Amyloidosis associated with dermatomyositis and features of multiple myeloma. The progression of amyloidosis associated with corticosteroid and cytotoxic drug therapy.

Described here is a 59 year old man with dermatomyositis and hypogammaglobulinemia. His muscle power improved after corticosteroid therapy, but extensive amyloidosis and repeated infections appeared. Bone marrow morphology suggested multiple myeloma, but treatment with cytotoxic drugs had no beneficial effect on the amyloidosis. Because of rapid progression of the amyloidosis and further infections, cytotoxic drug therapy was stopped, corticosteroid dosage was decreased, and supplementary immunoglobulin therapy was instituted. The infections occurred less frequently and the amyloidosis appeared to regress. This case suggests that immunosuppressive therapy may exacerbate amyloidosis. The literature is reviewed, and the possible role of humoral immunodeficiency in the pathogenesis of amyloidosis is discussed. It is suggested that supplementary immunoglobulin may be beneficial in amyloidosis.

Penicillamine-associated myasthenia gravis, antiacetylcholine receptor and antistriational antibodies.

Myasthenia gravis with thymic hyperplasia developed in a patient with Wilson's disease after eight years of penicillamine treatment. Four months prior to the onset of myasthenia, penicillin hypersensitivity was observed. Immunofluorescence on the excised thymus revealed immunoglobulin and complement deposition, but the myasthenia persisted after thymectomy and continuation of penicillamine therapy. Increased antiacetylcholine receptor antibody was demonstrable throughout. This patient subsequently became pregnant, enabling studies to be performed on the transplacental transfer of the immunoglobulin G (IgG) class antiacetylcholine receptor antibody. Eleven cases of rheumatoid arthritis with penicillamine-associated antistriational antibodies have also been observed; in three of these cases there was evidence of myasthenia gravis. These observations extend earlier reports of the association of penicillamine with myasthenia gravis and suggest that antistriational antibody, antiacetylcholine receptor antibody and thymic hyperplasia may be independent effects of penicillamine therapy.

Genetic studies in familial fibrosing alveolitis. Possible linkage with immunoglobulin allotypes (Gm).

A family containing 12 subjects spanning three generations and including six cases with clinical evidence of definite or probable fibrosing alveolitis has been investigated. Histologic confirmation was available for three cases. The subjects were between 15 and 54 years of age at diagnosis. Although the size of the sample is small, the mode of inheritance of fibrosing alveolitis within this family appeared to be dominant with incomplete penetrance. HLA typing showed that at least one of the affected siblings did not share any HLA haplotypes with other affected siblings in the third generation. This makes it unlikely that a disease gene would be in association with HLA genes on chromosome 6. In contrast, all affected siblings, as well as two as yet unaffected siblings, carried the immunoglobulin haplotype Gm 1. These studies indicate that familial fibrosing alveolitis in this family may be inherited by a dominantly inherited gene located on chromosome 14 close to the loci encoding for Gm.

Idiopathic inflammatory myopathies: optimum immunosuppressive treatment.

The idiopathic inflammatory myopathies include polymyositis and dermatomyositis, which tend to be responsive to drug therapy, and inclusion body myositis, which is often unresponsive or only partially responsive to drugs. Corticosteroids are considered the first line treatment of these disorders, and as well as being anti-inflammatory are immunosuppressive when used at dosages above prednisolone 20 mg/day or equivalent. In those patients who are refractory to corticosteroids, or are prone to develop complications from corticosteroids, second line drugs such as methotrexate, azathioprine or intravenous immunoglobulin should be introduced. These therapies tend to be slow acting, but response often occurs in 4 to 6 weeks and allows the dosage of corticosteroid to be reduced more rapidly. In those occasional patients with inflammatory myopathies that are refractory to corticosteroids and second line agents, one should consider adding in a third line agent such as cyclosporin, chlorambucil or cyclophosphamide. Although most clinicians would use these immunosuppressive drugs singly in combination with corticosteroids, multiple drug therapy should be considered in severe refractory cases.

Inflammatory myopathies: how to treat the difficult cases.

The initial approach to the treatment of patients with inflammatory myopathy is critical in determining the subsequent course and outcome. Prolonged administration of high doses of corticosteroids should be avoided and a second-line agent such as methotrexate or azathioprine should be introduced earlier rather than later. Intravenous immunoglobulin therapy has an important place if the myositis remains active, particularly in patients with dermatomyositis, and is the treatment of choice in patients with immunodeficiency who are not controlled by corticosteroids. In more resistant cases of polymyositis or dermatomyositis it may be necessary to use cyclophosphamide, cyclosporin or the promising newer immunosuppressive agents mycophenolate mofetil or tacrolimus to achieve disease control. The treatment of inclusion body myositis remains unsatisfactory but a trial of prednisolone and methotrexate is warranted in selected patients.

Chronic sensory neuropathy with anti-Ro antibodies without clinical features of Sjögren's syndrome.

We present the clinical, electrophysiological and serological findings of a patient with a 13-year history of a chronic sensory neuropathy associated with anti-Ro (SS-A) antibodies, in whom there were no clinical or pathological features of Sjögren's syndrome. Given the possible therapeutic implications we suggest that anti-Ro antibodies be sought in any patient presenting with a chronic sensory neuropathy, even in the absence of clinical or pathological features of Sjögren's syndrome.

Immune function in ankylosing spondylitis: apparent relationship between streptococcal responses and HLA B27.

Immune function has been evaluated in 54 patients with ankylosing spondylitis (AS) and 26 controls. Cell-mediated immunity was assessed by skin testing with ubiquitous antigens, and humoral immunity by antibody responses to tetanus toxoid and Salmonella typhi vaccinations, and resting titres of anti-Streptolysin O, anti-E Coli, and isohemagglutinins. The AS patients had reduced delayed hypersensitivity responses to Candida, augmented responses to Streptococcal antigen and relatively low ASO titres. There was no generalized depression of humoral immunity, as indicated by the normal tetanus and Salmonella O responses and hyper-response to Salmonella H antigen. The E. Coli and isohemagglutinin titres were normal. These results indicate that patients with AS present a complex immunological profile, including exaggerated responses to some antigens and impaired responses to others. In view of the very high incidence of HLA-B27 in AS, it is possible that these findings are related to the effects of HLA associated immune response genes.

Immunobiology of D-penicillamine.

D-penicillamine holds the key to a better understanding of autoimmunization and the pathogenesis of autoimmune disease. Analysis of its mode of action is complicated by its multiplicity of effects. In respect to anti-acetylcholine receptors and myasthenia gravis, the major effect may be at the level of immunoregulation and/or immunogenicity. Anti-striated muscle antibody is much more common and is influenced by the HLA antigen of the patient. Thus, HLA-linked immune response genes may be involved.

Myasthenia gravis and D-penicillamine.

There has been some uncertainty as to whether the apparent association between myasthenia gravis (MG) and D-penicillamine (D-P)-treated rheumatoid arthritis (RA) could be due to chance or whether the drug is responsible. In the absence of D-P, RA is found in association with MG, but this may simply reflect the high prevalence of RA. Although MG may be more common than expected after D-P treatment of RA, it probably occurs in only approximately 1% of such patients. In these circumstances, it is difficult to prove that D-P can induce MG, but compelling evidence in support for this possibility comes from the finding of differences between autoantibodies when spontaneous and D-P-associated MG are compared. These serologic differences could be explained in terms of an effect of D-P on antigen presentation and/or immunoregulation.

The association of sporadic inclusion body myositis and Sjögren's syndrome in carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype.

Sporadic inclusion body myositis (sIBM) usually occurs as an isolated condition, but it may occur in association with another autoimmune disorder such as Sjögren's syndrome. We reviewed sIBM cases with Sjögren's syndrome (sIBM/SS) from the Perth Inflammatory Myopathies Database to determine whether they are distinguishable from other sIBM cases. Six such cases were identified, representing 12% of all sIBM cases. Muscle biopsies confirmed the presence of an inflammatory myopathy with rimmed vacuoles and the characteristic muscle fibre inclusions of sIBM. Five of the six were females, contrasting with a 2:1 male preponderance in the rest of the sIBM cohort. The mean age-at-onset and the pattern of muscle weakness were similar in the two groups. Four out of five sIBM/SS patients treated with immune therapies had improvement in muscle strength lasting for 6-24 months, whereas only 27% of other sIBM patients improved. All 6 patients with sIBM/SS carried the HLA-DRB1*0301 allele, or its equivalent HLA-DR3 serological specificity, compared with 83% of other sIBM cases and all carried some or all of the major markers of the 8.1 MHC ancestral haplotype which is also associated with Sjögren's syndrome. Patients with sIBM/SS represent a subgroup of sIBM cases who are more likely to be female and carriers of HLA-DR3 and the 8.1 MHC ancestral haplotype, and are more likely to respond to treatment. The association of sIBM and Sjögren's syndrome is likely to be due to a common genetic predisposition linked to the MHC and supports the notion that sIBM has an autoimmune basis.

Polymyositis and myasthenia gravis: immunodeficiency disorders involving skeletal muscle.

Human polymyositis and aspects of myasthenia gravis may be consequences of subtle immunodeficiency states. Autoimmune processes leading to inflammatory muscle disease and the presence of associated tumours may reflect the partial loss of antibody-mediated homoeostatic mechanisms.

Prevalence of sporadic inclusion body myositis in Western Australia.

A 10-year retrospective review was conducted to ascertain the prevalence of inclusion body myositis (IBM) in Western Australia. Seventeen patients with sporadic IBM aged 45-90 years were identified and the prevalence of IBM was calculated to be 9.3 x 10(-6). The prevalence was higher in men (10.9 x 10(-6)) than in women (7.7 x 10(-6)). The mean age of onset of IBM was 56.6 years, and the mean delay between onset of symptoms and diagnosis was 4.4 years. The age-adjusted prevalence over the age of 50 years was 35.3 x 10(-6). The results suggest a higher prevalence of IBM than has previously been reported.

Immunoglobulin therapy in inflammatory myopathies.

A prospective open label trial of add on therapy with intravenous immunoglobulin (i.v.Ig) was carried out in 16 patients with inflammatory myopathy who had continued to deteriorate or had relapsed on conventional therapy. The response was assessed using isometric myometry, functional scales, MRC grading, and serum creatine kinase concentrations with a three month run in period before commencement of i.v.Ig. Five of seven patients with isolated dermatomyositis or polymyositis and all four patients with an overlap syndrome responded to i.v.Ig with partial or complete remission of disease and normalisation of serum creatine kinase concentrations. None of five patients with inclusion body myositis showed any functional improvement although myometry scores improved in some muscles in one case. It is concluded that i.v.Ig is an effective therapeutic option in patients with drug resistant polymyositis or dermatomyositis. However, further controlled trials are required to confirm the efficacy of this form of treatment and to establish optimal doses and administration regimes.

Penicillamine treatment of rheumatoid arthritis: relationship of proteinuria and autoantibodies to immune status.

Thirty-seven patients were studied before and during treatment with respect to immune status, clinical response and development of adverse effects and autoantibodies. The baseline immune status was not predictive in terms of the above features, apart from the fact that the group of 7 patients developing proteinuria had a tendency to low or subnormal IgG levels. The most marked clinical improvement was recorded in the group who had augmented skin test responses sometime during the treatment period. These patients also had the largest falls in the IgG, IgA and rheumatoid factor. Antinuclear antibody persisted or increased in titre in 38% of patients, but was not associated with poor prognosis or liability to side-effects. Autoantibodies to striational or smooth muscle occurred in 20% of patients, and there was a much higher incidence of proteinuria in this group. We have previously suggested that penicillamine may act by depressing humoral function, leading to augmentation of cell-mediated immunity. Although the present findings suggest that penicillamine does cause humoral depression in some cases, it is not clear how the drug induces the side-effects described.

Metal sensitivity causing loosened joint prostheses.

Metal sensitivity, as measured by an in-vitro assay on peripheral blood lymphocytes, was evaluated in patients with failed joint prostheses. Lymphocyte transformation to chromium, cobalt, and nickel was measured in 24 patients having revision surgery for a painful or loose prosthesis and compared with that in 11 patients who had a successful hip prothesis in situ for at least 2 years previously. A positive response (lymphocyte stimulation index greater than 3) to at least one of the metals was found in 71% of the revision group compared to 9% of controls (P < 0.01). The positive correlation between prosthesis failure and in-vitro metal sensitivity suggests that cell-mediated immunity to metals to metals may play a role in prosthesis failure. Furthermore, this simple in-vitro test may provide the basis of a useful diagnostic test for an often difficult clinical problem.

Immunological status may predict clinical outcome in BCG treated melanoma.

Twenty-seven patients with surgically resected stage II or III malignant melanoma were treated with bacillus Calmette-Guérin (BCG) and followed prospectively to determine whether relapse could be predicted. Peripheral blood mononuclear (lymphocyte plus monocyte) counts (PBM), T and B cell counts, phytohaemagglutinin (PHA) cytotoxicity, PHA transformation, antibody-dependent cell-mediated cytotoxicity (ADCC) and serum immunoglobulin concentrations were studied before and during therapy. Patients ultimately classified as having a poor clinical outcome (inoperable recurrence) were compared with those with a more favourable outcome. Prior to therapy, poor outcome patients had lower PBM and T cell counts but there was some overlap. After three months, these differences were more pronounced. Low PHA cytotoxicity was also associated with poor outcome; again the differences were more apparent at 3 months than prior to therapy. These results suggest that PBM, T cell counts and PHA cytotoxicity may predict poor outcome some months before inoperable recurrence in apparent clinically.

Dermal necrosis following coumarin: is it immunologically induced?

Two patients with dermal necrosis due to anticoagulation therapy with warfarin are reported. Both patients demonstrated some disturbance in immunological function. It appears possible that warfarin may act as a hapten in the induction of hypersensitivity to the drug. It is recommended that future cases should be studied to determine whether there is a defect in immunoregulation, and whether circulating immune complexes are responsible for the typical skin lesions.

HLA associations with inclusion body myositis.

Inclusion body myositis (IBM) is defined clinically by a characteristic pattern of progressive proximal and distal limb muscle weakness and resistance to steroid therapy, and histologically by the presence of distinctive rimmed vacuoles and filamentous inclusions as well as a mononuclear infiltrate in which CD8+ T cells are predominant. Muscle damage is believed to be mediated by autoimmune mechanisms, but very little information is available on the immunogenic features of IBM. MHC class I and DR antigens were typed on 13 caucasoid patients with IBM using standard serological techniques or by allele-specific oligonucleotide typing. Complement components C4 and properdin factor B (Bf) were typed by immunofixation after electrophoresis. Restriction fragment length polymorphisms (RFLP) in the class III region were analysed using cDNA probes for C4 and 21-hydroxylase (CYP21) after Taq 1 digestion. IBM was associated with DR3 (92%), DR52 (100%) and HLA B8 (75%). The phenotype data were examined for likely haplotypes by considering together the alleles at the class I, DR and complement loci along with the C4 and CYP21 RFLP. Ten of the DR3+ subjects had a 6.4-kb C4-hybridizing fragment characteristic of a deletion of C4A and CYP21-A. These patients probably carried all, or at least the class II and III regions, of the extended haplotype marked by B8/C4A*Q0/C4B1/BfS/DR3/DR52, which has been associated with several autoimmune diseases and is present in 11% of the healthy caucasoid population. Of the remaining subjects, two had evidence of the extended haplotype marked by B18/C4A3/C4BW*0/BfF1/DR3, which is present in less than 5% of the healthy population and has been associated with insulin-dependent diabetes mellitus. These data provide support for an autoimmune etiology for, and genetic predisposition to, IBM.

Cystic lymphangiomyoma of the colon causing protein-losing enteropathy.

This report documents a case of cystic lymphangiomyoma of the sigmoid colon in a 35-year-old woman who presented with symptoms of a protein-losing enteropathy. This case was unique in that it involved not only the colonic wall and mesentery but also extended into the retroperitoneum. Surgical excision of the affected segment has resulted in reversal of hypoproteinaemia and return to normal of the excessive faecal loss of 51Cr-labeled protein over a 2-year follow-up period.

Guillain-Barré syndrome and pemphigus foliaceus associated with D-penicillamine therapy.

The Guillain-Barré syndrome and pemphigus foliaceus occurred simultaneously in a patient on long-term treatment with D-penicillamine. It is proposed that both conditions may have developed as a result of a disturbance of immunoregulation caused by D-penicillamine.