Brian L. Kotzin

Treatment of Intractable Rheumatoid Arthritis with Total Lymphoid Irradiation

Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation (total dose, 2000 rad) in an uncontrolled feasibility study, as an alternative to long-term therapy with cytotoxic drugs such as cyclophosphamide and azathioprine. During a follow-up period of five to 18 months after total lymphoid irradiation, there was a profound and sustained suppression of the absolute lymphocyte count and in vitro lymphocyte function, as well as an increase in the ratio of Leu-2 (suppressor/cytotoxic) to Leu-3 (helper) T cells in the blood. Persistent circulating suppressor cells of the mixed leukocyte response and of pokeweek mitogen-induced immunoglobulin secretion developed in most patients. In nine of the 11 patients, these changes in immune status were associated with relief of joint tenderness and swelling and with improvement in function scores. Maximum improvement occurred approximately six months after irradiation and continued for the remainder of the observation period. Few severe or chronic side effects were associated with the radiotherapy.

Treatment of Intractable Lupus Nephritis with Total Lymphoid Irradiation

Ten patients with lupus nephritis and marked proteinuria (3.9 g or more/d) that did not respond adequately to treatment with prednisone alone or prednisone in combination with azathioprine were treated with total lymphoid irradiation in an uncontrolled feasibility study. Within 6 weeks after the start of total lymphoid irradiation, the serum albumin level rose in all patients in association with a reduction in the serum level of anti-DNA antibodies, an increase in the serum complement level, or both. Improvement in these variables persisted in eight patients followed for more than 1 year, with the stabilization or reduction of the serum creatinine level. Urinary leakage of albumin was substantially reduced in all patients. Side effects associated with radiotherapy included transient constitutional complaints in ten patients, transient blood element depressions in three, localized viral and bacterial infections in four, and ovarian failure in one. The results suggest that total lymphoid irradiation may provide an alternative to cytotoxic drugs in the treatment of lupus nephritis.

Efficacy of total lymphoid irradiation in intractable rheumatoid arthritis. A double-blind, randomized trial.

Twenty-six patients participated in a randomized, double-blind study of the efficacy of total lymphoid irradiation in the treatment of intractable rheumatoid arthritis. All 26 patients, for whom therapy with gold compounds and penicillamine had failed, would ordinarily have been considered candidates for cytotoxic or antimetabolite drug therapy. Thirteen patients randomly assigned to receive full-dose total lymphoid irradiation (2000 rad) and 11 patients assigned to receive control low-dose total lymphoid irradiation (200 rad) completed radiotherapy. Alleviation of joint disease activity was significantly greater in the high-dose group as judged by morning stiffness, joint tenderness, and functional assessment (global composite score) at 3 and 6 months after radiotherapy. The high-dose group had a marked reduction in both T-lymphocyte function and numbers, but this finding was not observed in the low-dose group. Complications seen in the high-dose but not low-dose group included transient neutropenia, thrombocytopenia, pericarditis, and pleurisy.

Changes in T-cell subsets in patients with rheumatoid arthritis treated with total lymphoid irradiation

Patients with intractable rheumatoid arthritis (RA) were treated with total lymphoid irradiation (TLI, 2000 rads). We previously reported long-lasting clinical improvement associated with marked suppression of in vitro lymphocyte function in this group. In an attempt to better understand the mechanism of immunosuppression and clinical changes observed after TLI, we studied in greater detail changes in peripheral blood T-cell subsets identified by monoclonal antibodies. Before TLI, RA patients had a higher percentage of Leu-3 (helper subset) cells and a lower percentage of Leu-2 (suppressor/cytotoxic subset) cells than normals. Immediately after TLI, the absolute numbers of both Leu-2 and Leu-3 cells were reduced by at least 90%. Within 6-12 weeks, the number of Leu-2 cells returned to the pretreatment levels, but the levels of Leu-3 cells remained depressed for months thereafter. The lack of repopulation of Leu-3 cells resulted in a marked increase in the ratio of Leu-2 to Leu-3 cells as compared to pretreatment values (1.73 +/- 0.23 vs 0.39 +/- 0.06), and in a decrease in the percentage and absolute number of total T (Leu-1 and Leu-4) cells. The failure of Leu-3 cells (which mediate predominantly helper/inducer functions) to repopulate the peripheral blood may contribute to the prolonged clinical immunosuppression observed after TLI. Similar changes in T-cell subsets were not observed in RA patients given remittive drugs or low doses (200 rads) of radiotherapy. Thus, TLI differs from other treatment modalities with regard to its prolonged selective effect on the Leu-3 subset.

The treatment of intractable rheumatoid arthritis with lymphoid irradiation

Abstract Subdisphragmatic lymphoid radiation was used as an alternative to cytotoxic drug therapy to treat six patients with progressive erosive rheumatoid arthritis. All were previously unresponsive to conventional therapy. Radiation (4,000 rad) was given to subdispbragmatic lymphoid tissues in fractionated doses of 150–250 rod each. Three of the six patients demonstrated long-lasting clinical improvement with a decrease in synovitis and morning stiffness and an increase in joint function. All six patients showed a profound depression in the peripheral blood lymphocyte count which persisted for at least six months. The irradiation was well tolerated; there have been no serious complications due to radiotherapy with follow-up ranging from 13 to 36 months. The substantial efficacy in some patients and the lack of severe toxicity in all suggests that radiotherapy deserves further study as an alternative to cytotoxic drugs in the treatment of rheumatoid arthritis.

Treatment of Autoimmune Disease with Total Lymphoid Irradiation Cellular and Humoral Mechanisms

The rationale for using total lymphoid irradiation (TLI) as an immunosuppressive treatment originated from studies of patients with lymphoid malignancies. TLI has been an accepted form of therapy for Hodgkins disease and non-Hodgkins lymphoma for over 15 years. This radiotherapy regimen induced profound immunologic abnormalities in these patients; however, it has proven to be relatively safe and well tolerated with few long-term side effects. More recent studies in both experimental animals and humans have further documented the profound long-lasting immunosuppression and relative lack of toxicity. We review here the development of TLI as an immunosuppressive treatment in autoimmune disease.

Total Lymphoid Irradiation

Total lymphoid irradiation (TLI) has become a useful tool for developing strategies to induce tissue specific transplantation tolerance and to treat autoimmune diseases in laboratory animals and humans. TLI was originally developed as a treatment for Hodgkin’s disease, and has been widely used during the past 20 years. Approximately 90% of patients with early stages of the disease are cured after TLI (1). Extensive follow-up observations of more than 1,000 patients in remission for up to 10 years have shown that there is no increased risk of hematologic malignancy or non-Hodgkin’s lymphoma after treatment with TLI alone (2–4). The incidence of severe complications with TLI, including bacterial infection, is approximately 1% (1).

Treatment of intractable rheumatoid arthritis with total lymphoid irradiation (TLI): immunological and clinical changes

Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation in a feasibility study. The mantle and the inverted Y fields were treated successively to a cumulative dose of 2000 rads. Nine of eleven patients showed at least a 35% improvement in three of four clinical parameters by six months and continued to maintain at least this level of improvement at their last observation points (13-28 months after TLI). There was a marked decrease in the percentage of total T cells and Leu-3 cells (helper), but an increase in the percentage of Leu-2 cells (suppressor/cytotoxic), resulting in a dramatic increase in the Leu-2/Leu-3 ratio. There was also a decrease in response to PHA, Con A and MLR.

Coronavirus SD-Induced Immunoregulatory Disturbances in a Murine Model of Demyelination

We previously reported the isolation of coronaviruses while working with autopsy tissue from patients with multiple sclerosis1 and have been investigating the pathogenesis of these viruses in mice. Inoculation of three to four week old C57BL/6 mice with coronavirus SD induces a syndrome characterized by hindlimb anesthesia, paresis, or both between 4 and 9 days post-infection.2 We now report the finding of an unusual immunologic derangement in these mice.

Use of Total Lymphoid Irradiation in Organ Transplantation

In the course of investigating the cellular basis of the immunodeficiency of patients with Hodgkin’s disease, we examined the number and function of T lymphocytes in the peripheral blood before and after treatment with total lymphoid irradiation (TLI).(1) Treated patients received a total of 4400 rads to the lymph nodes, thymus, and spleen (if not removed previously), in fractions of 200–250 rads to the subdiaphragmatic tissues. A similar schedule of radiation was given subsequently to the supradiaphragmatic tissues. The skull, lungs, kidneys, pelvis, and long bones were shielded with lead.