounded by epithelioid mononuclear inflammation with giant cells, consistent with rheumatoid lung node. The time that elapsed between the beginning of the first symptoms to LEF discontinuation was very long: 13 months in case 1 and 24 months in case 2. Discontinuation of LEF therapy was followed by an arrest in growth of lung nodules, resolution of limb pain, and gradual improvement of bone scan. A significant decrease of monocyte count and RF level in peripheral blood was observed during LEF therapy in both cases. Conclusion For the first time, we described rheumatoid lung nodulosis as complication of successful LEF therapy for RA. Hypertrophic pulmonary osteopathy with severe limbs pain and dry cough were the first manifestations of the lung nodulosis. Monocytopenia during LEF therapy is proposed to be involved in pathogenesis of this rare complication of LEF therapy.     

Rheumatoid nodulosis during methotrexate therapy in a patient with rheumatoid arthritis

We report a 62-year-old man with rheumatoid arthritis (RA) who developed nodulosis after methotrexate (MTX) treatment. The epithelioid cells of nodules were positive for matrix metalloproteinases (MMP)-2, MMP-3, MMP-9, and Ki67. The synovial tissues obtained from the same patient were negative for MMP-3, MMP-9, and Ki67. This study demonstrated that MTX-induced nodules are different from synovial tissues in terms of MMP expression, suggesting the presence of different pathologic mechanisms and differential MTX susceptibility.     

Accelerated nodulosis during methotrexate therapy in a patient with systemic lupus erythematosus and Jaccoud's arthropathy

SIR, Accelerated nodulosis (AN) is a well-known complicationof methotrexate (MTX) therapy in rheumatoid arthritis (RA) patients[1], characterized by the rapid appearance of small noduleson the hands, elbows and feet [1]. Although subcutaneous noduleshave been described in systemic lupus erythematosus (SLE) [2–5],we are unaware of reports of AN in SLE during MTX treatment. We report the case of a 34-yr-old female who was referred inOctober 1994 to a rheumatology department