Common rheumatoid arthritis treatment may be effective in treating immunoglobulin G4-related disease

IgG4-related disease is a recently-recognized multi-organ disease that mimics numerous rheumatologic conditions and other disorders and can affect nearly every organ in the body. The most common rheumatologic conditions mimicked by IgG4-RD are Sjögren's syndrome, granulomatosis with polyangiitis, systemic lupus erythematosus, and sarcoidosis. However, IgG4-RD can also mimic infections and malignancies, particularly lymphoma and pancreatic, renal or lung carcinoma. Although IgG4-RD was identified as a unified disease entity only within the past ten years, review of medical history has unearthed classic descriptions of patients published as early as the 1800s. It is likely that IgG4-RD is considerably older even than this. IgG4-RD is now known to link well over a dozen disease entities that were formerly regarded as single-organ conditions.

To determine if rituximab might be a successful treatment for IgG4-RD, a team of researchers recently tested the drug in 29 patients with the disease at Massachusetts General Hospital and the Mayo Clinic.

"New therapeutic strategies are required in IgG4-RD," notes Principal Investigator, John Stone, MD from the Massachusetts General Hospital, because it has become "abundantly clear in the last few years that glucocorticoids, the only other treatment believed to be effective in many cases, do not cure IgG4-RD or lead to longstanding disease remissions in most cases." In addition, preliminary investigations at the Massachusetts General Hospital by Dr. Stone's group demonstrated swift responses in IgG4-RD patients whose disease had been refractory to prednisone. Even more interesting was the targeted effect of B cell depletion: rituximab-treated patients demonstrated swift declines in the serum concentrations of IgG4 - but not in the concentrations of other immunoglobulin subclasses. These early intriguing findings led to the current trial.

All of the participants in the study had IgG4-RD (confirmed by a pathologist), including at least two of the major microscopic features of the disease. In addition, none of the participants were in remission at the beginning of the study.

The participants in the study had various organ systems affected by the disease, including the orbits, salivary glands, hypopharynx, lungs, lymph nodes, pericardium, pancreas, biliary tract, retroperitoneum, kidneys, and prostate. Based on the IgG4-RD Responder Index (a tool used to rate disease activity), the average score at the beginning of the study was 12.7. Additionally, the average serum IgG4 concentration was 534 mg/DL (compared to a normal rating of less than 121 mg/DL), but 12 participants had normal serum concentrations of IgG4 at the beginning of the study. The finding of normal serum IgG4 concentrations in the blood is not unusual, according to Dr. Stone, who observes that the key disease hallmarks are found within the tissues of involved organs.

The participants were treated with 1,000mg of rituximab at the beginning of the study and again at day 15, but none of the participants were treated with maintenance rituximab after day 15. The participants received 100mg of methylprednisolone (a steroid) with each rituximab treatment, as per the recommended infusion protocol. Only two of the participants were treated with prednisone in addition to rituximab, but the protocol called for rapid tapers of this concomitant medication by patients in the trial.

Each of the patients checked in for follow up at one, three, five, six, eight, 10 and 12 months after receiving their first dose of rituximab. During these visits, the researchers were looking at three main things: 1) how the disease responded to the treatment - specifically if it became less active; 2) If the participants had no disease flares before month six of the study; and 3) if participants had no need for steriods between the second and sixth months of the study. Patients meeting these three measurements met the primary outcome. Secondarily, the team was looking for disease remission, which was defined as having a disease activity score of zero.

Twenty-six of the patients followed for at least one month - and 22 of 24 of the patients followed for three months - achieved a decrease in disease activity without the use of steroids. Among the 23 participants who completed six months of follow up to date, 20 have achieved the three conditions of the primary outcome postulated by the researchers.

Only two of the 28 participants required an increase in prednisone after the first month of the study. Two participants were hospitalized during the study: one for Legionnaire's disease (which the participant had before the beginning of the study) and the other for a cold agglutinin-mediated autoimmune hemolytic anemia. Dr. Stone's team did not note any serious, unexpected side effects attributable to rituximab.

"The results of this trial mark an important step forward for patients with this disease and raise fascinating questions for future investigation," Dr. Stone says. "First, rituximab appears to offer an important new approach to therapy in patients with IgG4-RD, who would otherwise be consigned to lengthy or indefinite courses of steroids often combined with other potentially toxic medications of dubious value. Confirming these findings in a larger, randomized trial is important. Second, mechanistic studies on samples from IgG4-RD patients treated with rituximab may offer important insights about the pathophysiology of IgG4-RD, the mechanism of action of rituximab in this condition (and certainly others, as well), and the nuanced mechanisms of the human immune system."

Patients should talk to their rheumatologists to determine their best course of treatment.