Investment Thesis Of Forty Seven – Forty Seven (NASDAQ:FTSV)

Investment Thesis Of Forty Seven – Forty Seven (NASDAQ:FTSV)

<h1>Investment Thesis Of Forty Seven – Forty Seven (NASDAQ:FTSV)</h1>

Investment Thesis Of Forty Seven – Forty Seven (NASDAQ:FTSV)

C ompany overview Forty Seven, Inc. ( FTSV ) is a clinical stage biotech company headquartered in Menlo Park, CA. This company completed its IPO in June 2018 by raising $116 million with price of $16.00 per share. The company is focusing on immune-therapy field by developing novel checkpoint inhibitor to activate macrophages in the fight against cancer. The company’s lead program is a monoclonal antibody, Fu5F9 (5F9), targeting the receptor of Cluster of Differentiation 47 (CD47) which is over-expressed on many cancer cells, rendering tumor susceptible to macrophages. There are six ongoing clinical trials relating to the key asset, 5F9, and we do expect they will be the major catalyst in the next 12-18 months. The current clinical trials were based on the positive preclinical and clinical proof-of-concept data generated in the last few years. Below is the summary for those clinical trials and expected milestones.
Exhibit 1. FTSV Pipeline as of Oct. 2018
Source: company presentation
Exhibit 2. Milestones expected in the next 12-18 months
Product
Upcoming Milestone Event
Time
Estimated Impact
5F9
Phase 1b Ovarian expansion results
H1 2019
High
5F9 + Azacitidine
Phase 1b AML results
H1 2019
Medium
5F9 + Rituximab
Phase 2 NHL results
H1 2019
High
5F9 + Cetuximab
Phase 2 CRC results
H1 2019
High
5F9 + Avelumab
Phase 1b Ovarian results
H2 2019
High
5F9 + Atezolizumab
Phase 1b Bladder results
H2 2019
Medium
5F9 + Atezolizumab
Phase 1b AML results
H2 2019
Medium
AML: Acute myeloid leukemia; NHL: Non-Hodgkin’s lymphoma; CRC: colorectal cancer.
Source: data compiled by author
I nvestment overview Our bullish view on FTSV is based on the following factors: 1) promising clinical results in several cancer types including both hematological and solid tumors by showing proof-of-concept of utilizing macrophage for cancer treatment; 2) the company established a leading position in the field of targeting CD47 for cancer treatment by leveraging the powder of macrophage and the unique orthogonal approach for the combination therapy; 3) significant market for both hematological and solid tumors.
Scientific rationale for applying anti-CD47 antibody in the cancer treatment is derived from the following hypothesis. CD47 is a “don’t eat me” signaling protein over-expressed on many types of cancer cells. Cancer cells over-expressing CD47 can escape from macrophages’ phagocytosis process. By blocking CD47, those cancer cells are more vulnerable to the attacks from macrophages, which is the first response in human’s innate immune system.
Exhibit 3. The mechanism of Anti-CD47 in regulating macrophage’s phagocytosis for cancer treatment
Source: company presentation
In addition to the single agent activity from blocking CD47, we do expect there is a synergistic effect by combining anti-CD47 and PD-L1 or other therapies (e.g., Azacitidine, Rituximab, Cetuximab) together. By removing “don’t eat me” signaling, macrophage could engulf and digest cancer cells, which may potentially enhance T cell response which is the main force to kill cancer cells in the current understanding. These mechanisms have been demonstrated in preclinical model as well as some preliminary clinical studies.
Exhibit 4. Preclinical evidence on the synergistic effect of 5F9 and other therapies in AML and NHL
Source: Company S-1 document & presentation
Expression levels of CD47 across different tumor tissues are shown below. It is worth to note that ovarian cancer tissues show the highest expression at both RNA and protein levels across different cancers. It provides a good rationale to test the effect of 5F9 in ovarian cancer first. Colorectal cancer tissues also show decent expression of CD47 receptor, which suggests a reasonable chance to see the benefit in these two indications. The applications of 5F9 alone or combination therapy on these two indications are being tested in the clinical trials.
Exhibit 5. RNA expression of CD47 expressed in different solid tumors
Exhibit 6. Protein expression of CD47 expressed in different solid tumors
Source
P romising efficacy observed in some early-stage clinical trials 1) Impressive data from the combo of 5F9 and Rituximab in NHL
Key takeaway: The Phase 1 data showed promising efficacy results from the combo of 5F9 and Rituximab as listed below. The Phase 1 results showed that the combo has an ORR of 70% (40% complete response (CR)) for the treatment of relapsed or refractory Follicular lymphoma. Similarly, an ORR of 35% (30% CR) was observed for an aggressive NHL, diffuse large B cell lymphoma (DLBCL).
Exhibit 7. Response rates from Combo of 5F9 and Rituximab for NHL
Source: company presentation
Some historical data and the recent results released from a competitor targeting CD47 (TTI-621) could provide some context to better understand this positive result.
Exhibit 8. Response rates comparison from different clinical trials
Product
FL
DLBCL
NHL
Reference
5F9 + Rituximab
70% ORR (40% CR)
35% ORR (30% CR)
47% ORR (33% CR)
Company presentation
Rituximab alone
40% ORR (11% CR)
N/A
N/A
Davis, et al, JCO, 2000
Rituximab + chemo
N/A
26% ORR (7% CR)
N/A
Crump et al., Blood, 2017
TTI-621 + Rituximab
N/A
25% ORR (4% CR)
29% ORR (3% CR)
Trillium Therapeutics presentation
Source: data compiled by author
The current data compared favorably against the historical ORR data that re-treatment of rituximab alone on low-grade NHL or Follicular lymphoma patients who relapsed after a response to Rituximab therapy, which is 40% (11% CR). The large difference of 70% vs. 40% ORR and 40% CR vs. 11% CR indicates that adding 5F9 could provide additional benefits than Rituximab alone.
A pooled retrospective analysis to characterize response rates for refractory DLBCL after salvage therapy (combination of rituximab with chemotherapy) showed an ORR of 26% (7% of CR). The current data illustrates an advantage in terms of higher CR (30% vs. 7%) and the combination of 5F9/Rituximab provides an alternative approach without chemotherapy which may be very important to patients who cannot tolerate chemotherapy.
The data released from Trillium on Sept. 28, 2018, further strengthen the leader position for 5F9 as the combination of TTI-621 and Rituximab showed an ORR of 25% (4% CR) for DLBCL, which is lower than 35% of ORR (30% CR) achieved by 5F9 and Rituximab in the same indication.
Exhibit 9. Response rates from TTI-621 + Rituximab for NHL
Source: Trillium therapeutics presentation
In addition to the superiority of ORR, the combo of 5F9 and Rituximab also showed durable response as below. Two DLBCL patients improved their response: from SD to CR and PR to CR. The median duration of response not reached in either cohort with longest patient in CR for over 14 months. It is worth to note the response rate for NHL is based on the Lugano criteria, and the Lugano criteria are different from RECIST 1.1 which is used for solid tumors (just a reminder in case any confusion why some CR lines look like SD from RECIST perspective).
Exhibit 10. Durable responses observed in DLBCL and FL patients
Source: company presentation
Although, we note a relatively small number of patients (30 patients) were tested in this open-label study. The above analyses demonstrate the superiority of 5F9 in NHL and warrant further evaluation in a large clinical trial.
2) Demonstrated monotherapy activity for ovarian cancer
Key takeaway: 10% of ORR (2 out 21 in heavily pre-treated patients) was observed for the monotherapy of 5F9 in ovarian cancer. Both were heavily pre-treated patients failing seven or more previous treatment regimens. One of these patients had a durable partial response of more than six months in duration. Although the face value of ORR itself does not look impressive, it is very important to understand 5F9 is capable to show efficacy in heavily pre-treated ovarian cancer patients as monotherapy. It demonstrates that macrophage, this innate immune system, is possible to destroy cancer cells which have over-expression of CD47. It further sets up a good foundation for the future combo study with a PD-L1 agent, Bavencio (avelumab) to further test its synergistic effect.
Exhibit 11. Response rates of 5F9 monotherapy for ovarian cancer
Source: Company S-1 document
3) Unclear role of 5F9 from the combo of 5F9 + Cetuximab in colorectal cancer
Key takeaway: 9% of ORR was observed from the combo of 5F9 + Cetuximab in the relapsed and refractory CRC patients. However, it is difficult to decouple the efficacy of 5F9 from cetuximab given cetuximab itself could produce 12% ORR in patients who had exhausted all available treatment options for metastatic colorectal cancer ( Leiz, et al., ASCO, 2003 ). In addition, we noticed that these two patients are KRAS wild type which is susceptible to cetuximab treatment. Given the totality of this data, it is unclear whether 5F9 could provide additional benefit in this combo compared to Cetuximab alone.
Exhibit 12. Response rates of 5F9 + Cetuximab for colorectal cancer
Source: Company S-1 document
Good safety and tolerability for 5F9 5F9 is safe and generally well-tolerated in high doses. The most common adverse effects were CD47-mechanism-based effects such as anemia. Other reported adverse events include headache, fatigue, pyrexia, chills, and nausea. No consistent adverse events were observed at high exposure. More than 190 patients have been treated and no MTD was reached with dose escalation up to 45 mg/kg.
Exhibit 13. Adverse events from 5F9 in the dose escalation study
Source: company presentation
Due to high expression of CD47 in aged red blood cells, 5F9 brings the adverse effect of anemia. In order to solve this problem, the company designed a proprietary dosing regimen into the clinical trials in which clinicians administer a priming dose of 1 mg/kg of 5F9 that is sufficient to eliminate the aged red blood cells and trigger the process of reticulocytosis. This priming dose enables a much higher dose in subsequent weeks that do not cause further reduction of red blood cells. The priming dose was optimized and 1 mg/kg of 5F9 was finalized due to 90% blockage of CD47 on red blood cells without drug-limiting toxicity.
Exhibit 14. Manageable anemia by a proprietary dosing regimen
Source: Company S-1 document
M arket estimation of 5F9 for leading indications 1) Relapsed/Refractory diffuse large B-cell lymphoma (R/R DLBCL)
Exhibit 15. Current therapy for Relapsed/Refractory diffuse large B-cell lymphoma (R/R DLBCL)
Product/Company
Target
Efficacy
Status
Line of treatment
Delivery/dosing frequency
Yescarta/Gilead (NASDAQ: GILD ) (Kite)
CAR-T (CD19)
ORR: 73%; CR:52%
Approved in Oct. 2017
3rd line +
IV infusion
Kymriah/Novartis (NYSE: NVS )
CAR-T (CD19)
ORR: 59%; CR:14%
Approved in April 2018
3rd line +
IV infusion
CAR017/Celgene (NASDAQ: CELG ) (Juno)
CAR-T (CD19)
ORR: 80%; CR:55%
Expected approval in 2019
3rd line +
IV infusion
Rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)
CD20 + Chemotherapy
ORR: 26%; CR:7%
SOC for salvage therapy
2nd line +
SC and IV
Source: data compiled by author
Although 5F9 showed a better response rate compared to the traditional salvage therapy (Rituximab + chemo), the recent approval of CAR-T (CD19) products provides superior ORR compared to 5F9 for DLBCL. CAR017, another CAR-T product from Celgene is expected to be approved by 2019. With three CAR-T products in the market, it will be a tough competition for 5F9 in DLBCL. However, we do see some differentiation of 5F9 from CAR-T products: 1) CAR-T products require extracting T cells from patients and modifying the T cell ex-vivo. It may take up to 22 days turnaround before infusion back to patients; 2) potentially serious and rarely fatal side effects; 3) high cost.
Based on the estimation of incidence, there are 18,150, 27,500, and 7,150 new patients diagnosed with DLBCL annually in the US, EU, and Japan, respectively. R/R DLBCL accounts for approximately one-third of patients with DLBCL. For patients eligible for stem cell transplant (SCT), SCT is the first choice and typically there are 50% of patients who do not qualify for SCT due to various reasons. After SCT procedure, around 50% of those patients will have progressive disease, eventually. Given the competitive landscape but unique mechanism of 5F9 mentioned above, we estimate 5F9 will reach 20% of market share in this indication at peak sale. We also project 5F9 will be approved as early as end of 2021 due to fast-track designation. It might only need one pivotal study starting in 2019/2020 as long as the efficacy could repeat in a large clinical trial. Other CAR-T products got approved in a similar manner. The net price after discount in the US and EU are $120K and 80K, respectively, which is in line with the current treatment cost. Based on the current promising data, we assign 25% of POS for this drug getting approval.
Without appropriate treatment, the lifespan for R/R DLBCL is less than one year; therefore, we use the incidence of DLBCL for the revenue model.
Exhibit 16. Market model for R/R DLBCL
Market model for R/R DLBCL
US
EU
Japan
Incidence of DLBCL
0.000055
0.000055
0.000055
Population
330 million
500 million
130 million
DLBCL patients
18150
27500
7150
R/R DLBCL %
33%
33%
33%
R/R DLBCL patients
5990
9075
2360
% of ineligible for SCT, relapse after SCT
75%
75%
75%
Patients eligible for 5F9
4492
6806
1770
Market share
20%
20%
20%
Patients treated
898
1361
354
Net price ($)
120000
80000
80000
Revenue ($)
107 million
109 million
28 million
Total revenue ($)
245 million
POS %
25%
Risk-adjusted revenue ($)
61 million
Source: market model estimated by author. Ref: Incidence ; R/R DLBCL %: ( Raut et al., 2014 ); % of ineligible for SCT, relapse after SCT: ( Vose et al., Blood, 1992 )
2) Relapsed/Refractory follicular lymphoma (R/R FL)
The market of Relapsed/Refractory follicular lymphoma is also crowded with a few PI3K medicines approved in the last few years. However, we think the advantage of 5F9 in terms of high ORR and CR will position it well in this competitive market. If the favorable CR % could maintain in a large clinical trial later, we predict a 30% of market share for this indication at peak sale. Given 70% ORR observed so far, we assign 35% of POS for this indication getting approval.
Exhibit 17. Current therapy for Relapsed/Refractory follicular lymphoma (R/R FL)
Product/Company
Target
Efficacy
Status
Line of treatment
Delivery/dosing frequency
Duvelisib/Verastem (NASDAQ: VSTM )
Phosphatidylinositol-3-kinase (PI3K)
ORR: 43%; CR:1%
Approved in Sept. 2018
3rd line +
capsule/twice daily
Aliqopa/Bayer ( OTCPK:BAYZF )
PI3K
ORR: 59%; CR:14%
Approved in Sept. 2017
3rd line +
IV infusion/weekly for 28-day cycle
Zydelig/Gilead
PI3K
ORR: 54%; CR:8%
Approved in July 2014
3rd line +
tablet/twice daily
Source: data compiled by author
Exhibit 18. Market model for R/R FL
Market model for FL
US
EU
Japan
Incidence of FL
0.000026
0.000026
0.000026
Population
330 million
500 million
130 million
FL patients
8580
13000
3380
R/R FL %
20%
20%
20%
R/R FL % patients
1716
2600
676
Market share %
30%
30%
30%
Patients treated
515
780
203
Net price ($)
120000
80000
80000
Revenue ($)
62 million
62 million
16 million
Total revenue ($)
140 million
POS %
35%
Risk-adjusted revenue
50 million
Source: market model estimated by author. Ref: ( Incidence ); R/R FL % 🙁 Ref ).
3) Recurrent ovarian cancer
Other than traditional chemo and hormone therapies for the treatment of ovarian cancer, target therapy becomes mainstay for recurrent ovarian cancer in recent years including several PARP inhibitors. We estimate 5F9 could be used as a 3rd/4th line of treatment for recurrent ovarian cancer and reach 30% market of share at peak sale (12% of total recurrent ovarian cancer patients).
Exhibit 19. Current agents (target therapy) for recurrent ovarian cancer
Product/Company
Target
Status
Line of treatment
Delivery/dosing frequency
Lynparza/ AZN
PARP
approved in 2014
3/4 line for recurrent ovarian cancer
oral/twice daily
Zejula/Tesaro (NASDAQ: TSRO )
PARP
approved in 2017
3/4 line for recurrent ovarian cancer
oral/once daily
Rubraca/Clovis (NASDAQ: CLVS )
PARP
approved in 2016
3/4 line for recurrent ovarian cancer
oral/twice daily
Source: data compiled by author
The current average duration of survival after recurrence of ovarian cancer is about 12 to 18 months with traditional chemotherapy. With new target therapy, like PARP, we do expect an increase of survival for a few months. Here we are assuming a mean duration of treatment for 1.5 years for recurrent ovarian cancer.
Exhibit 20. Market model for Recurrent OC
Market model for Recurrent OC
US
EU
Japan
Incidence of OC
0.000116
0.000116
0.000116
Women population
165 million
250 million
65 million
OC patients
19140
29000
7540
Recurrent %
70%
70%
70%
Recurrent OC patients
13398
20300
5278
% 3rd line +
40%
40%
40%
Patients eligible for 5F9
5359
8120
2111
Market share % in 3rd line +
30%
30%
30%
Patients treated
1608
2436
633
Net price ($)
120000
80000
80000
Revenue ($)
289 million
292 million
76 million
Total revenue ($)
658 million
POS %
25%
Risk-adjusted revenue
164 million
Source: data compiled by author. Ref: Incidence
4) Advanced colorectal cancer
Given the large market for colorectal cancer, we think this indication could provide significant upside if the ongoing trial shows positive results in 2019. We only assign 10% of POS for this indication based on the current results which did not provide a conclusive evidence for 5F9 in the treatment of CRC. We project it will reach 15% of market at peak sale.
Exhibit 21. Current therapy for advanced colorectal cancer
Product/Company
Target
Indication
Efficacy
Status
Line of treatment
Delivery/dosing frequency
Bevacizumab + chemo/Roche ( OTCQX:RHHBY )
angiogenesis inhibitors
Metastatic colorectal cancer
OS improvement (median OS 13.0 months vs. 10.8 months)
approved in 2004
1st and 2nd
IV/every 2-week
Cetuximab + best supportive care (BSC) /BMS
angiogenesis inhibitors
EGFR-expressing metastatic colorectal cancer, No KRAS mutation
ORR improvement (23 vs. 11%)
approved in 2005
1st and 2nd
IV/weekly
Panitumumab +best supportive care (BSC) /AMGEN
angiogenesis inhibitors
EGFR-expressing metastatic colorectal cancer, No KRAS mutation
PFS improvement (96 days vs. 60 days)
approved in 2009
1st and 2nd
IV/every 2-week
Ramucirumab + chemo /Lilly
second generation of angiogenesis inhibitors
Metastatic colorectal cancer
OS improvement (13.3 months vs. 11.7 months); PFS improvement (5.7 months vs. 4.5 months)
approved in 2015
2nd
IV/every 2-week
Regorafenib/Bayer
multikinase inhibitor
Metastatic colorectal cancer (wild type or mutated KRAS)
OS (6.4 vs. 5.0 months) and PFS (1.9 vs. 1.7 months, p<0.001) improvement
approved in 2012
2nd
oral/once daily
Ziv-aflibercept + chemo/sanofi-aventis
angiogenesis inhibitor
Metastatic colorectal cancer
OS (13.5 vs. 12.1 months) and PFS (6.9 vs. 4.7 months) improvement, ORR (20% vs. 11%)
approved in 2012
2nd
IV/every 2-week
Source: data compiled by author
Stage IV colon cancer patient has a relative 5-year survival rate of about 14%, therefore, we are assuming a mean duration of treatment for 2 years for advanced CRC.
Exhibit 22. Market model for advanced CRC
Market model for CRC
US
EU
Japan
Incidence of CRC
0.000410394
0.000603
0.000389
Population
330 million
500 million
130 million
CRC patients
135430
447136
50570
Advanced CRC %
35%
35%
35%
Advanced CRC patients
47401
156498
17700
Market share %
15%
15%
15%
Patients treated
7110
23475
2655
Net price ($)
120000
80000
80000
Revenue ($)
1706 million
3756 million
425 million
Total revenue ($)
5887 million
POS %
10%
Risk-adjusted revenue
589 million
Source: data compiled by author. Ref: Incidence1 ; Incidence 2 ; Incidence3
5) AML and bladder cancer
We are not assigning valuation for these two indications due to low POS and lack of clinical data. For AML, we did not observe convincing data for 5F9 in this indication as none of the 18 patients showed remission of AML, and only 1 patient showed a stable disease for this monotherapy trial. In addition, Celgene' s clinical trial for CC-90002, another antibody targeting CD47, was terminated in AML and MDS on Oct. 8, 2018 due to no sufficiently encouraging efficacy. It further confirmed our assessment of low POS for this indication. Regarding bladder cancer, there is no data yet available for bladder indication for the combo therapy (5F9 + atezolizumab).
S trong interest in innate immune system by other large biotech/pharma companies We have witnessed some big biotech and pharma companies were investing in innate immune system recently. A few examples are listed below.
1. On April 4, 2018, Boehringer Ingelheim had a license agreement with OSE immunotherapeutics (OSE) to jointly develop OSE-172, which blocks SIRPα receptor and then trigger immune response from innate immune system. OSE will receive a €15 million upfront payment and potential additional short-term milestones of up to €15 million upon initiation of a phase 1 clinical study. Assuming all milestones are met, OSE will receive more than €1.1 billion.
2. On Aug 28, 2018, Genentech announced a collaboration with Affimed NV ( AFMD ) to develop and commercialize novel NK cell engager-based immunotherapeutics to treat multiple cancers. Affirmed will receive $96 million upfront and committed funding and is eligible for up to an additional $5.0 billion including milestone payments, and royalties on sales.
C ompetitive landscape Exhibit 23. Competitive landscape for targeting CD47 receptor
Source: Company presentation
Based on the landscape, it is clear that 5F9 is a first-in-class drug candidate targeting CD47 with at least 18-month ahead of other similar candidates in this field. It has six clinical trials including NHL, Ovarian, Colorectal, AML, and Bladder cancers. Trillium Therapeutics ( TRIL ) is the closest competitor to Forty Seven; however, the recent data released from Trillium on TTI-621 showed less efficacy compared to 5F9 for NHL, further solidify the leader position for 5F9. Forty Seven has established a few collaborations with some lead players in the oncology field including Genentech, Merck KGaA ( OTCPK:MKGAY ), and Eli Lilly (NYSE: LLY ).
Strong IP position & R esolved IP litigation Forty Seven has a strong IP position via a license agreement with Stanford for a series of patents related to the lead candidate, 5F9. These patents are expected to expire between 2029-2034 excluding any extension of patent term that may be available. On July 2018, Forty Seven announced a settlement and license agreement with Synthon Pharmaceuticals. This agreement provides a non-exclusive, worldwide sub-license to commercialize anti-CD47 antibodies including 5F9, to treat cancer in combination with other antibodies, such as cetuximab and rituximab. It resolved previous IP dispute with Synthon on the combination of 5F9 with those antibodies and removed the uncertainty of developing and commercializing the combination from IP perspective.
Valuation The price target is $14 based on the current DCF model. We are using a 13% of WACC which is consistent with the risk for clinical stage biotech companies, and a terminal growth of 3% as we maintain 17% of revenue for R&D expense in the modeling. Also, ZF9 is an antibody product which has less generic competition even after patent expiration. The current number of shares is 30 million and we expect it will reach to 60 million before it turns to profitable by 2024 (cash burn is 60-80 million/year and it needs to raise another 300-400 million, which account for 30 million of shares for an average of $14 per share).
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
Terminal value
EBIT
-39
-78
-84
-82
-123
-56
6
115
224
246
265
290
314
344
374
402
429
429
FCF
-36
-71
-79
-83
-112
-74
3
118
167
209
218
227
246
270
294
319
322
346
3567
Discounted FCF
-35
-63
-62
-57
-69
-40
1
50
63
70
64
59
57
55
53
51
46
43
447
WACC
13%
TG Rate
3%
PV of FCF
287
PV of Terminus
447
Total PV
734
Cash
88
Equity Value
822
FD Shares
60
Target share price ($)
14
Risk Analysis In addition to the typical risks associated with clinical stage biotechnology companies, potential risks specific to Forty Seven are as follows:
Clinical risk. Forty Seven has been betting heavily on CD47 target. Literally, there is no pipeline focusing on other targets. Although we observed very positive results in a few indications, those trials were open-labelled with small number of patients (<30 patients for each indication). The current study could introduce bias and a few patients' response rate changes could significantly affect the % of response rate. We have observed some other immune-therapy agents showing promising results in early clinical trials but eventually could not repeat the results in a large clinical trial.
Scientific risk. The concept of using macrophage to engulfing cancer cells is intriguing and it was demonstrated in some preclinical models and early clinical trials. However, leveraging innate immune system to treat cancer has not gained substantial success as no product approved yet. Since 5F9 is the first-in-class drug candidate targeting CD47, not much previous experience could de-risk the validity of this target in humans, thus the risk is high especially without a good scientific understanding of good biomarker.
Disclosure: I am/we are long TRIL.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
Additional disclosure: Opinions offered here are not personalized recommendations. Readers are expected to do their own due diligence or consult an investment professional if needed prior to making investment decisions. Although I do my best to present factual research, I cannot guarantee the completeness or accuracy of the information due to complexity involved in biotech section in general.
Editor's Note: This article covers one or more stocks trading at less than $1 per share and/or with less than a $100 million market cap. Please be aware of the risks associated with these stocks.

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Shelton tackles biggest challenge – Striker battles chronic disease

<h1>Shelton tackles biggest challenge – Striker battles chronic disease</h1>

Shelton tackles biggest challenge – Striker battles chronic disease

6 7
One of Jamaica’s most prolific goalscorers, Luton Shelton has been battling amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig’s disease. At 32 years old, Shelton could still play football at the highest level, however, not much was seen of him since his return to his boyhood club Harbour View FC in the 2016-17 season of the Red Stripe Premier League.
His second stint at the club was a short-lived one owing to constant ailments and niggling injuries.
The Gleaner was invited into his upper St Andrew home where he resides with his wife Bobbette. The couple, who has been together for 13 years, will celebrate their fifth year of marriage in December. They have three young children aged nine, eight, and three.
Despite his now slurred speech because of ALS, Shelton still tries to express himself to The Gleaner vocally and always with a smile. This deteriorating speech, his father Luton Shelton, Sr, said, was one of the first signs that his health was seriously in decline. Because of the strain on his vocal chords and the difficulty for others not around him regularly to understand him, his father and wife interpreted on his behalf.
“For about a year and a half or nearly two years, we thought, more or less, he had minor strokes,” Luton Sr said. “First, the voice slurred. We don’t know of him having high blood pressure because strokes are really associated with high blood pressure and that kind of thing.
“One of the times, I thought because he was in Denver (in Colorado) and it’s cold, he contracted a cold. It went on and on until the voice started to get worse. He did a series of tests as it got worse – tests to his voice box, MRIs, a series of bloodwork – and they didn’t find anything conclusive in terms of cancer, STIs (sexually transmitted diseases), or anything to associate with the cause. They were some expensive tests.
Disease more aggressive
“I found a friend who had it and she came and talked to him to give him more hope. He felt more hopeful then, but it started to take a more aggressive form,” said Luton Sr.
He explained that ALS is not a sudden illness, but one that progressively worsens the afflicted’s condition. “It’s a progressive illness that takes its toll stage by stage,” he said. “Stage by stage doesn’t mean in days or in months, but it can be over a period of time. We’re trying in terms of seeking medical advice. We have been doing it here (in Jamaica).”
The former national striker’s father told The Gleaner that his son visited nutritionists looking for a solution but didn’t see any improvement. “That was for about six months, and we didn’t see a change. He was even diagnosed with milder symptoms. It’s still a multi-neuron disease – myasthenia gravis. We were taking the medication for it, which didn’t cure it but it kind of contained the sickness. This would have made him recover his voice, some of his strength. He was on steroids – Prednisone.”
Prednisone is a drug used to treat auto-immune diseases such as ALS and myasthenia gravis. It is also used to suppress the immune system.
Our lives revolve around him – Bobbette
Like the caring wife she has been, Bobbette, with Luton’s hand in hers, sat beside him. She seemed to have an almost telepathic understanding of her husband. Bobbette understood his utterances even better than his father and said that it was because she now spends all her time with him; however, she does not mind.
“Basically, our lives revolve around him because he needs everything,” she said. “It wasn’t even something to think twice about. I made a vow and I’m here for him. His father is here, and everyone is here to help out and rally around him. It wasn’t hard to transition, just to accommodate him and his needs.”
Luton Sr describes his feelings towards his daughter-in-law as grateful because of her dedication.
“When Bobbette came into his life, she was always there with him on every journey. He started to branch out and had his own family. But it’s a sad thing to know how it has transpired,” he said.
“It’s hard. I can remember one time, she literally collapsed. She’s the literal breadgiver. Being a wife and having their kids around, she has to do most of the things (around the house). I remember one day he woke and she had so many things to do and he couldn’t get to her. He was like, ‘Daddy, you need to go see what’s happening with her.’ It was a good thing because … she didn’t even know when she got to the hospital.”
Luton Sr is mindful that his son’s condition will worsen and he worries that he will then need a gastric feeding tube. He and Bobbette are also aware that at this point, they will also need a nurse, with professional training, for round-the-clock care.
The sports ministry will donate $5 million to Shelton’s cause.

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The Management of Acute Anterior Uveitis Complicating Spondyloarthritis: Present and Future

<h1>The Management of Acute Anterior Uveitis Complicating Spondyloarthritis: Present and Future</h1>

The Management of Acute Anterior Uveitis Complicating Spondyloarthritis: Present and Future

Review Article The Management of Acute Anterior Uveitis Complicating Spondyloarthritis: Present and Future Martina Biggioggero , 1 Chiara Crotti , 2 Andrea Becciolini , 1 Elisabetta Miserocchi , 3 and Ennio Giulio Favalli 1
1 Department of Rheumatology, Gaetano Pini Institute, Milan, Italy 2 Department of Clinical Sciences and Health Community, University of Milan, Division of Rheumatology, Gaetano Pini Institute, Milan, Italy 3 Department of Ophthalmology, Scientific Institute San Raffaele, Milan, Italy
Correspondence should be addressed to Martina Biggioggero ;
Received 16 June 2018; Revised 5 September 2018; Accepted 26 September 2018; Published 14 October 2018
Academic Editor: Hiroshi Tanaka
Copyright © 2018 Martina Biggioggero et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract
Spondyloarthropathies (SpA) encompass a group of chronic inflammatory diseases sharing common genetic and clinical features, including the association with HLA-B27 antigen, the involvement of both the axial and the peripheral skeleton, the presence of dactylitis, enthesitis, and typical extra-articular manifestations such as psoriasis, inflammatory bowel disease, and acute anterior uveitis (AAU). The latter is commonly reported as a noninfectious acute inflammation of the anterior uveal tract and its adjacent structures. AAU may affect more than 20% of SpA patients representing the most common extra-articular manifestation of the disease. Considering the potential consequences of untreated AAU, early diagnosis and aggressive treatment are crucial to avoid complications of remittent or chronic eye inflammation, such as visual loss and blindness. The management of SpA has dramatically improved over the last decades due to the development of new treat-to-target strategies and to the introduction of biologic disease modifying antirheumatic drugs (bDMARDs), particularly tumor necrosis factor alpha inhibitors (TNFis), currently used for the treatment of nonresponder patients to conventional synthetic agents. Along with the improvement of musculoskeletal features of SpA, bDMARDs provided an additional effect also in the management of AAU in those patients who are failures to topical and systemic conventional therapies. Nowadays, five TNFis, one interleukin-17, and one interleukin 12/23 blocker are licensed for the treatment of SpA, with different proven efficacy in preventing and treating ocular involvement. The aim of this review is to summarize the current options and to analyze the future perspectives for the management of SpA-associated AAU. 1. Introduction
Spondyloarthropathies (SpA) embrace different chronic inflammatory diseases sharing common genetic (association with HLA-B27 antigen) and clinical features. The principal symptoms are inflammatory chronic back pain, peripheral arthritis (typically asymmetric monoarthritis or oligoarthritis predominantly affecting the joints of the lower extremities), dactylitis, and enthesitis [ 1 ]. The disease course is usually complicated by extra-articular manifestations (EAMs), such as psoriasis, inflammatory bowel disease (IBD), and acute anterior uveitis (AAU) [ 2 ]. The latter is commonly reported as a noninfectious acute inflammation of the anterior uveal tract and its adjacent structures, which may affect more than 20% of SpA patients representing the most common EAM of the disease [ 3 ]. Considering the potential consequences of untreated AAU, early diagnosis and aggressive treatment are crucial to avoid the complications of remittent or chronic eye inflammation such as visual loss and blindness.
In this contest of very heterogeneous disease phenotype, the importance of personalised multidisciplinary management of the disease is mandatory. In the last decades, the development of new classification criteria allowing an earlier diagnosis and the availability of biologic and targeted synthetic therapies has vastly improved the management of SpA patients. Among biologic disease modifying antirheumatic drugs (bDMARDs), tumor necrosis factor alpha inhibitors (TNFis) are currently widely used for the treatment of SpA. To date, five TNFis (infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol) have been licensed for SpA by the European Medicines Agency and the US Food and Drug Administration. Recently, new potential treatment targets in SpA emerged enhancing the available treatment options with novel mechanisms of action. In particular, blockers of interleukin-17 (IL-17; secukinumab and ixekizumab), interleukin 12/23 (IL-12/23; ustekinumab), and phosphodiesterase-4 (PDE4; apremilast) were included in the therapeutic armamentarium for SpA.
Although the efficacy and safety profiles of the different available therapies have been clearly demonstrated for the management of musculoskeletal features of SpA, different performances in preventing and treating ocular involvement were proven.
The aim of this review is to summarize the current options and to analyze the future perspectives for the management of SpA-associated AAU. 2. Classification of Uveitis and Epidemiology of AAU
Uveitis is one of the most common causes of blindness and represent a broad spectrum of disorders characterized by inflammation of the uveal tract (iris, ciliary body, and choroid) and its adjacent structures (vitreous humour, retina, optic nerve, and vessels). According to the Standardization of Uveitis Nomenclature (SUN) criteria, uveitis can be classified according to the anatomic site of inflammation into anterior (characterized by the presence of intraocular inflammation in the anterior chamber), intermediate (inflammation of the pars plana), posterior (inflammation of the posterior segment), or panuveitis (involving anterior and posterior segment) [ 14 ]. Uveitis can also be clinically classified by etiology as infectious (bacterial, viral, fungal, or parasitic), noninfectious (with known or unknown systemic association), and masquerade (heterogeneous group of eye diseases that mimic chronic intraocular inflammation). Noninfectious uveitis may be associated with many systemic autoimmune conditions or may occur without extraocular involvement (Table 1 ) [ 14 ]. Accurate data on prevalence of uveitis are lacking, because of differences in clinical and methodological case finding methods, but the reported annual incidence of uveitis is between 17 and 52 per 100.000 persons and the prevalence is 38-714 per 100.000 persons, despite the variability among different geographic areas worldwide [ 15 ]. Uveitis can occur at any age, but this disease more commonly affects the working population between 20 and 59 years. No prevalence variations are observed according to gender, but some forms present a sex predominance (i.e., juvenile idiopathic arthritis-related uveitis, more common in female, and HLA-B27 associated uveitis, more common in male) [ 16 , 17 ]. As shown by epidemiological data, incidence differs among ethnicities: posterior uveitis and panuveitis are, respectively, the second and third most frequent locations in the Western countries (21% and 7%, respectively) [ 18 ]; this distribution may suggest a potential role played by genetic factors. Table 1: Autoimmune disorders associated with noninfectious uveitis.
Anterior uveitis is the most common type of uveitis encountered in Western countries, while posterior and panuveitis are more frequently seen in developing countries due to the higher incidence of infectious uveitis involving the posterior segment of the eye. As mentioned before, the link between SpA and uveitis has been well described, since uveitis is the most common EAM in SpA and its main clinical presentation is with acute onset. However, about 50% of patients tend to have recurrent disease. [ 19 ]. It has been shown that AAU is the most common SpA-related type of uveitis accounting for almost 85% of cases in the USA [ 20 ]. A study conducted on more than 500 Spanish patients referred to an ophthalmologic centre for AAU reported that SpA was the most frequent systemic disease associated with AAU, diagnosed in about one quarter of cases [ 21 ]. In the DUET study, the prevalence of presumed idiopathic AAU, which was found to be associated with a SpA, was about 40% of patients [ 22 ]. The authors proposed an algorithm for early referral from ophthalmologists, in order to promptly diagnose an underlying SpA in presumed idiopathic AAU. Furthermore, HLA-B27 uveitis is commonly a nongranulomatous AAU [ 23 ]; so far, the lifetime cumulative incidence of AAU is higher in HLA-B27 positive subjects compared to general population, 1% versus 0.2%, respectively [ 24 ]. In the DUET study, HLA-B27 demonstrated to be the strong predictor of underlying SpA; in fact on multiple regression the detection of HLA-B27 was associated with an Odd’s Ratio of 38.6. They suggest combining HLA-B27 positivity with low back pain to significantly improve the probability of an early diagnosis (sensitivity 95%, specificity 98%, and Likelihood Ratio 56 in the DUET algorithm) [ 22 ]. According to a systematic meta-analysis, the prevalence of AAU in SpA is 32.7% [ 19 ]. Prevalence enhances with disease duration, reaching 43% for over 30 years of disease [ 19 ], and varies between different forms: it is lower in undifferentiated SpA (13%) while it is higher in ankylosing spondylitis (AS) (33.2%) [ 19 ]. As shown by Zeboulon and colleagues [ 19 ], prevalence changes also according to the sex of patient: female prevalence is higher than male (Odds Ratio [OR] 1.3; confidence interval [CI] 95% 1,1-1,4). However, data on sex differences in prevalence of AAU have not been fully elucidated in the literature [ 25 – 27 ]. 3. Pathogenesis of AAU in SpA
Definitive data about pathogenesis of AAU in SpA are still lacking, albeit some reports derived from experimental animal models have contributed to point out some evidences. Unlike other classical systemic inflammatory disorders, SpA are not characterized by defined serological markers to assist the diagnosis (e.g., autoantibodies), with the exception of HLA-B27 (a class I major histocompatibility complex–encoded allele). HLA-B27 is commonly linked to the whole group of diseases and in particular to AS [ 28 ] and has been included in the clinical arm of the classification criteria of axial SpA provided by the Assessment of Spondyloarthritis International Society (ASAS) [ 29 ]. Moreover, HLA-B27 has been associated with the development of SpA-related AAU [ 30 – 32 ], which is significantly more common in HLA-B27 positive patients compared to the negative ones (27.7% versus 9.7%, respectively; p<0.05) [ 33 ]. From a pathogenic point of view, HLA-B27 is involved in the development of SpA together with a rich mixture of over 20 genes [ 34 ] and with environmental factors such as entheseal mechanical stress and gut microbiome [ 35 , 36 ]. Despite the more recent advances, our understanding of the molecular mechanisms of HLA-B27 in the pathogenesis of SpA and in particular SpA-related AAU is far from being complete. Models of HLA-B27 transgenic rats and mice develop spontaneous inflammatory diseases in gastrointestinal tract, vertebral joints, skin, and nails, but uveitis is infrequent, suggesting the need of additional factors in the induction of AAU [ 37 , 38 ]. Another significant association between AAU and SpA was observed for other three nonmajor histocompatibility complex loci: IL23R, the intergenic region 2p15, and ERAP1 [ 39 ]. Besides the genetic component, the development of AAU involves other factors. The intravitreal injection of Gram-negative endotoxin can induce a bilateral, dose-dependent, self-limited AAU [ 40 ]. Moreover, recurrent uveitis similar to human AAU has been demonstrated in transgenic rats infected with Salmonella or Yersinia [ 41 ], suggesting the potential role for concomitant infections in determining the onset of full-blown AAU in individuals carrying a HLA-B27 genetic susceptibility to the disease. Finally, TNF alpha levels were observed to be high in both aqueous humor and serum of patients affected by noninfectious uveitis, with a direct correlation with the disease activity [ 42 ]. 4. Clinical Presentation of AAU
The most common ocular symptoms of AAU are acute eye pain, redness, and intense photophobia. Nonspecific visual changes such as floaters and different degrees of visual acuity loss may be present [ 43 ]. AAU associated with SpA is frequently characterized by sudden onset and is often unilateral or unilateral alternating, anterior and recurrent.
Anterior uveitis associated with SpA is typically a nongranulomatous type of uveitis characterized by the presence of fine keratic precipitates visible at the slit lamp examination of the anterior segment. Intraocular pressure is usually low due to severe inflammation of the ciliary body. In severe forms of acute anterior uveitis, hypopyon and fibrin can be visualized as a white and dense clot in the anterior chamber.
Posterior synechia, cataract, and secondary glaucoma are the most common ocular complications of uveitis. In about 15 to 20 % of patients the uveitis may have a more severe and chronic course and may involve the posterior segment with macular edema, retinal vasculitis, and papillitis leading to visual loss [ 44 ].
Some authors speculate on the prognosis of HLA-B27 related AAU, reporting a higher frequency of recurrence and a worse outcome compared with HLA-B27 negative patients [ 45 , 46 ].
The use of bDMARDs could significantly affect the prognosis of AAU associated with SpA [ 47 ]. In fact, the clinical course and the number of relapses of AAU have been hugely improved by TNFis [ 48 ]. Furthermore, the overall prognosis of AAU is quite good in TNFis treated SpA and only a minority of patients reported permanent visual loss [ 49 ]. 5. Treatment of AAU in SPA
The management of uveitis reserves actually several clinical challenges. The therapeutic approach for uveitis requires careful consideration regarding etiology, involved anatomic site, chronicity, prior medication failure, and potential ophthalmic and systemic risks of proposed therapy: a definite diagnosis is crucial to establish an appropriate therapy. Treatment of noninfectious uveitis may be local, systemic, or a combination of the two. The therapeutic strategy evaluates the underlying diagnosis, severity of the disease, laterality, and presence of comorbidities. The treatment of SpA associated AAU should include the management of acute attack and the prevention of recurrences. 5.1. Topical Therapy
The first-line symptomatic treatment of acute attack of AAU consists in a cycloplegic agent combined with corticosteroids, which may be administered systemically, topically, or by subconjunctival injection. Periocular prednisolone acetate and intraocular dexamethasone are the most commonly used local treatment in patients with HLA-B27 associated uveitis with posterior pole complications. In a minority of cases, subconjunctival corticosteroid injections may be needed, only when a marked anterior segment inflammation results in significant loss of vision [ 50 ]. In the SITE (Systemic Immunosuppressive Therapy for Eye Diseases) cohort periocular corticosteroids were found to be effective in reducing intraocular inflammation and improving visual acuity in AAU [ 51 ]. An exciting area of research sustained by recent advances in bioengineering is the development of intravitreal implants releasing corticosteroids or other compounds. These delivery devices may be classified into surgical nonbiodegradable and bioerodible implants, with different durations and safety profiles [ 38 ]. These novel approaches for the delivering of therapeutic substances derive from the need of developing local therapies characterized by faster effect on targeted tissues, avoiding undesirable systemic side effects. The available ocular implants have been mainly developed for releasing corticosteroids such as dexamethasone or fluocinolone acetonide [ 52 ]. Topical cycloplegics are often used in tandem with topical corticosteroids to break and to prevent the formation of posterior synechiae. 5.2. Conventional Synthetic DMARDs Disease-Modifying Antirheumatic Drugs (csDMARDs)
The key for the treatment of noninfectious uveitis relapsing or refractory to topic therapy is the control of systemic inflammation generated by the underlying autoimmune disease [ 53 ]. Systemic corticosteroids are often administered when topical treatment is inadequately effective, especially for bilateral uveitis. However, the prolonged use of moderate to high doses is significantly limited by serious side effects related to corticosteroid cumulative dose over time [ 54 ], leading to the potential introduction of an immunosuppressive agent as a corticosteroid-sparing therapy. The addition of methotrexate produced the resolution of noninfectious uveitis, despite corticosteroid withdrawal, in about 60% of patients within one year [ 55 ]. Furthermore, it decreases the frequency of AAU flares during the progressive tapering of systemic corticosteroids treatment [ 56 ]. Data on sulfasalazine for the treatment of AAU are very limited, with a single paper reporting a significant reduction in the number of AAU flares and improvement in visual acuity in SpA [ 56 ]. Similarly, leflunomide had only few anecdotal data regarding the treatment of uveitis [ 57 ]. Azathioprine is moderately effective in the treatment of noninfective uveitis, mainly the intermediate form of the disease [ 58 ]. The use of systemic cyclosporine for intermediate and posterior uveitis is well described by several papers showing a comparable efficacy with corticosteroids [ 59 ]. In particular, cyclosporine offered both a complete remission in more than 30% and a significant corticosteroid-sparing effect in at least 20% of treated patients [ 60 ]. However, the lack of data on the treatment of anterior uveitis and the overall unfavorable long-term safety profile, in terms of nephrotoxic effects and hypertension, are main limitations for the extensive use of cyclosporine for the management of SpA-related AAU. Other systemic immunomodulatory medications for uveitis are now very infrequently used because of their potential toxicity, particularly for alkylating agents, in consideration of the availability of more targeted therapies such as biologics.
In conclusion, systemic immunosuppressive drugs have a potential in the management of AAU, even if their use showed no proven efficacy in the treatment of axial and enthesopathic involvement of SpA, limiting the opportunity to treat SpA-related AAU and the underlying disease with the same drug. 5.3. Biologic and Targeted Synthetic DMARDs
To date SpA has fewer therapeutic options than rheumatoid arthritis and could exhibit heterogeneous therapeutic responses considering different site involvements. Given the complexity of SpA, a tailored management of the disease that includes targeted DMARDs (biologic and small molecules) is mandatory. 5.3.1. Role of Targeted DMARDs in SpA
Biologic DMARDs are defined as manufactured therapies by recombinant DNA (deoxyribonucleic acid) technology and include bioengineered soluble receptors, monoclonal antibodies, Fab fragments, and cytokines that affect the expression of pro- and anti-inflammatory components of the immune system. To date the major class of bDMARDs employed in SpA care is the successful use of TNF blockade in persistently high disease activity despite conventional treatments [ 61 ]. TNFis can be divided into three categories: a fusion protein that forms unstable complexes with the TNF (etanercept), monoclonal antibodies recognizing and binding to TNF (infliximab, adalimumab, and golimumab), and a Fab’ fragment of a monoclonal antibody coupled with polyethylene glycol (certolizumab pegol). TNFis demonstrated to be highly effective in targeting the different disease musculoskeletal manifestations and could ameliorate the disability and quality of life, acting on general symptoms such as fatigue. Long-term follow-up studies suggest a retention rate maintained for several years of treatment with an optimal safety profile [ 62 ]. Nevertheless, a significant proportion of patients showed an inadequate or poor response and others experienced drug-related adverse events. Consequently, alternative mechanisms of action (MoA) may be welcomed for these patients. The IL-23/IL-17 axis is strongly implicated in the pathogenesis of SpA and there is increased interest in the potential role of therapeutic strategies targeting this way. Secukinumab, a high-affinity, fully human monoclonal antibody that selectively inhibits IL-17A, showed a rapid-onset efficacy in treating SpA with a wide range of clinical benefits [ 63 – 69 ]. Ixekizumab, a monoclonal antibody that selectively targets interleukin-17A actually licensed for PsO, improved the signs and symptoms of patients with active PsA with a safety profile [ 70 , 71 ]. Ustekinumab, an anti-IL-12/IL-23 monoclonal antibody, is safe and effective for patients with active PsA and AS [ 72 – 74 ]. Recently, the therapeutic armamentarium for PsA has been enriched with apremilast, a phosphodiesterase-4 inhibitor that demonstrated clinically meaningful sustained improvements with a good tolerance and safety profile [ 75 – 77 ]. 5.3.2. Role of Targeted DMARDs in AAU
To date, bDMARDs have been used off-label to treat AAU because none of these therapies has been approved yet for adults, despite that their clinical efficacy has been reported in an amount of clinical cases and case series [ 78 ].
TNF alpha is essential in the intraocular immune response and in the autoregulation of the physiologic apoptosis of ocular cells. Preclinical studies give several evidences that TNF blocking can be a possible therapeutic strategy in uveitis. In fact, TNFis switch the immune response towards a Th2 prevalent mechanism, decreasing also disease activity [ 79 ]. Experimental autoimmune uveitis models highlighted that TNF alpha is increased not only in the typical autoimmune uveitis inflammatory infiltrates, but also in some retinal cells [ 80 ]. Moreover, the production of TNF alpha is regulated by ocular resident cells, macrophages, and activated T cells [ 81 ], possibly influencing the disease course. TNF alfa has a pivotal role in the pathogenesis of uveal inflammation; firstly, it recruits leukocytes to the eye in the early phase of the disease, through chemokines production and promotion of leukocytes adhesion to vascular endothelium. Secondly, TNF alpha promotes maturation of dendritic cells, improving the ability to act as presenting cells to T cells. Thirdly, TNF alpha can directly activate macrophages and promote T cells-effector function. Lastly, as mentioned, TNF alpha leads to apoptosis, of both infiltrating cells and resident ocular cells [ 82 ]. In clinical studies TNF alpha directly causes tissue damage through reactive oxygen species, breaking down the blood-ocular barrier and promoting angiogenesis [ 83 ]. TNF alpha could be related to endothelial tissue by the upregulation of vascular endothelial growth factor, whose effect is linked to cystoid macular edema and choroidal neovascularization [ 84 ]. These evidences give support to the use of TNFis in clinical practice. In fact, TNFis are the most frequently reported biologic drugs for the treatment of uveitis (Table 2 ). As was mentioned above, TNF alpha levels are high in both aqueous humor and the serum of patients affected by noninfectious uveitis; moreover there is a direct correlation between TNF alpha levels and the disease activity [ 42 ]. Table 2: Characteristics of main trials on Spondyloarthritis-related anterior acute uveitis treated with biological DMARDs.
Retrospective studies on TNFis have been focused on underlying systemic disease with associated uveitis and some prospective studies have been successfully completed [ 78 ]. Several studies suggest that monoclonal antibodies are more effective than soluble receptors for the treatment of uveitis. The most important real-life experience reported with infliximab and adalimumab showed a clinical remission in over 60% of treated patients [ 15 ]. Further studies are needed to clarify a controversial area that is the potential paradoxical role of TNFis as a cause of uveitis [ 85 , 86 ].
In animal models infliximab has shown a good safety profile and efficacy in the treatment of uveitis and dry eye and in scarring healing on the eye’s surface [ 87 – 89 ]. It is successfully used also in Behçet associated uveitis and in JIA associated forms [ 90 ]. Infliximab has shown to be effective also in uveitis associated with other systemic immune mediated conditions rather than SpA, such as, sarcoidosis or inflammatory bowel diseases [ 91 ]. In a prospective study conducted on 23 patients with various underlying etiologies of resistant uveitis, 78 % of patients on infliximab therapy reported a clinical success at week 10, as judged by a composite clinical end point combining visual acuity, control of intraocular inflammation, ability to taper concomitant therapy, and improvement of fluorescein angiography and/or optical coherence tomography [ 92 ]. In a retrospective study on recalcitrant uveitis treated with infliximab, 81.8% of the patients achieved clinical remission and only 58.3% required additional immunomodulatory medications [ 93 ]. The mechanism of action of infliximab is related to the neutralization of soluble and membrane-bound form of TNF, as explained by its rapid and effective action, inhibiting a broad range of TNF action, as mentioned above [ 83 ]. Controversial results were obtained with intravitreal injection of infliximab when systemic administration is not indicated. Initially, this new route of administration showed promising results with a significant visual acuity improvement and macular thickness reduction in patients with chronic noninfectious uveitis [ 94 , 95 ], unfortunately not confirmed in subsequent studies, reporting electroretinographic abnormalities, severe panuveitis, and modest efficacy for the long-term control of uveitis [ 96 – 98 ]. Adalimumab has a number of publications supporting its efficacy and good safety profile for the treatment of uveitis; it has demonstrated good responses in SpA-associated uveitis and HLA-B27-associated uveitis [ 91 ]. Recently, three prospective multicenter open-label phase III trials (VISUAL I, II, and III) have been conducted to assess the effectiveness and safety of adalimumab versus placebo [ 99 – 101 ]. In the VISUAL I study, 217 active noninfectious intermediate uveitis, posterior uveitis, or panuveitis, despite prior prednisone treatment for 2 or more weeks, were randomly assigned in a 1:1 ratio to receive adalimumab (a loading dose of 80 mg followed by a dose of 40 mg every 2 weeks) or matched placebo. The median time to adalimumab failure was 24 weeks, with an early and sustained separation of the treatment-failure curves, indicating that patients receiving adalimumab were significantly less likely to have treatment failure than those who received placebo. The VISUAL II trial assessed that adalimumab versus placebo significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in 229 patients with inactive, noninfectious uveitis controlled by systemic corticosteroids. Treatment failure occurred more frequently in the placebo group compared with the adalimumab one (55% versus 39%), as the time to treatment failure was significantly improved in the adalimumab group compared with the placebo one (p=0,004). The rate of adverse events was similar between groups. The impact of adalimumab on immunosuppressant use in 371 patients with active or inactive noninfectious intermediate, posterior, or panuveitis was analysed in the VISUAL III study, in which the long-term treatment with adalimumab reflected a reduction in csDMARDs dose and dependence in both groups.
Recently, these evidences had led to Food and Drug Administration and European Medicines Agency approval of adalimumab for the management of noninfectious intermediate uveitis, posterior uveitis, and panuveitis in adults. Adalimumab is licensed for the treatment of pediatric chronic noninfectious AAU in patients from 2 years of age, who have had an inadequate response to conventional therapies or in whom conventional therapy is inappropriate.
Etanercept is a therapeutic option in SpA but its efficacy on uveitis is much debated [ 11 , 48 , 91 , 102 , 103 ]. Braun and colleagues reported a greater reduction in uveitis flares with infliximab compared with etanercept in AS [ 48 ]. Similar results were observed in a retrospective analysis on 2115 AS patients with a higher risk of new-onset uveitis in patients treated with etanercept compared with monoclonal antibodies (infliximab and adalimumab) [ 12 ]. Galor et al. [ 104 ] compared etanercept to infliximab for the treatment of a variety of inflammatory eye diseases including HLA-B27-associated uveitis, showing a greater efficacy of infliximab compared with etanercept in decreasing the number of uveitis recurrences (0 versus 59%, respectively). On the other hand, in a meta-analysis Migliore et al. compared TNFis versus placebo in the treatment of uveitis in AS patients reporting a positive efficacy of all TNFis, including etanercept [ 103 ]. Accordingly, Kim et al. described a similar rapid improvement of uveitis with a reduction of the number of flare-ups in patients treated with infliximab, adalimumab, or etanercept [ 11 ].
Golimumab and certolizumab pegol efficacy in the treatment of uveitis has been reported only in few case reports and small case series of heterogeneous subgroups of patients, including patient nonresponders to prior TNFi [ 7 , 105 – 110 ]. Further data are needed to make any statement.
The ability of other mechanisms of action to manage uveitis in SpA is still under delineation. The involvement of IL-23-IL17 pathway and the consequent pivotal role of autoreactive T cells in the pathogenesis of noninfectious uveitis provide a rationale for treatment of AAU with IL-17 inhibitors [ 33 ]. However, secukinumab did not meet the primary efficacy end points as a therapy in uveitis not specifically SpA-related in three RCTs versus placebo but reported a beneficial effect in reducing concomitant csDMARDs use [ 111 ]. A prospective nonrandomized pilot study to investigate ustekinumab as a possible treatment for active intermediate uveitis, posterior uveitis, or panuveitis (STAR study) is now ongoing (ClinicalTrials.gov Identifier: NCT02911116 ). Apremilast was not studied in AAU SpA-related. Ocular involvement is actually under assessment in a phase 3 randomized double-blind study designed to evaluate the efficacy and safety of apremilast in active Behcet’s disease (ClinicalTrials.gov Identifier: NCT02307513 ) [ 112 ]. 6. Future Perspectives
Although targeted therapies have provided a larger armamentarium to treat uveitis, challenges remain. Among small molecules, tofacitinib is an oral inhibitor of Janus kinase (JAK) 1 and 3 that is under investigation for the treatment of AS [ 113 ] and PsA in patients previously not responder to csDMARDs [ 114 ] or to TNFis [ 115 ]. To date, no clinical trials evaluating the efficacy of JAK inhibitors in uveitis have been conducted. The immunomodulatory effect of topical ophthalmic tofacitinib has been evaluated in dry eye disease, with a reduction of conjunctival cell surface HLA-DR expression and tear levels of proinflammatory cytokines and inflammation markers after 8 weeks of treatment [ 116 ]. 7. Conclusions
The management of SpA and related AAU is extremely complex due to the pleomorphic characteristics of these diseases. Multidisciplinary approach is mandatory to achieve the target of an early diagnosis and aggressive treatment, in order to prevent disease progression and damage. The treatment armamentarium of SpA has been considerably improved over the last decades due to the development of new targeted drugs that provided an additional effect also in the management of AAU. The first line of treatment in AAU remains a combination of topical corticosteroids and mydriatic agents, reserving systemic corticosteroids for patients with refractory and severe involvement. The introduction of corticosteroid-sparing csDMARDs is a therapeutic option. Among csDMARDs, methotrexate and cyclosporine reported the most solid data in AAU treatment with an acceptable safety profile. TNFis are the most frequently used bDMARDs in the treatment of both SpA and AAU. In particular, monoclonal antibodies TNFis resulted more effective than etanercept in AAU potentially due to the paradoxical effect and a lower efficacy of the fusion protein. New mechanisms of action targeting the IL-23-IL17 pathway are still under delineation and further data are needed to make any statement. Conflicts of Interest
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Wertheim et al., “A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes,” JAMA Ophtalmology , vol. 123, no. 7, pp. 903–912, 2005. View at Publisher · View at Google Scholar · View at Scopus M. Farvardin, M. Afarid, M. Mehryar, and H. Hosseini, “Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis,” Retina , vol. 30, no. 9, pp. 1530–1535, 2010. View at Publisher · View at Google Scholar · View at Scopus M. Giganti, P. M. Beer, N. Lemanski, C. Hartman, J. Schartman, and N. Falk, “Adverse events after intravitreal infliximab (Remicade),” Retina , vol. 30, no. 1, pp. 71–80, 2010. View at Publisher · View at Google Scholar · View at Scopus L. Arias, J. M. Caminal, M. B. Badia, M. J. Rubio, J. Catala, and O. Pujol, “Intravitreal infliximab in patients with macular degeneration who are nonresponders to antivascular endothelial growth factor therapy,” Retina , vol. 30, no. 10, pp. 1601–1608, 2010. View at Publisher · View at Google Scholar · View at Scopus L. Wu, E. Hernandez-Bogantes, J. A. Roca, J. F. Arevalo, K. Barraza, and A. F. Lasave, “Intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: A pilot study from the Pan-American collaborative retina study group,” Retina , vol. 31, no. 2, pp. 298–303, 2011. View at Publisher · View at Google Scholar · View at Scopus G. J. Jaffe, A. D. Dick, A. P. Brézin et al., “Adalimumab in patients with active noninfectious uveitis,” The New England Journal of Medicine , vol. 375, no. 10, pp. 932–943, 2016. View at Publisher · View at Google Scholar · View at Scopus Q. D. Nguyen, P. T. Merrill, G. J. Jaffe et al., “Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial,” The Lancet , vol. 388, no. 10050, pp. 1183–1192, 2016. View at Publisher · View at Google Scholar · View at Scopus E. B. Suhler, A. Adán, A. P. Brézin et al., “Safety and Efficacy of Adalimumab in Patients with Noninfectious Uveitis in an Ongoing Open-Label Study: VISUAL III,” Ophthalmology , vol. 125, no. 7, pp. 1075–1087, 2018. View at Publisher · View at Google Scholar B. Raffeiner, F. Ometto, L. Bernardi, C. Botsios, and L. Punzi, “Inefficacy or paradoxical effect? Uveitis in ankylosing spondylitis treated with etanercept,” Case Reports in Medicine , vol. 2014, Article ID 471319, 4 pages, 2014. View at Publisher · View at Google Scholar A. Migliore, E. Bizzi, M. Bernardi, A. Picchianti Diamanti, B. Laganà, and L. Petrella, “Indirect comparison between subcutaneous biologic agents in ankylosing spondylitis,” Clinical Drug Investigation , vol. 35, no. 1, pp. 23–29, 2015. View at Publisher · View at Google Scholar · View at Scopus A. Galor, V. L. Perez, J. P. Hammel, and C. Y. Lowder, “Differential Effectiveness of Etanercept and Infliximab in the Treatment of Ocular Inflammation,” Ophthalmology , vol. 113, no. 12, pp. 2317–2323, 2006. View at Publisher · View at Google Scholar · View at Scopus J. Sieper, R. Landewé, M. Rudwaleit et al., “Effect of Certolizumab Pegol Over Ninety-Six Weeks in Patients With Axial Spondyloarthritis: Results from a Phase III Randomized Trial,” Arthritis & Rheumatology , vol. 67, no. 3, pp. 668–677, 2015. View at Publisher · View at Google Scholar V. Llorenç, M. Mesquida, M. Sainz de la Maza et al., “Certolizumab Pegol, a New Anti-TNF- α in the Armamentarium against Ocular Inflammation,” Ocular Immunology and Inflammation , pp. 1–6, 2016. View at Publisher · View at Google Scholar M. Rudwaleit, J. T. Rosenbaum, R. Landewé et al., “Observed Incidence of Uveitis Following Certolizumab Pegol Treatment in Patients With Axial Spondyloarthritis,” Arthritis Care & Research , vol. 68, no. 6, pp. 838–844, 2016. View at Publisher · View at Google Scholar M. Cordero-Coma, V. Calvo-Rio, A. Adan et al., “Golimumab as rescue therapy for refractory immune-mediated uveitis: a three-center experience,” Mediators of Inflammation , vol. 2014, Article ID 717598, 5 pages, 2014. View at Publisher · View at Google Scholar E. Miserocchi, G. Modorati, I. Pontikaki, P. L. Meroni, and V. Gerloni, “Golimumab treatment for complicated uveitis,” Clinical and Experimental Rheumatology , vol. 31, no. 2, pp. 320-321, 2013. View at Google Scholar · View at Scopus E. Miserocchi, G. Modorati, I. Pontikaki, P. L. Meroni, and V. Gerloni, “Long-term treatment with golimumab for severe uveitis,” Ocular Immunology and Inflammation , vol. 22, no. 2, pp. 90–95, 2014. View at Publisher · View at Google Scholar · View at Scopus A. D. Dick, I. Tugal-Tutkun, S. Foster et al., “Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials,” Ophthalmology , vol. 120, no. 4, pp. 777–787, 2013. View at Publisher · View at Google Scholar · View at Scopus P. Lin, E. B. Suhler, and J. T. Rosenbaum, “The future of uveitis treatment,” Ophthalmology , vol. 121, no. 1, pp. 365–376, 2014. View at Publisher · View at Google Scholar · View at Scopus W. P. Maksymowych, D. V. Heijde, X. Baraliakos et al., “Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients,” Rheumatology , 2018. View at Google Scholar P. Mease, S. Hall, O. FitzGerald et al., “Tofacitinib or adalimumab versus placebo for psoriatic arthritis,” The New England Journal of Medicine , vol. 377, no. 16, pp. 1537–1550, 2017. View at Publisher · View at Google Scholar · View at Scopus D. Gladman, W. Rigby, V. F. Azevedo et al., “Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors,” The New England Journal of Medicine , vol. 377, no. 16, pp. 1525–1536, 2017. View at Publisher · View at Google Scholar · View at Scopus J.-F. Huang, R. Yafawi, M. Zhang et al., “Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease,” Ophthalmology , vol. 119, no. 7, pp. e43–e50, 2012. View at Publisher · View at Google Scholar · View at Scopus Follow Us

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Pets Are Like Family. But as Health Costs Rise, Few Are Insured That Way.

<h1>Pets Are Like Family. But as Health Costs Rise, Few Are Insured That Way.</h1>

Pets Are Like Family. But as Health Costs Rise, Few Are Insured That Way.

Medical treatments can run thousands of dollars, and more owners are choosing to pay for them. Drug makers and insurers have taken notice.

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Oct 12, Allergy Shots for Dogs | Effectiveness & Side Effects

<h1>Oct 12, Allergy Shots for Dogs | Effectiveness & Side Effects</h1>

Oct 12, Allergy Shots for Dogs | Effectiveness & Side Effects

Allergy Shots for Dogs Overview
Immunotherapy (aka hyposensitization, commonly called “allergy shots”) is a type of conventional dog allergy medication which is sometimes used as a “last resort”.
Allergy shots are recommended to dogs who do not respond to any other conventional allergy therapies such as corticosteroids (e.g. Prednisone) or antihistamines (e.g. Benadryl).
Allergy shots involve injecting the dog with antigens weekly. (Antigens are foreign proteins to which a particular dog has shown allergic symptoms). The antigen(s) to be injected is determined after intradermal skin testing. Intradermal Skin Testing
In order to get accurate and valid results from the intradermal skin testing, the dog patient has to be off all types of allergy medications (i.e. antihistamines and corticosteroids) for a period of time (your vet will let you know exactly how long).
During the skin testing, the dog will be tested for possible allergic reactions to a number of substances (altogether about 60 substances are being tested).
Usually, the dog will have to be sedated for the testing. How Do Allergy Shots Work?
Although the exact mechanism is not clear, we can find several theories.
According to one theory, immunotherapy can reduce IgE levels.
IgE is a special kind of antibodies that attach to mast cells and allergens (foreign proteins). They cause the mast cells to “explode” and release large amounts of chemicals including histamines, which trigger the common allergic reactions in dogs.
According to another theory, with allergy shots, the dog’s body will gradually become more tolerant of the foreign proteins. The thinking is, the dog’s body may be induced to develop some type of cells that can suppress allergic reactions to the foreign proteins.
As a result, the dog will show fewer and less severe allergy symptoms when he does actually get into contact with the allergen(s). Why are Allergy Shots Not Commonly Used in Dogs?
Many veterinarians propose to use allergy shots as a last resort to treat dog allergies. There are several reasons for this. Time Consuming: One of the main reasons is that the treatment process takes a long time. At least one year is needed to ascertain whether the dog patient is actually responding positively to the allergy shots. Not As Effective: Compared to other allergy treatments (such as steroids, antihistamines, etc.), immunotherapy is not as effective. Only about 60-70 percent of dog patients show positive responses to the shots. Possible Side Effects: Allergy shots for dogs may potentially cause some adverse effects to the dog patient.
For example, the dog may actually develop allergic responses to the shots themselves! That is to say, the dog’s patient may become allergic to the antigens that have been injected into the body.
Signs of side effects include skin irritations (e.g. hives, rashes, itching), swelling of the face, nausea and vomiting, diarrhea, and in rare cases, breathing difficulties and collapse. Costs: Allergy shots are not cheap! First, for the intradermal skin testing, depending on the clinic, it costs at least $100 or more (including sedation). For the required 12 allergy shots, the cost is approximately $150. Natural Allergy Remedies
If your dog has allergies, before considering allergy shots, perhaps it is an good idea to give natural remedies a try. Remedies such as herbs, supplements, etc. can be used to alleviate allergy symptoms in dogs and boost the dog’s immune system.

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Gout Hobbles Plenty of Commoners, Too

Gout Hobbles Plenty of Commoners, Too

You may think of gout as a disease that afflicts wealthy, overweight middle-aged men who are prone to overindulgence. Known since antiquity as the patrician malady and a disease of kings, gout clearly had a penchant for people who could afford a l…

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Seroquel is used for treating schizophrenia or bipolar disorder. Seroquel is an atypical antipsychotic. It affects certain receptors in the brain. This may help to improve symptoms associated with schizophrenia and bipolar disorder. INSTRUCTIONS generic for seroquel.
Use Seroquel as directed by your doctor. Take Seroquel by mouth with or without food. Continue to take Seroquel even if you feel well. Do not miss any dose. Do not suddenly stop taking Seroquel without first talking with your doctor. You may have an increased risk of side effects. If you need to stop Seroquel or add a new medicine, your doctor will gradually lower your dose. If you miss a dose of Seroquel, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.
Ask your health care provider any questions you may have about how to use Seroquel. STORAGE generic for seroquel.
Store Seroquel at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Seroquel out of the reach of children and away from pets.
Active Ingredient: Quetiapine fumarate. Safety information generic for seroquel. Do NOT use Seroquel if: you are allergic to any ingredient in Seroquel.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Seroquel. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you: if you are pregnant, planning to become pregnant, or are breast-feeding if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement if you have allergies to medicines, foods, or other substances if you or a family member has a history of bipolar disorder (manic depression), suicidal thoughts or attempts, mental or mood problems, or diabetes if you drink alcohol or have a history of alcohol or substance abuse if you have Alzheimer disease, dementia, or trouble swallowing, or you are very overweight if you have a history of heart problems (eg, heart attack, heart failure, irregular heartbeat), stroke, blood vessel problems, high blood cholesterol levels, or high or low blood pressure if you have history of blood problems (eg, low white blood cells), liver problems, thyroid problems, cataracts, narrow-angle glaucoma, seizures, neuroleptic malignant syndrome (NMS), high blood prolactin levels, or breast cancer.
Some medicines may interact with Seroquel. Tell your health care provider if you are taking any other medicines, especially any of the following: Alpha-blockers (eg, doxazosin) or medicine for high blood pressure because the risk of low blood pressure and fainting may be increased Azole antifungals (eg, ketoconazole), divalproex, fluvoxamine, HIV protease inhibitors (eg, ritonavir), macrolide antibiotics (eg, erythromycin), or telithromycin because they may increase the risk of Seroquel’s side effects Barbiturates (eg, phenobarbital), carbamazepine, corticosteroids (eg, prednisone), phenytoin, rifampin, or thioridazine because they may decrease Seroquel’s effectiveness Dopamine receptor agonists (eg, pramipexole) or levodopa because their effectiveness may be decreased by Seroquel.
This may not be a complete list of all interactions that may occur. Ask your health care provider if Seroquel may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine. Important safety information: Seroquel may cause drowsiness, dizziness, or decreased vision. These effects may be worse if you take it with alcohol or certain medicines. Use Seroquel with caution. Do not drive or perform other possible unsafe tasks until you know how you react to it. Talk with your doctor before you use medicines that may cause drowsiness (eg, sleep aids, muscle relaxers) while you are using Seroquel; it may add to their effects. Ask your pharmacist if you have questions about which medicines may cause drowsiness. Seroquel may cause dizziness, lightheadedness, or fainting; alcohol, hot weather, exercise, or fever may increase these effects. This may be more likely to occur when you start to take Seroquel, and also if your dose increases. To prevent these effects, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects. Do not drink alcohol while you are using Seroquel. Do not become overheated or dehydrated in hot weather or while you are being active; heatstroke, dizziness, or fainting may occur. Several weeks may pass before your symptoms improve. Do NOT take more than the recommended dose or use for longer than prescribed without checking with your doctor. Children, teenagers, and young adults who take Seroquel may be at increased risk for suicidal thoughts or actions. Watch all patients who take Seroquel closely. Contact the doctor at once if new, worsened, or sudden symptoms, such as depressed mood; anxious, restless, or irritable behavior; panic attacks; or any unusual change in mood or behavior, occur. Contact the doctor right away if any signs of suicidal thoughts or actions occur. Seroquel may rarely cause a prolonged, painful erection. This could happen even when you are not having sex. If this is not treated right away, it could lead to permanent sexual problems such as impotence. Contact your doctor right away if this happens. Seroquel may raise your blood sugar. High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If these symptoms occur, tell your doctor right away. Neuroleptic malignant syndrome (NMS) is a possibly fatal syndrome that can be caused by Seroquel. Symptoms may include fever; stiff muscles; confusion; abnormal thinking; fast or irregular heartbeat; and sweating. Contact your doctor at once if you have any of these symptoms. Some patients who take Seroquel may develop muscle movements that they cannot control. This is more likely to happen in elderly patients, especially women. The chance that this will happen or that it will become permanent is greater in those who take Seroquel in higher doses or for a long time. Muscle problems may also occur after short-term treatment with low doses. Tell your doctor at once if you have muscle problems with your arms; legs; or your tongue, face, mouth, or jaw (eg, chewing movements, mouth puckering, puffing of cheeks, tongue sticking out) while taking Seroquel. Rarely, Seroquel may lower the ability of your body to fight infection. Avoid contact with people who have colds or infections. Tell your doctor if you notice signs of infection like fever, sore throat, rash, or chills. Seroquel may increase the amount of a certain hormone (prolactin) in your blood. Symptoms may include enlarged breasts or decreased sexual ability in men missed menstrual period or nipple discharge in women. Contact your doctor right away if any of these symptoms occur. Lab tests, including complete blood cell counts, blood sugar or cholesterol levels, liver function, or eye exams, may be performed while you use Seroquel. You may also receive regular weight checks while you use Seroquel. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments. Use Seroquel with caution in the elderly; they may be more sensitive to its effects, especially uncontrolled muscle movements. Increased blood pressure has been reported in children and teenagers who use Seroquel. Children and teenagers should receive regular blood pressure checks while they use Seroquel. Seroquel should be used with extreme caution in children younger 10 years; safety and effectiveness in these children have not been confirmed. Pregnancy and breast-feeding: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Seroquel while you are pregnant. It is not known if Seroquel is found in breast milk. Do not breastfeed while taking Seroquel. Side effects generic for seroquel.
All medicines may cause side effects, but many people have no, or minor, side effects.
Check with your doctor if any of these most common side effects persist or become bothersome:
Constipation; dizziness; drowsiness; dry mouth; increased appetite; lightheadedness; nasal congestion; nausea; sore throat; stomach pain or upset; tiredness; vomiting; weakness; weight gain.
Seek medical attention right away if any of these severe side effects occur:
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); confusion; fainting; fast, slow, or irregular heartbeat; fever, chills, or persistent sore throat; increased saliva production or drooling; increased sweating; memory loss; menstrual changes; muscle pain, stiffness, or weakness; new or worsening mental or mood changes (eg, aggressiveness, agitation, anxiety, depression, exaggerated feeling of well-being, hallucination, hostility, impulsiveness, inability to sit still, irritability, panic attacks, restlessness); numbness or tingling; persistent, painful erection; seizures; severe or prolonged dizziness or headache; shortness of breath; suicidal thoughts or actions; swelling of the hands, legs, or feet; symptoms of high blood sugar (eg, increased thirst, hunger, or urination; unusual weakness); tremor; trouble concentrating, speaking, or swallowing; trouble sleeping; trouble walking or standing; uncontrolled muscle movements (eg, arm or leg movements, jerking or twisting, twitching of the face or tongue); vision changes.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider.
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I had been taking .5ml, half a dropper, of 1000mg concentration once a day just before bed. I recently added another .5ml in the morning after my morning prednisone. I originally began taking CBD with the hope that it would help with the inflammation. It didn’t seem to make a difference. But I’ve been able to taper my pred dose relatively easily so far, from 15 to 8 over about a month, so maybe it’s been of some benefit. Guess I’ll know better when the pred is a little lower.

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<h1>First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR)</h1>

First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR)

Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidel…

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