Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study.

OBJECTIVE: To estimate minimally important differences (MIDs) in scores for the modified Rodnan Skin Score (mRSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in a clinical trial on diffuse systemic sclerosis (SSc). PARTICIPANTS AND METHODS: 134 people participated in a 2-year, double-blind, randomised clinical trial comparing efficacy of low-dose and high-dose D-penicillamine in diffuse SSc. At 6, 12, 18 and 24 months, the investigator was asked to rate the change in the patient's health since entering the study: markedly worsened, moderately worsened, slightly worsened, unchanged, slightly improved, moderately improved or markedly improved. Patients who were rated as slightly improved were defined as the minimally changed subgroup and compared with patients rated as moderately or markedly improved. RESULTS: The MID estimates for the mRSS improvement ranged from 3.2 to 5.3 (0.40-0.66 effect size) and for the HAQ-DI from 0.10 to 0.14 (0.15-0.21 effect size). Patients who were rated to improve more than slightly were found to improve by 6.9-14.2 (0.86-1.77 effect size) on the mRSS and 0.21-0.55 (0.32-0.83 effect size) on the HAQ-DI score. CONCLUSION: MID estimates are provided for improvement in the mRSS and HAQ-DI scores, which can help in interpreting clinical trials on patients with SSc and be used for sample size calculation for future clinical trials on diffuse SSc.

Relapse of polymyositis after prolonged remission.

We describe the case of a patient with polymyositis and anti-Jo-1 antibodies who experienced a relapse of his inflammatory muscle disease after 7 years of clinical remission. Our review of the literature shows that remission is achieved in 25-68% of patients treated with high dose corticosteroids as part of their initial therapy. Relapse rates after complete remission vary from 6 to 43% in the few studies where this information is available. Late relapses after initial remission appear to be unusual, but may be more frequent in patients like this one with antisynthetase syndrome.

Septic sacroiliitis.

Two cases of septic sacroiliac (SI) joint arthritis are presented to illustrate the difficulty of diagnosing and treating this uncommon osteoarticular infection. The patients presented are a 68-year-old woman with septic sacroiliitis caused by Streptococcus agalactiae and a 20-year-old man with Salmonella infantis infection involving the SI joint. The recent literature is reviewed and compared with previously published series. Of the 177 cases we reviewed, 47 (27%) occurred in pediatric patients. The mean age was 20 years. Only six patients (3%) were older than 60 years of age. Magnetic resonance imaging (MRI) is most useful for defining extent of infection, osteomyelitis, and abscess formation in the SI joint. Computed tomography (CT) is valuable for defining the extent of bone involvement and for guidance of percutaneous needle arthrocentesis. Other imaging modalities are useful primarily in the initial evaluation of patients with a nonspecific presentation. Four to six weeks of intravenous (i.v.) antibiotic therapy is recommended. Indications for surgical intervention include abscess formation, osteomyelitis, sequestrum of necrotic bone, and failure to respond to i.v. antibiotic therapy.

Treatment-resistant diffuse calcinosis in scleroderma.

A case of limited cutaneous systemic sclerosis with severe diffuse subcutaneous calcification is presented. The patient experienced multiple complications of calcinosis from this condition and was completely resistant to all treatment modalities. A detailed analysis of the calcific crystals revealed hydroxyapatite and octacalcium phosphate. Possible treatment strategies for calcinosis in scleroderma are reviewed in the context of this case.

Cross-linked elastin and collagen degradation products in the urine of patients with scleroderma.

OBJECTIVE: To measure the urinary excretion of specific cross-link amino acid markers for mature elastin (desmosine [DES] and isodesmosine [IDES]) and fibrillar collagen (hydroxylysylpyridinoline [HP] and lysylpyridinoline [LP]) in systemic sclerosis (SSc) patients and healthy controls. METHODS: Urine specimens from 20 patients with SSc and 22 controls were assessed for DES, IDES, HP, and LP using high performance liquid chromatography and ultraviolet absorption spectroscopy, in combination with an isotope dilution technique in which the urine specimen was spiked with isotopically labeled cross-link amino acids. RESULTS: Mean +/- SD levels of urinary DES and IDES were elevated in SSc patients by 2-3-fold, and urinary HP and LP by 3-4-fold, compared with controls (DES 21.0 +/- 9.4 versus 7.5 +/- 1.4 micrograms/gm creatinine; HP 109.0 +/- 72.9 versus 24.9 +/- 5.7 nmoles/mmole creatinine). Nineteen of the 20 SSc patients had urinary DES and HP values that were > 3 SD above the control mean. A significant elevation in the HP:LP ratio in SSc patients as compared with controls (mean +/- SD 6.9 +/- 1.5 versus 5.5 +/- 1.3) indicated a soft tissue origin for much of the increased HP. CONCLUSION: Patients with SSc have higher levels of urinary cross-link amino acids specific for the degradation of mature collagen and elastin. These markers distinguish most SSc patients from healthy controls.

Raynaud's phenomenon.

Raynaud's phenomenon occurs in about 5% of the adult population, and most individuals do not seek medical attention for the condition. In symptomatic patients with Raynaud's phenomenon, it is useful to categorize the condition as primary or secondary. In addition to providing a framework for epidemiologic and therapeutic protocols, such classification may reflect basic pathophysiologic differences. Occupation-related Raynaud's phenomenon has been recognized recently as a major cause of lost wages and productivity. Neurogenic and "local fault" hypotheses to explain primary Raynaud's phenomenon are still being studied. In secondary Raynaud's phenomenon, obliterative arteriopathy and the role of endothelial-derived products have been the focus of intense research interest. Under some circumstances, the combination of nailfold capillary microscopy and autoantibody analysis can identify patients with primary Raynaud's phenomenon that is likely to evolve into a secondary form of Raynaud's phenomenon. Although information from this type of analysis may be overinterpreted, the prognostic yield is highest for patients destined to develop systemic sclerosis-related disorders. Newer vasodilating agents and antithrombotic drugs may offer benefit for patients with both primary and secondary Raynaud's phenomenon.

Human immunoglobulin production in immunodeficient mice: enhancement by immunosuppression of host and in vitro activation of human mononuclear cells.

The affect of host and donor related factors on successful engraftment of human cells into mice was examined to minimize the variability that has been observed in successful development of human-mouse chimera for the study of human disease and immune physiology and regulation. Human immunoglobulin production in severe combined immunodeficiency (SCID) mice engrafted with human peripheral blood mononuclear cells (PBMC) was augmented by immunosuppressing recipient mice and activating donor PBMC. Immunosuppression of recipient mice with 3 Gy of gamma-irradiation induced a 10-fold increase in human IgG in the sera of engrafted SCID mice. Variation in production of human IgG in recipient mice correlated with preinjection phenotype and activation status of injected PBMC. Mice injected with PBMC with a low CD4/CD8 ratio (less than 0.5) produced no detectable circulating human immunoglobulin. When the CD4/CD8 ratio was greater than 1.5, human IgG was detected in sera of PBMC-recipient SCID mice. Serum IgG increased 10-fold following in vitro activation of donor PBMC with anti-CD3, IL-2 and Staphylococcus aureus. Successful engraftment and serum IgG production was evidenced by an increase in the recovery of activated human IgG+ cells in the spleens of mice with maximal IgG production. Optimization of functional engraftment required modification of both the host (SCID mice) and the donor cells.

Cryptococcal meningitis in systemic lupus erythematosus.

Two cases of cryptococcal meningitis occurring in patients with systemic lupus erythematosus (SLE) are presented, and 24 additional cases from the literature are reviewed. The insidious onset of this infrequent complication is emphasized. The nonspecific neurological findings associated with this infection are often mistakenly diagnosed as a central nervous system manifestation of SLE. Earlier diagnosis and effective antifungal therapy have improved the prognosis of cryptococcal meningitis in SLE patients in recent years. Strategies for the treatment of patients with this complication are discussed.

Seronegative symmetric polyarthritis in Sezary syndrome.

We describe a patient with Sezary syndrome and seronegative symmetric polyarthritis. Detailed analysis of the synovial membrane, including T lymphocyte subset delineation, demonstrated that malignant synovial infiltration was the direct cause of arthritis in this patient.

Abnormally high level of C4b binding protein and deficiency of free fraction of protein S in a patient with systemic lupus erythematosus and recurrent thromboses.

A patient with systemic lupus erythematosus and numerous thrombotic accidents was found to have a deficiency of the free fraction of protein S, most likely due to an abnormally high level of C4b binding protein. These abnormalities, unique in comparison to 4 other patients with hypercoagulation states, were partially corrected with cyclophosphamide. There was no evidence of a consumption of complement components. The interactions between the hemostasis system and the complement cascade are discussed.

The generation of hybridomas secreting human monoclonal antibodies reactive with type II collagen.

Human monoclonal antibodies reactive with type II collagen were obtained from patients with rheumatoid arthritis and relapsing polychondritis by fusion of cells with the human-mouse myeloma analogue HMMA2.11 TG/0. Direct fusion of peripheral blood or bone marrow mononuclear cells was unsuccessful in obtaining antibody producing hybridomas although fusion efficiency was high (1 hybridoma per 25,400 mononuclear cells fused). Polyclonal, Epstein Barr Virus transformed B cell lines derived from peripheral blood and bone marrow mononuclear cells after direct transformation, in vitro secondary immunization, and/or CD8 depletion were found to produce antibodies that reacted with type II collagen. Antibody producing EBV transformed B cells were fused with the human-mouse myeloma analogue HMMA2.11 TG/0 and six separate, stable IgM antibody producing hybridomas obtained. These results demonstrate the difficulty in obtaining human monoclonal autoantibodies, particularly of IgG isotypes, using readily accessible sources of cells in patients with chronic autoimmune diseases without expansion and preselection.

Urate-mediated inflammation in nodal osteoarthritis: clinical and roentgenographic correlations.

We studied 25 patients with crystal-proven gout or roentgenographic evidence of gouty arthritis, or both, in finger joints involved with nodal osteoarthritis (OA). These patients were elderly (mean age 71.4 years), and 72% of them were receiving diuretic therapy. Roentgenographic findings, in addition to features typical of OA, included soft tissue densities (tophi), with or without calcification, large intraarticular erosions, characteristic nonmarginal cortical erosions, and periarticular osteolysis. We conclude that urate crystals mediate episodes of acute inflammation in certain patients with nodal OA. This association is noted primarily in elderly patients of both sexes, especially in those receiving diuretic therapy.

Severe aortic stenosis in systemic lupus erythematosus and mucopolysaccharidosis type II (Hunter's syndrome).

Cardiac manifestations of the mucopolysaccharidoses often include valvular regurgitation, but stenotic lesions are quite rare. This report describes a 30-year-old man with mucopolysaccharidosis type II (Hunter's syndrome) and systemic lupus erythematosus who developed severe progressive aortic stenosis and died. Autopsy examination revealed evidence of various cardiac mucopolysaccharide disease including valvular leaflets thickened and distorted with fibrocalcific nodules. A brief review of previously reported valvular disease in Hunter's syndrome and other mucopolysaccharidoses is presented. This is also the first report of a patient with both systemic lupus and a mucopolysaccharidosis.

Progressive systemic sclerosis: mode of presentation, rapidly progressive disease course, and mortality based on an analysis of 91 patients.

The overwhelming majority of patients with PSS present with combinations of Raynaud's phenomenon, sclerodactyly, polyarthralgias, or swelling of an extremity. However, the clinical presentation of PSS may be atypical; 14% of patients in the present series initially sought medical attention for symptoms other than Raynaud's phenomenon, tight skin, or joint pain. In the present series, only 31% of patients fulfilled the ARA criteria for PSS at the time of initial medical evaluation. Most patients manifested advanced disease by the time the criteria were fulfilled. The ARA criteria for the classification of PSS appear to have limited value with regard to making the diagnosis in an individual patient. Rapidly progressive PSS occurred in 17.6% of patients in this series and represents a particularly fulminant form of the disease whose course may not be predictable on clinical grounds at the time of initial medical evaluation or diagnosis. Patients destined to develop renal or cardiorespiratory failure usually do so in the first 3 years of disease. Close observation of PSS patients during the first 12 to 18 months may serve to identify those individuals who will undergo an accelerated disease course. Prognosis for patients with rapidly progressive PSS is poor and is associated with significantly higher mortality compared with patients with a more protracted disease course. Future therapeutic trials in PSS should be designed with the recognition that a subgroup of patients with this disorder will have a rapidly progressive disease course.

Successful combined medical and surgical treatment of a lower extremity sclerodermal ulcer.

Combined medical and surgical treatment of a chronic lower extremity ulcer in a patient with systemic scleroderma is described. Recent pharmacological advances including calcium channel blockers, meticulous surgical care, and skin grafting offer promise for more consistent wound closure in sclerodermal skin ulcerations.

Gold lung: recent developments in pathogenesis, diagnosis, and therapy.

Gold lung is a hypersensitivity pneumonitis to gold-containing compounds. It can be distinguished from rheumatoid lung by its subacute or acute onset, diffuse interstitial and/or alveolar filling pattern on chest roentgenogram, presence of lymphocytes on BAL with an inverse helper/suppressor ratio, and response to withdrawal of gold and/or corticosteroid therapy. Other in vitro assays of gold hypersensitivity using peripheral blood lymphocytes are only sporadically positive and, therefore, of limited value in making the diagnosis. Physicians prescribing organic gold compounds should elicit pulmonary complaints throughout the duration of therapy. When patients receiving gold therapy present with signs and symptoms consistent with an acute or subacute hypersensitivity pneumonitis, the gold therapy should be withheld and a diagnostic workup initiated.