Despite better awareness, curative treatments remain elusive in IgG4 disease
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Despite strong biomarkers and an improved understanding of the many systems involved in IgG4 disease, no curative therapy exists, according to a speaker at the virtual American College of Rheumatology State-of-the-Art Clinical Symposium.
The two major subtypes of IgG4 disease are proliferative and fibrotic, according to John H. Stone, MD, MPH, the Edward A. Fox chair in medicine at Massachusetts General Hospital. “This is a useful way of thinking about this disease,” he said in his presentation.
Proliferative disease is marked by multi-organ involvement. It is serologically active, with classic pathological features. “Response to treatment with immunosuppressive therapy is excellent,” Stone said.
Patients with fibrotic disease do not have atopy in the retroperitoneum, according to Stone. “These patients typically do not have elevated serum IgG4 concentrations,” he said. “The pathology can show classic IgG4 disease, but the tissue is fibrotic, and they typically do not respond to treatment.”
Stone covered biomarkers in the context of treatment, organ damage that can occur in IgG4 disease and ongoing clinical trials of novel therapies.
While every patient can be different, Stone offered details of a case patient to demonstrate how comprehensive IgG4 disease can be.
The patient had enlarged parotid, sublingual and submandibular glands, evidence of disease in the pancreas and the biliary system, lesions the kidneys and lung involvement. The patient’s pituitary gland was impacted, along with his prostate. “The combination of pancreatic and biliary involvement is diagnostic of IgG4 disease,” Stone said.
Albumin was low in this patient, while globulin fraction and C4 were very high. “Complement levels were so low as to resemble lupus nephritis,” Stone said. “The patient had been slowly dying for 3 years.”
The patient had obliterative phlebitis and extranodal germinal centers. “We observed consistent histopathology across all organs affected by IgG4 disease,” Stone said, noting that this is a hallmark of the condition.
Stone suggested that an anti-CD19 antibody would be most effective in such a patient, but that no such therapy was available in 2012, the time of this description. However, the patient was treated with the anti-CD20 drug rituximab (Rituxan, Genentech). “A month later, he was substantially improved,” he said. “‘Resurrected’ — that was the patient’s term.”
This brought the discussion to biomarkers. “We are fortunate to have a good biomarker in this disease for many patients,” Stone said, noting that IgG4 is elevated in 75% of patients. “The higher it is, the more reliable it is as a biomarker.”
Moreover, ongoing elevation of IgG4 after treatment should raise the issue of retreatment, according to Stone.
As for other indicators, Stone noted that patients with IgG4 related retroperitoneal fibrosis do not have elevated IgG4. In addition, erythrocyte sedimentation rate may be elevated, while C-reactive protein may be low. “There is a dissociation there,” Stone said.
IgG1 may be slightly elevated, as may IgE, particularly in patients with kidney disease. Eosinophilia in the periphery may also occur. “All of these are reasonable biomarkers,” Stone said.
Regarding duration of treatment response, Stone suggested that this can be “quite variable.” While both prednisone and rituximab can put patients into prolonged remission, retreatment with rituximab may be necessary.
Patients worldwide are often started on a prednisone dose of 40 mg per day. Clinicians in Asia will taper this down to a dose of 5 mg to 10 mg per day, while clinicians in Europe and North America are likely to taper patients off steroids, albeit at the peril of relapse risk.
“We have no treatment that cures IgG4 disease,” Stone said.
The damage caused by IgG4 disease is “an important topic,” according to Stone. “The pancreas is usually the hardest hit,” he said, noting that it can become small and scarred, and that patients often become diabetic.
Amylase and lipase often are reduced, while renal failure may also occur, as may liver failure from biliary tract disease.
As for current clinical trials, the first large international clinical trial for the anti-CD19 therapy inebilizumab (Uplizna, Viela Bio) is currently enrolling. “We think this will be the first successful clinical trial in IgG4 disease,” Stone said.
Elotuzumab (Empliciti, Bristol Myers Squibb) is a SLAMF7 CD319 therapy also currently under investigation, while a second approach targeting B cells using rilzabrutinib (Sanofi), is moving through clinical trials.
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Stone JH. IgG4. Presented at: American College of Rheumatology State-of-the-Art Clinical Symposium. April 9-11, 2021 (virtual meeting).
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