Effectiveness of etanercept vs cyclophosphamide as treatment for patients with amyloid A amyloidosis secondary to rheumatoid arthritis.

OBJECTIVES: To compare the effectiveness of an alkylating agent with that of a biologic agent in the treatment of patients with amyloid A (AA) amyloidosis secondary to RA and to assess the association of the serum AA (SAA) 1.3 allele with treatment. METHODS: CYC and etanercept (ETN) were administered to 62 and 24 RA patients, respectively, who were confirmed with biopsy as having AA amyloidosis. We evaluated whether the SAA1.3 allele, a factor indicating genetic risk and poor prognosis of Japanese RA patients with AA amyloidosis, influenced treatments and retrospectively analysed the effectiveness of both agents via statistical methods. RESULTS: Two treatment groups were similar, except for the SAA1.3 genotype (P = 0.015) and duration of AA amyloidosis since diagnosis (P < 0.001). Also, patients given ETN had somewhat worse renal function, i.e. 24-h proteinuria (P = 0.02), at the initiation of treatment. ETN demonstrated greater effectiveness than CYC, as shown by significantly improved levels of serum CRP and serum albumin (both P < 0.01) and estimated glomerular filtration rate (eGFR; P = 0.032). ETN improved survival (P = 0.025), and the hazard ratios for the risk of death endpoint with eGFR and 24-h proteinuria were significant by P = 0.024 and P = 0.025, respectively. The SAA1.3 allele did not affect the response to medications in AA amyloidosis secondary to RA. CONCLUSION: ETN treatment was more effective than CYC treatment, and CRP, albumin and eGFR may be valuable biomarkers for analysis. The SAA1.3 allele was not a factor affecting treatment in Japanese patients with AA amyloidosis secondary to RA.

Cutaneous nodules in patients with rheumatoid arthritis: a case report and review of literatures.

We report a case of 57-year-old Japanese woman with an overlap syndrome of both rheumatoid arthritis (RA) and autoimmune hepatitis, who developed multiple skin nodules. An extensive biopsies of the nodules revealed rheumatoid neutrophilic dermatitis, showing panniculitis without vasculitis, combining with granulomatous formation histopathologically. Since cutaneous nodules in patients with RA are very complex, differential diagnosis should be done according to disease activities, medications used, and pathological findings. We suggest that the differences in histopathological findings of cutaneous nodules in patients with RA depend on their immunological conditions based on disease activities including therapeutic effects.

Etanercept can induce resolution of renal deterioration in patients with amyloid A amyloidosis secondary to rheumatoid arthritis.

The benefit of biological therapies in rheumatoid arthritis (RA) treatment is well known, but their role in amyloid A (AA) amyloidosis secondary to RA is unclear. The aim of this study was to clarify the clinical benefit of etanercept in RA patients with AA amyloidosis. We treated 14 RA patients who had serum amyloid A protein (SAA) 1.3 allele, with biopsy-confirmed AA amyloidosis with etanercept and investigated the efficacy of etanercept treatment, focusing on renal function retrospectively. The AA amyloidosis improved and stabilized after 89.1 ± 27.2 weeks. Proteinuria decreased from 2.24 ± 0.81 to 0.57 ± 0.41 g/day (P < 0.01) and SAA fell from 250 ± 129 to 26 ± 15 µg/ml (P < 0.01), respectively. Diarrhea secondary to gastrointestinal AA amyloidosis was less. Overall, the serum creatinine levels did not benefit with treatment, but in those with a creatinine values <2.0 mg/dl the creatinine level continued to fall (P = 0.021). Serum albumin increased following 96 weeks of etanercept treatment (P = 0.003). Etanercept treatment led to clinical improvement in proteinuria and serum albumin levels accompanied by a fall in SAA levels.

CD8+ T lymphocytes infiltrate predominantly in the inflammatory foci of MPO-ANCA-positive thoracic hypertrophic pachymeningitis in a patient with HLA-A24.

Hypertrophic pachymeningitis (HP) is extremely rare and an inflammatory process that thickens the dura mater. A 59-year-old Japanese woman developed backache, became paraplegic, and magnetic resonance imaging revealed diffuse thickening of the thoracic dura mater encompassing the spinal cord. Although a test for myeloperoxidase antineutrophil cytoplasmic autoantibody (MPO-ANCA) was shown to be positive, vasculitis was not found and CD8(+) T lymphocytes that predominated in the inflammatory foci. Both interleukin (IL)-2 and IL-6 were markedly elevated in not only sera but also cerebrospinal fluids, very much higher in the latter. Human leukocyte antigen (HLA) typing revealed A24 positivity, suggesting this molecule was interacting with CD8(+) T lymphocytes. It was suggested that immunological disharmony and autoimmunity would play a pivotal role in the development of HP under genetic background of HLA-A24, and HP would be one feature of multiple organ involvement in ANCA-associated diseases.

Primary biliary cirrhosis (PBC)-CREST overlap syndrome with coexistence of Sjögren's syndrome and thyroid dysfunction.

Calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia (CREST) syndrome, a limited form of systemic sclerosis, is sometimes complicated by primary biliary cirrhosis (PBC). A 52- and 61-year-old Japanese woman with PBC-CREST overlap syndrome accompanied by Sjögren's syndrome, and Hashimoto's thyroiditis, and Graves' disease, respectively, are reported. They had suffered from Raynaud's phenomena, sclerodactyly, morning stiffness, arthralgia, and sicca symptoms during these several years. They exhibited an increased level of alkaline phosphatase, gamma-glutamyl transpeptidase, positive antibodies against mitochondria and centromere, and hyperglobulinemia without any cholestatic symptoms. Histological findings from liver biopsy specimens were consistent with those of PBC. Clinically, they were diagnosed as both asymptomatic PBC and incomplete CREST syndrome. Their human leukocyte antigen typing showed both DR4 and DR8 positive. The association of the four autoimmune conditions is clinically and etiologically important. Although a combination of these diseases is rare, it is of importance to keep in mind that various autoimmune diseases could occur simultaneously. Of critical importance is that an active diagnostic attitude towards them is admirable, and that early diagnosis and therapy are needed.

A study of ten Japanese patients with seronegative spondylarthropathy: a tentative proposal.

We reviewed ten patients with seronegative spondylarthropathy (SNSA), who all fulfilled the European Spondylarthropathy Study Group criteria for spondylarthropathy (SpA); seven patients also met the Amor criteria for SpA. Seronegative spondylarthropathy was not a uniform syndrome but rather a wide spectrum of complex disease with characteristics of sacroiliitis and enthesopathy. The most frequent symptom at diagnosis of SNSA was inflammatory low back pain, followed by asymmetric oligoarthralgia and Achilles tendonitis and/or plantar fasciitis. Systemic complications were revealed as eye and skin involvement. Imaging methods including pelvic radiography, scintigraphy, and computed tomography scanning were useful in detecting spondylarthropathic changes, which were characteristic of SNSA. Human leukocyte antigen (HLA) typing showed various patterns among patients, in which HLA-B27 was positive in three patients with ankylosing spondylitis. HLA-B51, which is a well-known genetic factor associated with Behçet's disease (BD), was positive in two patients who were apparently distinct from BD. Two patients with palmoplantar pustulosis showed symptoms and signs characteristic of SNSA. Although we have few SNSA patients in the present study, we would like to propose that HLA-B51 positive SpA would be considered as a subset of SNSA, and that pustulotic SpA also would be classified as a member of SNSA. This led us to suggest the possibility to change the concept of SNSA proposed by Moll et al. The optimal treatment remains to be defined, but sulfasalazine was effectively used with almost all patients in combination with nonsteroidal anti-inflammatory drugs.

Gustatory sweating due to autonomic neuropathy in a patient with amyloidosis secondary to rheumatoid arthritis.

Abstract Autonomic neuropathy, although often reported to occur in patients with AL (amyloid of light chain of immunoglobulin) amyloidosis, is extremely rare in AA (amyloid A) amyloidosis. We describe a patient with AA amyloidosis secondary to rheumatoid arthritis (RA) in whom autonomic neuropathy resulted in gustatory sweating during the end stage of RA. We discuss the importance of gustatory sweating as a characteristic sign of autonomic nervous system dysfunction in AA amyloidosis secondary to RA, and stress the availability of cardiovascular autonomic tests as an indicator of autonomic neuropathy in not only AL amyloidosis but also AA amyloidosis.

Efficacy of cyclophosphamide combined with prednisolone in patients with AA amyloidosis secondary to rheumatoid arthritis.

Secondary amyloid A (AA) amyloidosis is an uncommon yet important complication of rheumatoid arthritis (RA). It is one of the most relentless of the extra-articular features of RA, and suitable treatments have not yet been found. We studied the efficacy of cyclophosphamide (CYC) combined with prednisolone (PSL) in amyloidotic patients who had serum amyloid A (SAA) 1.3 genotype, which is a risk factor for secondary amyloidosis in Japanese RA patients. Fifteen RA patients who were SAA1.3 homo- and heterozygotes with biopsy-confirmed AA amyloidosis were treated with a combination of CYC and PSL. Laboratory variables of C-reactive protein (CRP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), serum albumin (Alb), serum creatinine (Cre) and Lansbury's index were carried out by statistical analysis of changes between before and during the medication. According to the Mann-Whitney rank test, CRP, RF, ESR, Alb and Cre levels improved significantly with the combination treatment (p<0.05). Also, paired t-tests showed significance in Lansbury's index between before and during the medication (p=0.007). CYC combined with PSL ameliorated not only laboratory markers but also clinical rheumatoid activity in patients with amyloidosis secondary to RA, whose genotypes were SAA1.3 homo- and heterozygous. CRP, ESR, RF, Alb and Cre will be surrogate markers of therapeutic efficacy. The combination of CYC and PSL appears to be beneficial for Japanese RA patients who are SAA1.3 homo- and heterozygous carriers, associated with secondary AA amyloidosis.

Polyarteritis nodosa limited to calf muscles: a case report and review of the literature.

We describe an unusual case of a 38-year-old woman with a localised form of polyarteritis nodosa (PAN) manifested by acute onset of severe calf pain. Magnetic resonance imaging of the lower legs showed abnormal signal intensity of the outer calves muscle. Biopsies of the gastrocnemius revealed an acute necrotising arteritis with marked non-specific fasciitis. The diseased muscle improved with corticosteroid administration alone. The fascial involvement likely contributed to the severity of the clinical features of PAN, which may be related to a previous hepatitis B virus infection.