Alexander Rozin

Rheumatoid lung nodulosis and osteopathy associated with leflunomide therapy

BackgroundLeflunomide (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.ObjectivesTwo cases with new and accelerated development of rheumatoid lung nodulosis during LEF therapy were described in this study.MethodsLEF 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.ResultsBoth 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.ConclusionFor 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.

Vitamin D, Parathyroid Hormone, and Acroosteolysis in Systemic Sclerosis

Objective Sclerodactyly with acroosteolysis (AO) and calcinosis are prominent features of systemic sclerosis (SSc), but the pathogenesis of these findings is poorly understood. Vitamin D and parathyroid hormone (PTH) have a crucial role in bone metabolism and resorption and may affect AO and calcinosis. We assessed vitamin D and PTH in patients with SSc. Methods Medical records of 134 consecutive patients with SSc (American College of Rheumatology criteria) followed at the rheumatology department during the years 2003–2006 were reviewed for clinical assessment, laboratory evaluation [including 25(OH) vitamin D, calcium, phosphorus, alkaline phosphatase, PTH, creatinine, and albumin]; imaging data confirming AO and/or calcinosis. Patients followed routinely at least once a year were included (81 patients). Of these, 60 patients’ medical records were found to have complete, relevant clinical, laboratory, and radiographic imaging. Results Thirteen patients had diffuse disease and 47 limited disease — 51 women and 9 men, 44 Jews and 16 Arabs; mean age 55 ± 14 years; disease duration 8 ± 6 years. AO with or without calcinosis was observed in 42 patients (70%). Vitamin D deficiency was found in 46% of patients (16 out of 44 Jewish patients, 10 out of 16 Arab patients). PTH was elevated in 21.7% of patients. Significant correlations were observed between acroosteolysis and PTH (p = 0.015), calcinosis (p = 0.009), and disease duration (p = 0.008), and between PTH and vitamin D levels (p = 0.01). All patients had normal serum concentrations of calcium, phosphorus, magnesium, and albumin, and liver and kidney functions. Conclusion In this group of Mediterranean patients with SSc, the incidence of vitamin D deficiency and secondary hyperparathyroidism was surprisingly high. This finding correlated with the occurrence of AO and calcinosis. Low levels of vitamin D may reflect silent malabsorption and might be a risk factor for secondary hyperparathyroidism and bone resorption. Traditional dress habits and low exposure to sun may contribute to vitamin D deficiency in an Arab population but do not explain all the findings. The pathogenesis of these findings needs to be corroborated in other SSc populations.

Relapse of rheumatoid arthritis after substitution of oral for parenteral administration of methotrexate

We read with interest the letters: “Is parenteral methotrexate worth trying?” by Osman and Mulherin1 and “Intramuscular methotrexate in inflammatory rheumatic disease” by Burbage, Gupta, and Lim.2 We would like to present our findings, which indicate that parenteral methotrexate (MTX) may be more efficient than oral MTX at the same dose and in the same patients with inflammatory joint disease. During the second half of 2000 we were faced with an unexpected shortage of parenteral MTX (ABIC, Israel) which lasted for more than five months, and patients were switched to oral MTX (Lederle, Germany). This gave us the opportunity to evaluate the difference in efficacy of parenteral versus oral administration of low dose MTX. Eight patients (seven female) with a mean age of 55 (38–70) years, who fulfilled the following criteria, were analysed retrospectively: ( a ) all had inflammatory joint diseases (four seropositive rheumatoid arthritis (RA), two seronegative RA (revised American Rheumatism Association criteria for RA), and two RA-like psoriatic arthropathy); ( b ) all were receiving parenteral MTX and were in complete clinical remission (fulfilling at least five of six …

Pulmonary Arteries Involvement in Takayasu's Arteritis: Two Cases and Literature Review

OBJECTIVES To review pulmonary arteritis (PA) complicated by pulmonary arterial hypertension (PAH) in Takayasus arteritis (TA). METHODS Two cases of PA and PAH in TA patients and similar cases published in the Medline database from 1975 to 2009 were reviewed. RESULTS Forty-six cases (females 89.1%, Asians 65%, mean age 34.6 years) were analyzed, 42.2% of which had PAH. Isolated PA was reported in 31.8%. Respiratory symptoms were presented as dyspnea (75.5%), chest pain (48.9%), hemoptysis (42.2%), and cough (17.7%). Hypertension, vascular bruits, and diminished/absent pulses were reported in 48.9% of patients. A diagnosis of PA was based on abnormal uptake on pulmonary perfusion scan and a finding of stenosis, narrowing, occlusion, and irregularity on computed tomography or magnetic resonance imaging, and/or pulmonary angiography. Patients were treated with glucocorticoids (77.5%), disease-modified antirheumatic drugs (35%), and warfarin (20%); only a few were treated with biological agents. Vascular procedures were performed in 52.5% of cases, on pulmonary arteries in 37.5% with good results. The outcome was death in 20.5% of PA patient and 33.3% in PAH patients. CONCLUSIONS TA may be complicated by life-threatening PA and PAH. Clinical signs are not specific and may be masked by involvement of the aorta and its branches. Treatment with glucocorticoids and disease-modified antirheumatic drugs has only partial effect, which may be intensified by biological agents. Invasive procedures on pulmonary arteries may be a complementary option. PA and PAH in TA patients should be recognized early and treated promptly for prevention of irreversible vascular damage.

Is SAPHO syndrome a target for antibiotic therapy

The etiology of the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome remains unclear. Infectious factors are proposed to be relevant in the etiopathogenesis of the disease. To our knowledge, this is the first reported case of a proposed relationship between Staphylococcusaureus cultured from plantar pustule and SAPHO syndrome, which was successfully treated with co-trimoxazole (CTM) (sulfamethoxazole/trimetoprim). CTM might be the drug of choice for therapy for SAPHO syndrome because of combined antibiotic and immunomodulatory properties. Hypersensitivity testing of the medication in vitro was performed to identify, in the preclinical stage, the hypersensitivity reaction to CTM, which may have been severe.

SAPHO syndrome: Is a range of pathogen-associated rheumatic diseases extended?

SAPHO syndrome, representing a constellation of synovitis, acne, palmo-plantar pustulosis, hyperostosis, and osteitis, is now recognized as a distinct medical entity: a reactive infectious osteitis. Genetic, immunological, and bacterial mechanisms are implicated in the development of the disease. Diagnostic problems may arise due to non-complete manifestations of SAPHO: either acne and arthritis or acne and anterior wall osteitis with an unclear pustulosis history. The interventional study of Assmann et al. is a significant addition to a long range of publications showing an association of SAPHO with Propionibacterium acnes. Randomized control studies are needed to confirm the effects of antibiotic therapy.

Documenting and explaining the common AAB pattern in music and humor: Establishing and breaking expectations.

The AAB pattern consists of two similar events followed by a third dissimilar event. The prevalence of this pattern in the aesthetic domain may be explained as violation of expectation: A minimum of two iterations is required to establish a repetitive pattern; once established, it is most efficient to promptly violate the expected continuance of the pattern to produce the maximal aesthetic effect. We demonstrate the prevalence of this pattern (in comparison to AB or AAAB) in a representative sample of a variety of musical genres and in a representative sample of repetitive genre of jokes. We also provide experimental evidence that the AAB pattern in jokes is maximally effective in producing a humor response in participants.

Depletion of B lymphocytes in rheumatoid arthritis patients modifies IL-8-anti-IL-8 autoantibody network

Cytokines and chemokines are key regulatory molecules involved in rheumatoid arthritis (RA). B-cell depletion therapy improves RA clinically but its mechanism is not completely understood. One possible mechanism for this therapy is the modification of the proinflammatory cytokine homeostasis of RA. We show here that the levels of the proinflammatory chemokine IL-8 in serum samples from RA patients unexpectedly increased by up to 100-fold 8 weeks after the administration of rituximab, despite clinical improvement. We also show that RA patients produced anti-IL-8 autoantibodies and that their levels dropped after RTX treatment. Moreover, we identified antibody-IL-8 immune complexes in the synovial fluid and serum of RA patients, and found that the amount of these complexes decreased after the administration of RTX. Our results indicate that B-cell depletion therapy modifies the cytokine-autoantibody network by reducing the levels of anti-cytokine autoantibodies and, consequentially, the formation of antibody-cytokine immune complexes.

Ultrasound measurement of the acromioclavicular joint

The acromioclavicular joint (ACJ) is a widely used, versatile and complex gliding synovial joint that provides stability and increases function; the ability to raise the arm above the head with a greater degree of arm rotation. The ACJ is vulnerable to trauma, instability, dislocation, osteoarthritis and synovitis.1 The ACJ is assessed for dislocation, fluid collection, cysts and bone erosions,2 3 but measurement of normal ACJ parameters is still unclear. That makes it difficult to interpret ACJ pathology.4 Ultrasound (US) enables direct imaging of the ACJ and has been proven to be as accurate as x ray assessment.4 The aim of the present study was to obtain US dimensions of the ACJ in healthy volunteers. US assessment (SonoSite Titan with 5–10 MHz L38 linear …

Alopecia areata and relapsing polychondritis or mosaic autoimmunity? The first experience of co-trimoxazole treatment

A 13 year old girl presented with auricular chondritis and recurrent episodes of unexplained chest pain, arthritis, bronchitis, conjunctivitis, prolonged steroid resistant alopecia areata, and a history of recurrent tonsillitis. Both the mosaic of autoimmunity and relapsing polychondritis were considered in the differential diagnosis. The patient was successfully treated with co-trimoxazole. The significance of co-trimoxazole, which is an antibiotic and an immunomodulatory drug, in the treatment of autoimmune disease is discussed.