Niacinamide as treatment for scleroderma (systemic sclerosis)

Yet another “incurable” disease has been demonstrated to be nothing more but energetic deficiency in disguise. According to mainstream medicine, scleroderma (also known as systemic sclerosis) is an incurable chronic, autoimmune, progressive, fibrotic disease that attacks virtually all organs and can lead to significant disability and even death if it affects some of the more vital organs such as lungs, heart, pancreas, etc. No known treatment for the condition exists, and as such treatment is “supportive” – i.e. mainly glucocorticoids for acute exacerbations, and immunosuppressive drugs for chronic “treatment”. In other words, not much different than other autoimmune conditions such as multiple sclerosis, Lupus, rheumatoid arthritis, psoriasis, etc. Interestingly enough, it has been known for at least 5 decades that the disease has an endotoxin component as a cause since administering TLR4 (endotoxin receptor) antagonists such as ketotifen or Benadryl (diphenhydramine) has been able to cure the disease in some patients and greatly retard its progression in others. The fact that endotoxin has a causative role in this condition should have directed the medical authorities to dig further into the energetic aspect of this disease, but not much has been done in this direction considering that medicine does not believe functional disorders (energetic deficiency) can lead to structural ones (systemic sclerosis). Now, the study below adds more evidence in favor of the crucial role metabolism/energy plays in this disease. It demonstrates that depletion of NAD+ can directly lead to the formation of fibrotic tissue identical to the one seen in humans with the condition. Conversely, alleviating the NAD+ depletion by blocking its consumption (CD38 inhibitor) or providing an NAD+ precursor such as nicotinamide (riboside) can fully prevent the structural lesions associated with the disease. The HED of nicotinamde (riboside) was 30mg/kg and the treatment was administered for just 3 weeks. Just as importantly, the study found that the formation of scars is entirely controlled by energy availability. In other words, the higher the metabolic rate and the higher the energetic production/reserves of the organism, the less scar formation occurs (from any cause). This corroborates Peat’s writings and multiple publications noting that wound healing in young children is scar-less, and this is now known to be due to the much higher metabolic rate of adolescent humans.

“…”We found that scleroderma inflammation dramatically increases CD38, an enzyme that normally breaks down a metabolic nutrient, NAD+. When NAD+ levels decrease, tissue injury becomes chronic and progresses to scar formation rather than to healthy repair,” says study author John Varga, M.D., division chief of rheumatology at Michigan Medicine. According to the study, treatments that prevented NAD+ reduction in the mice, whether by boosting the levels of the nutrient genetically or pharmacologically, prevented scarring in the skin, lungs and abdominal wall. “This is one of the first studies to find a relationship between CD38 and scleroderma, as well as the linking between inflammation and metabolism to skin and organ scarring,” says study author Johann Gudjonsson, M.D. Ph.D., a dermatologist at Michigan Medicine. Boosting NAD+ via the precursor nicotinamide riboside, a safe and inexpensive dietary supplement, prevented skin and other organ scarring, providing the researchers a previously undiscovered pathogenic role of CD38 in scleroderma scarring. “These results open the door to entirely novel treatments for fibrosis and scleroderma. Using precision medicine, these treatments could be selectively targeted to block CD38 in scleroderma patients who have elevated CD38,” says study author Bo Shi, Ph.D., a research assistant professor of dermatology at Northwestern Medicine. The research findings also create possibilities for restoring levels of NAD+ using pre-existing drugs, or well tolerated dietary supplements. Both of these therapeutic approaches are entirely novel strategies to halt scleroderma’s most debilitating side effect.”

“…In view of the substantial fibrosis protection accompanied by a rise of NAD+ levels that was noted in mice lacking CD38, the principal NAD+-consuming enzyme, we sought to determine if organismal NAD+ boosting by either selectively blocking its CD38-mediated hydrolysis and/or by NAD+ precursor supplementation will mitigate fibrosis. To this end, 18-month-old female mice maintained for 2 weeks on either standard chow diet or chow supplemented with nicotinamide riboside (NR, 3 g/kg chow) were treated with a thiazoloquin(az)olin(on)e compound 78c selective for the CD38 NADase (). Treatment with 78c (30 mg/kg weight) administered by daily oral gavage was initiated concomitantly with a two-week course of daily subcutaneous bleomycin injections, and mice remained on NR-supplemented chow diet and continued daily 78c gavage until sacrifice at day 21 (Figure 3A). On standard chow diet, mice treated with bleomycin suffered significant weight loss (maximal 40% at day 11), which however was substantially attenuated in mice on an NR-supplemented chow diet combined with the CD38 inhibitor 78c (Figure 3B). Dietary NR supplementation by itself, or combined with 78c treatment, resulted in a ∼5-fold increase in skin NAD+ levels compared to mice treated with bleomycin only (Figure 3E). Notably, boosting NAD+ in bleomycin-treated mice resulted in significantly improved skin fibrosis, including attenuated increase in dermal thickness, skin collagen content, and fibrotic gene expression, as well as the number of ASMA (alpha smooth muscle actin)-positive myofibroblasts in the lesional dermis (Figures 3C, 3D, 3F, 3G, S4A and S4B). In the skin, the anti-fibrotic efficacy of supplementation with NR was greater compared to the efficacy of CD38 inhibitor treatment. This differential response might reflect limited tissue penetration of the CD38 inhibitor. The expansion of the fibrotic dermis was inversely correlated with tissue levels of NAD+, directly linking NAD+ boosting in the anti-fibrotic effect (Figure 3E). Strikingly, NAD+ boosting by either NR supplementation or via CD38 inhibition also afforded mice robust protection from pulmonary fibrosis, with significantly ameliorated radiological and histological fibrotic changes in the lungs coupled with reduced collagen accumulation and fibrotic gene expression (Figures 3C and 3H–3K). Monocytes and macrophages are thought to play an important role in the pathogenesis of organ fibrosis in SSc and in mouse models of the disease (). Significant accumulation of macrophages in both the dermis and the lungs from bleomycin-treated mice was mitigated with NAD+ boosting via treatment of mice with CD38 inhibitor or NR supplementation alone or in combination (Figure S5A and S5B). In particular, the combination treatment markedly attenuated the accumulation of CD11b + macrophages in the skin (Figure S5C) and CD64+CD11b+Sigleclow (myeloid derived) infiltrating macrophages in the lung, while having no significant effect on CD64+CD11b+Siglechigh (tissue resident) macrophages (Figure S5D). In view of the pivotal role that macrophages and other myeloid-derived leukocytes play in SSc pathogenesis (), the decrease in macrophage accumulation observed in mice with NAD+ boosting might contribute to the anti-fibrotic effect of this intervention.”